Textbook of Cardiovascular Medicine

Braunwald: Heart Disease: A Textbook of Cardiovascular Medicine, 6th ed., Copyright © 2001 W. B. Saunders Company Part...

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Braunwald: Heart Disease: A Textbook of Cardiovascular Medicine, 6th ed., Copyright © 2001 W. B. Saunders Company

Part I - GENERAL CONSIDERATIONS OF CARDIOVASCULAR DISEASE 1 - Global Burden of Cardiovascular Disease 2 - Economics and Cardiovascular Disease Part II - EXAMINATION OF THE PATIENT 3 - The History 4 - Physical Examination of the Heart and Circulation 5 - Electrocardiography 6 - Exercise Stress Testing 7 - Echocardiography 8 - Radiology of the Heart and Great Vessels 9 - Nuclear Cardiology 10 - Newer Cardiac Imaging Modalities: Magnetic Resonance Imaging and Computed Tomography 11 - Cardiac Catheterization 12 - Coronary Angiography and Intravascular Ultrasonography 13 - Relative Merits of Cardiovascular Diagnostic Techniques Part III - NORMAL AND ABNORMAL CARDIAC FUNCTION 14 - Mechanisms of Cardiac Contraction and Relaxation 15 - Assessment of Normal and Abnormal Cardiac Function 16 - Pathophysiology of Heart Failure 17 - Clinical Aspects of Heart Failure: High-Output Failure; Pulmonary Edema 18 - Treatment of Heart Failure: Pharmacological Methods 19 - Treatment of Heart Failure: Assisted Circulation 20 - Heart and Heart-Lung Transplantation 21 - Management of Heart Failure 22 - Genesis of Cardiac Arrhythmias: Electrophysiological Considerations 23 - Management of the Patient with Cardiac Arrhythmias 24 - Cardiac Pacemakers and Cardioverter-Defibrillators 25 - Specific Arrhythmias: Diagnosis and Treatment 26 - Cardiac Arrest and Sudden Cardiac Death 27 - Hypotension and Syncope Part IV - HYPERTENSIVE AND ATHEROSCLEROTIC CARDIOVASCULAR DISEASE 28 - Systemic Hypertension: Mechanisms and Diagnosis

28 - Systemic Hypertension: Mechanisms and Diagnosis 29 - Systemic Hypertension: Therapy 30 - The Vascular Biology of Atherosclerosis 31 - Risk Factors for Atherosclerotic Disease 32 - Primary and Secondary Prevention of Coronary Heart Disease 33 - Lipid-Lowering Trials 34 - Coronary Blood Flow and Myocardial Ischemia 35 - Acute Myocardial Infarction 36 - Unstable Angina 37 - Chronic Coronary Artery Disease 38 - Percutaneous Coronary and Valvular Intervention 39 - Comprehensive Rehabilitation of Patients with Coronary Artery Disease 40 - Diseases of the Aorta 41 - Peripheral Arterial Diseases 42 - Extracardiac Vascular Interventions Part V - DISEASES OF THE HEART, PERICARDIUM, AND PULMONARY VASCULAR BED 43 - Congenital Heart Disease in Infancy and Childhood 44 - Congenital Heart Disease in Adults 45 - Acquired Heart Disease in Children 46 - Valvular Heart Disease 47 - Infective Endocarditis 48 - The Cardiomyopathies and Myocarditides 49 - Primary Tumors of the Heart 50 - Pericardial Diseases 51 - Traumatic Heart Disease 52 - Pulmonary Embolism 53 - Pulmonary Hypertension 54 - Cor Pulmonale Part VI - MOLECULAR BIOLOGY AND GENETICS 55 - Principles of Cardiovascular Molecular Biology and Genetics 56 - Genetics and Cardiovascular Disease Part VII - CARDIOVASCULAR DISEASE IN SPECIAL POPULATIONS

57 - Cardiovascular Disease in the Elderly 58 - Coronary Artery Disease in Women 59 - Cardiovascular Disease in Athletes 60 - Medical Management of the Patient Undergoing Cardiac Surgery 61 - General Anesthesia and Noncardiac Surgery in Patients with Heart Disease Part VIII - CARDIOVASCULAR DISEASE AND DISORDERS OF OTHER ORGAN SYSTEMS 62 - Hemostasis, Thrombosis, Fibrinolysis, and Cardiovascular Disease 63 - Diabetes Mellitus and the Cardiovascular System 64 - The Heart in Endocrine Disorders 65 - Pregnancy and Cardiovascular Disease 66 - Rheumatic Fever 67 - Rheumatic Diseases and the Cardiovascular System 68 - Cardiovascular Abnormalities in HIV-Infected Individuals 69 - Hematological-Oncological Disorders and Cardiovascular Disease 70 - Psychiatric and Behavioral Aspects of Cardiovascular Disease 71 - Neurological Disorders and Cardiovascular Disease 72 - Renal Disorders and Cardiovascular Disease

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Heart Disease A TEXTBOOK OF CARDIOVASCULAR MEDICINE

6th EDITION Edited by EUGENE BRAUNWALD M.D., M.D. (hon), Sc.D. (hon), F.R.C.P. Vice President for Academic Programs, Partners HealthCare System Distinguished Hersey Professor of Medicine Faculty Dean for Academic Programs at Brigham and Women;cqs Hospital and Massachusetts General Hospital Harvard Medical School Boston, Massachusetts

DOUGLAS P. ZIPES M.D. Distinguished Professor of Medicine, Pharmacology, and Toxicology Director, Krannert Institute of Cardiology Director, Division of Cardiology Indiana University School of Medicine Attending Physician University Hospital, Wishard Memorial Hospital, and Roudebush Veterans

Affairs Hospital Indianapolis, Indiana

PETER LIBBY M.D. Mallinckrodt Professor of Medicine Harvard Medical School Chief, Cardiovascular Medicine Brigham and Women;cqs Hospital Boston, Massachusetts

W.B. SAUNDERS COMPANY A Harcourt Health Sciences Company Philadelphia London New York St. Louis Sydney Toronto

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W.B. SAUNDERS COMPANY A Harcourt Health Sciences Company The Curtis Center Independence Square West Philadelphia, Pennsylvania 19106 Library of Congress Cataloging-in-Publication Data Heart disease: a textbook of cardiovascular medicine[edited by] Eugene Braunwald, Douglas P. Zipes, Peter Libby.--6th ed. p. cm. Includes bibliographical references and index. ISBN 0-7216-8561-7 1. Heart--Diseases. 2. Cardiovascular system--Diseases. I. Braunwald, Eugene. II. Zipes, Douglas P. III. Libby, Peter. [DNLM: 1. Heart Diseases. 2. Cardiovascular Diseases. WG 210 H43445 2001] RC681. H36 2001 616.1'2--dc21 00-025391 Editor-in-Chief: Richard Zorab Developmental Editor: Lynne Gery Manuscript Editors: Sue Reilly, Anne Ostroff Production Manager: Frank Polizzano Illustration Specialist: Rita Martello Book Designer: Karen O'Keefe Owens Heart Disease: A Textbook of Cardiovascular Medicine 0-7216-8549-8 (Single Volume) 0-7216-8561-7 (2-Volume Set) 0-7216-8562-5 (Volume 1) 0-7216-8563-3 (Volume 2)

0-8089-2258-0 (International Edition) Copyright © 2001, 1997, 1992, 1988, 1984, 1980 by W.B. Saunders Company. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Printed in the United States of America. Last digit is the print number: 9 8 7 6 5 4 3 2 1




To: Elaine, Karen, Allison, and Jill Joan, Debra, Jeffrey, and David Beryl, Oliver, and Brigitte




Contributors

DAVID H. ADAMS M.D. Associate Professor of Surgery, Harvard Medical School; Associate Chief, Division of Cardiac Surgery, Brigham and Women's Hospital, Boston, Massachusetts Medical Management of the Patient Undergoing Cardiac Surgery JOSHUA ADLER M.D. Assistant Clinical Professor of Medicine, University of California, San Francisco; Director, Ambulatory Practices, University of California, San Francisco, Medical Center, San Francisco, California General Anesthesia and Noncardiac Surgery in Patients with Heart Disease NADIR M. ALI M.D. Assistant Professor of Medicine, Baylor College of Medicine, Houston; Interventional Cardiologist, Clear Lake Regional Medical Center, Webster, Texas Hemostasis, Thrombosis, Fibrinolysis, and Cardiovascular Disease ELLIOTT M. ANTMAN M.D.

Associate Professor of Medicine, Harvard Medical School; Director, Samuel A. Levine Cardiac Unit, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts Acute Myocardial Infarction; Medical Management of the Patient Undergoing Cardiac Surgery WILLIAM F. ARMSTRONG M.D. Professor of Internal Medicine and Director, Echocardiography Laboratory, University of Michigan Health System; Associate Clinical Chief, Division of Cardiology, and Associate Chair for Network Development, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan Echocardiography ARTHUR J. BARSKY M.D. Professor of Psychiatry, Harvard Medical School; Director of Psychosomatic Research, Brigham and Women's Hospital, Boston, Massachusetts Psychiatric and Behavioral Aspects of Cardiovascular Disease GEORGE A. BELLER M.D. Ruth C. Heede Professor of Cardiology and Professor of Internal Medicine, University of Virginia School of Medicine; Chief, Cardiovascular Division, Department of Internal Medicine, University of Virginia Health System, Charlottesville, Virginia Relative Merits of Cardiovascular Diagnostic Techniques JOHN BITTL M.D. Interventional Cardiologist, Ocala Heart Institute, Ocala, Florida Coronary Angiography and Intravascular Ultrasonography ROBERT O. BONOW M.D. Professor of Medicine, Northwestern University Medical School; Chief, Division of Cardiology, Northwestern Memorial Hospital, Chicago, Illinois Cardiac Catheterization; Chronic Ischemic Heart Disease HARISIOS BOUDOULAS M.D. Director, Overstreet Teaching and Research Laboratory, Division of Cardiology, The Ohio State University College of Medicine and Public Health; Staff Cardiologist, The Ohio State University Medical Center, Columbus, Ohio Renal Disorders and Cardiovascular Disease

EUGENE BRAUNWALD M.D., M.D.(hon), Sc.D. (hon), F.R.C.P. Vice President for Academic Programs, Partners HealthCare System; Distinguished Hersey Professor of Medicine and Faculty Dean for Academic Programs at Brigham and Women's Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts The History; Physical Examination of the Heart and Circulation; Pathophysiology of Heart Failure; Clinical Aspects of Heart Failure: High-Output Heart Failure: Pulmonary Edema; Acute Myocardial Infarction; Unstable Angina; Chronic Coronary Artery Disease; Valvular Heart Disease; The Cardiomyopathies and Myocarditides KENNETH R. BRIDGES M.D. Associate Professor of Medicine, Harvard Medical School; Director, Joint Center for Sickle Cell and Thalassemic Disorders, Brigham and Women's Hospital, Boston, Massachusetts Hematological-Oncological Disorders and Cardiovascular Disease MICHAEL R. BRISTOW M.D., Ph.D. Professor of Medicine and Head, Division of Cardiology, University of Colorado Health Sciences Center, Denver, Colorado Treatment of Heart Failure: Pharmacological Methods; Management of Heart Failure HUGH CALKINS M.D. Professor of Medicine, Johns Hopkins University; Director of the Arrhythmia Service and Clinical Electrophysiology Laboratory, Johns Hopkins Hospital, Baltimore, Maryland Hypotension and Syncope CHRISTOPHER P. CANNON M.D. Assistant Professor of Medicine, Harvard Medical School; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts Unstable Angina AGUSTIN CASTELLANOS M.D. Professor of Medicine, University of Miami School of Medicine; Director, Clinical Electrophysiology, University of Miami School of Medicine and Jackson Memorial Medical Center, Miami, Florida

Cardiac Arrest and Sudden Cardiac Death BERNARD R. CHAITMAN M.D. Professor of Medicine, Cardiology Division, St. Louis University School of Medicine; Chief of Cardiology, St. Louis University Hospital, St. Louis, Missouri Exercise Stress Testing MELVIN D. CHEITLIN M.D., M.A.C.C. Emeritus Professor of Medicine, University of California, San Francisco; Former Chief of Cardiology, San Francisco General Hospital, San Francisco, California Cardiovascular Disease in the Elderly STEVEN D. COLAN M.D. Associate Professor of Pediatrics, Harvard Medical School; Chief, Division of Noninvasive Cardiology, and Senior Associate in Cardiology, Children's Hospital, Boston, Massachusetts Acquired Heart Disease in Children WILSON S. COLUCCI M.D. Professor of Medicine and Physiology, Boston University School of Medicine; Chief, Cardiovascular Medicine, Boston University Medical Center, Boston, Massachusetts Pathophysiology of Heart Failure; Clinical Aspects of Heart Failure; Primary Tumors of the Heart MARK A. CREAGER M.D. Associate Professor of Medicine, Harvard Medical School; Director, Vascular Center, Brigham and Women's Hospital, Boston, Massachusetts Peripheral Arterial Diseases ADNAN S. DAJANI M.D. Professor of Pediatrics, Wayne State University School of Medicine; Director, Division of Infectious Diseases, Children's Hospital of Michigan, Detroit, Michigan Rheumatic Fever MICHAEL D. DAKE M.D. Associate Professor of Radiology and Medicine (Pulmonary), Stanford University; Chief, Cardiovascular and Interventional Radiology, Stanford Medical Center, Stanford, California

Extracardiac Vascular Interventions CHARLES J. DAVIDSON M.D. Associate Professor of Medicine, Northwestern University Medical School; Chief, Cardiac Catheterization Laboratories, Northwestern Memorial Hospital, Chicago, Illinois Cardiac Catheterization PAMELA S. DOUGLAS M.D. Dr. Herman and Aileen Tuchman Professor of Cardiovascular Medicine and Head, Section of Cardiovascular Medicine, University of Wisconsin-Madison Medical School, Madison, Wisconsin Coronary Artery Disease in Women URI ELKAYAM M.D. Professor of Medicine and Director, Heart Failure Program, University of Southern California School of Medicine, Los Angeles, California Pregnancy and Cardiovascular Disease ANTHONY L. ESTRERA M.D. Chief Resident, Thoracic Surgery, Baylor College of Medicine, Houston, Texas Traumatic Heart Disease JOHN A. FARMER M.D. Associate Professor, Section of Cardiology and Atherosclerosis, Department of Medicine, Baylor College of Medicine; Chief of Cardiology, Ben Taub General Hospital, Houston, Texas Lipid-Lowering Trials HARVEY FEIGENBAUM M.D. Distinguished Professor of Medicine and Director, Echocardiography Laboratories, Indiana University School of Medicine and Krannert Institute of Cardiology, Indianapolis, Indiana Echocardiography STACY D. FISHER M.D. Instructor in Medicine/Cardiology, University of Rochester School of Medicine and Dentistry; Attending Physician and Fellow in Adult Congenital Heart Disease, University of Rochester Medical Center and Children's Hospital at Strong, Rochester, New York

Cardiovascular Abnormalities in HIV-Infected Individuals GERALD F. FLETCHER M.D. Professor of Medicine, Mayo Medical School; Cardiovascular Disease, Prevention and Rehabilitation, Mayo Clinic, Jacksonville, Florida Comprehensive Rehabilitation of Patients with Coronary Artery Disease WILLIAM F. FRIEDMAN M.D. J. H. Nicholson Professor of Pediatrics (Cardiology) and Senior Dean for Academic Affairs, University of California, Los Angeles (UCLA), School of Medicine, Los Angeles, California Congenital Heart Disease in Infancy and Childhood PETER GANZ M.D. Associate Professor of Medicine, Harvard Medical School; Director of Cardiovascular Research, Cardiac Catheterization Laboratory, Brigham and Women's Hospital, Boston, Massachusetts Coronary Blood Flow and Myocardial Ischemia WILLIAM GANZ M.D. Professor of Medicine, University of California, Los Angeles (UCLA), School of Medicine; Senior Research Scientist, Cedars-Sinai Medical Center, Los Angeles, California Coronary Blood Flow and Myocardial Ischemia J. MICHAEL GAZIANO M.D., M.P.H. Assistant Professor of Medicine, Harvard Medical School; Co-Director, Cardiovascular Epidemiology, Division of Preventive Medicine, Brigham and Women's Hospital; Director, Massachusetts Veterans' Epidemiology and Research Center, Boston VA Healthcare Systems, Boston, Massachusetts Global Burden of Cardiovascular Disease; Primary and Secondary Prevention of Coronary Heart Disease JACQUES GENEST M.D. Associate Professor of Medicine, McGill University; Director, Division of Cardiology, McGill University Health Center, Montreal, Quebec, Canada Risk Factors for Atherosclerotic Disease BERNARD J. GERSH M.D., M.B., Ch.B., D.Phil.

Professor of Medicine, Mayo Medical Center; Consultant in Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota Chronic Ischemic Heart Disease MICHAEL M. GIVERTZ M.D. Assistant Professor of Medicine, Boston University School of Medicine; Clinical Director, Cardiomyopathy Program, Boston Medical Center, Boston, Massachusetts Clinical Aspects of Heart Failure ARY L. GOLDBERGER M.D. Associate Professor of Medicine, Harvard Medical School; Director, Margret and H.A. Rey Laboratory for Nonlinear Dynamics in Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts Electrocardiography SAMUEL Z. GOLDHABER M.D. Associate Professor of Medicine, Harvard Medical School; Staff Cardiologist, Director of Cardiac Center's Anticoagulation Service, and Director of Venous Thromboembolism Research Group, Brigham and Women's Hospital, Boston, Massachusetts Pulmonary Embolism LEE GOLDMAN M.D., M.P.H. Julius R. Krevans Distinguished Professor and Chair, Department of Medicine and Associate Dean for Clinical Affairs, School of Medicine, University of California, San Francisco; Attending Physician, University of California Medical Center, San Francisco, California General Anesthesia and Noncardiac Surgery in Patients with Heart Disease ANTONIO M. GOTTO JR. M.D., D.Phil. The Stephen and Suzanne Weiss Dean and Professor of Medicine, Weill Medical College of Cornell University, New York, New York Lipid-Lowering Trials WILLIAM J. GROH M.D. Assistant Professor of Medicine, Indiana University School of Medicine, Indianapolis, Indiana Neurological Disorders and Cardiovascular Disease DAVID L. HAYES M.D.

Consultant, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, Mayo Medical School, Rochester, Minnesota Cardiac Pacemakers and Cardioverter-Defibrillators CHARLES B. HIGGINS M.D. Professor of Radiology, University of California, San Francisco, California Newer Cardiac Imaging Modalities: Magnetic Resonance Imaging and Computed Tomography MARK A. HLATKY M.D. Professor of Health Research and Policy and of Medicine (Cardiovascular Medicine), and Chair, Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California Economics and Cardiovascular Disease GARY S. HOFFMAN M.D. Harold C. Schott Chair for Rheumatic and Immunologic Diseases and Professor of Medicine, Cleveland Clinic/Ohio State University; Chairman, Rheumatic and Immunologic Diseases, and Director, Center for Vasculitis Care and Research, Cleveland Clinic, Cleveland, Ohio Rheumatic Diseases and the Cardiovascular System ERIC M. ISSELBACHER M.D. Instructor in Medicine, Harvard Medical School; Medical Director, Thoracic Aortic Center, Massachusetts General Hospital, Boston, Massachusetts Diseases of the Aorta NORMAN M. KAPLAN M.D. Clinical Professor of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas Systemic Hypertension: Mechanisms and Diagnosis; Systemic Hypertension: Therapy ADOLF W. KARCHMER M.D. Professor of Medicine, Harvard Medical School; Chief, Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts Infective Endocarditis RALPH A. KELLY M.D.

Associate Professor of Medicine, Harvard University; Associate Physician, Division of Cardiology, Brigham and Women's Hospital, Boston, Massachusetts Treatment of Heart Failure: Pharmacological Methods RICHARD E. KUNTZ M.D. Associate Professor of Medicine, Harvard Medical School; Brigham and Women's Hospital, Boston, Massachusetts Percutaneous Coronary and Valvular Intervention THOMAS H. LEE M.D., S.M. Associate Professor of Medicine, Harvard Medical School; Medical Director, Partners Community HealthCare, Inc., Boston, Massachusetts Guidelines: Electrocardiography; Guidelines: Use of Exercise Tolerance Testing; Guidelines: Use of Echocardiography; Guidelines: Management of Heart Failure; Guidelines: Cardiac Radionuclide Imaging; Guidelines: Ambulatory Monitoring and Electrophysiological Testing; Guidelines: Use of Cardiac Pacemakers and Antiarrhythmia Devices; Guidelines: Diagnosis and Management of Acute Myocardial Infarction; Guidelines: Management of Unstable Angina/Non-ST Segment Elevation Myocardial Infarction; Guidelines: Management of Chronic Ischemic Heart Disease; Guidelines: Management of Valvular Heart Disease; Guidelines: Prevention, Evaluation, and Treatment of Infective Endocarditis; Guidelines: Summary of Guidelines for Reducing Cardiac Risk With Noncardiac Surgery; Guidelines: Management of Valvular Disease in Pregnancy JEFFREY M. LEIDEN M.D., Ph.D. Adjunct Professor of Biological Sciences, Harvard School of Public Health; Executive Vice President, Pharmaceuticals, and Chief Scientific Officer, Abbott Laboratories, Abbott Park, Illinois Principles of Cardiovascular Molecular Biology and Genetics CARL V. LEIER M.D. Overstreet Professor of Medicine and Pharmacology, Division of Cardiology, The Ohio State University College of Medicine and Public Health; Staff Cardiologist, The Ohio State University Hospitals, Columbus, Ohio Renal Disorders and Cardiovascular Disease GLENN N. LEVINE M.D.

Assistant Professor of Medicine, Baylor College of Medicine; Director, Cardiac Catheterization Laboratory, Houston VA Medical Center, Houston, Texas Hemostasis, Thrombosis, Fibrinolysis, and Cardiovascular Disease PETER LIBBY M.D. Mallinckrodt Professor of Medicine, Harvard Medical School; Chief, Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts Vascular Biology of Atherosclerosis; Risk Factors for Atherosclerotic Disease; Peripheral Vascular Disease; Diabetes Mellitus and Cardiovascular Disease; Hematological-Oncological Disorders and Cardiovascular Disease STEVEN E. LIPSHULTZ M.D. Professor of Pediatrics and Professor of Oncology, University of Rochester School of Medicine and Dentistry; Chief of Pediatric Cardiology, University of Rochester Medical Center and Children's Hospital at Strong, Rochester, New York Cardiovascular Abnormalities in HIV-Infected Individuals WILLIAM C. LITTLE M.D. Chief of Cardiology and Professor of Medicine, Wake Forest University School of Medicine, Bowman Gray Campus; Associate Chief of Professional Services, North Carolina Baptist Hospital, Winston-Salem, North Carolina Assessment of Normal and Abnormal Cardiac Function BRIAN F. MANDELL M.D., Ph.D. Clinical Professor of Medicine, Penn State University School of Medicine, Hershey, Pennsylvania; Associate Professor of Medicine, Ohio State University School of Medicine, Columbus, Ohio; Education Program Director, Rheumatic and Immunologic Diseases, Cleveland Clinic Foundation, Cleveland, Ohio Rheumatic Diseases and the Cardiovascular System JOANN E. MANSON M.D., Dr.P.H. Professor of Medicine, Harvard Medical School; Chief, Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts Primary and Secondary Prevention of Coronary Heart Disease DANIEL B. MARK M.D., M.P.H. Professor of Medicine, Duke University Medical Center; Director, Outcomes Research

and Assessment Group, Duke Clinical Research Institute, Durham, North Carolina Economics and Cardiovascular Disease BARRY J. MARON M.D. Director, Cardiovascular Research Division, Minneapolis Heart Institute Foundation, Minneapolis, Minnesota Cardiovascular Disease in Athletes KENNETH L. MATTOX M.D. Professor and Vice Chairman, Department of Surgery, Baylor College of Medicine; Chief of Staff and Chief of Surgery, Ben Taub General Hospital, Houston, Texas Traumatic Heart Disease VALLERIE V. McLAUGHLIN M.D. Assistant Professor of Medicine, Rush Medical College; Associate Director, Rush Heart Institute, Center for Pulmonary Heart Disease, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois Cor Pulmonale JOHN M. MILLER M.D. Professor of Medicine, Indiana University School of Medicine; Director, Clinical Cardiac Electrophysiology, Indiana University Medical Center, Indianapolis, Indiana Management of the Patient with Cardiac Arrhythmias DOUGLAS N. MINIATI M.D. Postdoctoral Research Fellow, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California Heart and Heart-Lung Transplantation DAVID M. MIRVIS M.D. Professor of Preventive Medicine and Medicine, University of Tennessee; Director, The Center for Health Services Research, Memphis, Tennessee Electrocardiography ROBERT J. MYERBURG M.D. Professor of Medicine and Physiology, University of Miami School of Medicine; Director, Division of Cardiology, University of Miami School of Medicine and Jackson Memorial Medical Center, Miami, Florida

Cardiac Arrest and Sudden Cardiac Death RICHARD W. NESTO M.D. Associate Professor of Medicine, Harvard Medical School, Boston; Chairman, Cardiovascular Medicine, Lahey Clinic Medical Center, Burlington, Massachusetts Diabetes Mellitus and the Cardiovascular System JANE W. NEWBURGER M.D., M.P.H. Professor of Pediatrics, Harvard Medical School; Associate Cardiologist-in-Chief, Children's Hospital, Boston, Massachusetts Acquired Heart Disease in Children KEITH R. OKEN M.D. Senior Associate Consultant, Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Jacksonville, Florida Comprehensive Rehabilitation of Patients with Coronary Artery Disease JEFFREY E. OLGIN M.D. Assistant Professor of Medicine, Indiana University School of Medicine, Indianapolis, Indiana Specific Arrhythmias: Diagnosis and Treatment LIONEL H. OPIE M.D., D.Phil., D.Sc., F.R.C.P. Professor of Medicine, University of Cape Town; Director, Cape Heart Centre, University of Cape Town Medical School, Cape Town, South Africa Mechanisms of Cardiac Contraction and Relaxation JOSEPH K. PERLOFF M.D. Streisand/American Heart Association Professor of Medicine and Pediatrics, University of California, Los Angeles, School of Medicine, Division of Cardiology, Departments of Medicine and Pediatrics, UCLA Center for the Health Sciences, Los Angeles, California Physical Examination of the Heart and Circulation WILLIAM S. PIERCE M.D. Evan Pugh Professor of Surgery, The Pennsylvania State University College of Medicine; The Milton S. Hershey Medical Center, Department of Surgery, Section of Artificial Organs, Hershey, Pennsylvania

Treatment of Heart Failure: Assisted Circulation JEFFREY J. POPMA M.D. Associate Professor of Medicine, Harvard Medical School; Director, Interventional Cardiology, Brigham and Women's Hospital, Boston, Massachusetts Coronary Arteriography; Percutaneous Coronary and Valvular Intervention J. DAVID PORT Ph.D. Associate Professor of Medicine/Cardiology and Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado Treatment of Heart Failure: Pharmacological Methods REED E. PYERITZ M.D., Ph.D. Professor of Human Genetics, Medicine, and Pediatrics and Chair, Department of Human Genetics, MCP Hahnemann School of Medicine, Philadelphia, Pennsylvania Genetics and Cardiovascular Disease BRUCE A. REITZ M.D. Professor and Chairman, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California Heart and Heart-Lung Transplantation STUART RICH M.D. Professor of Medicine, Rush Medical College; Director, Rush Heart Institute Center for Pulmonary Heart Disease, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois Pulmonary Hypertension; Cor Pulmonale WAYNE E. RICHENBACHER M.D. Professor of Surgery and Anatomy and Cell Biology and Professor, Division of Cardiothoracic Surgery, The University of Iowa College of Medicine, Iowa City, Iowa Treatment of Heart Failure: Assisted Circulation PAUL M RIDKER M.D., M.P.H. Associate Professor of Medicine, Harvard Medical School; Director of Cardiovascular Research, Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts

Risk Factors for Atherosclerotic Disease; Primary and Secondary Prevention of Coronary Heart Disease ROBERT C. ROBBINS M.D. Assistant Professor, Department of Cardiothoracic Surgery, Stanford University School of Medicine; Director of Heart and Heart-Lung Transplantation, Stanford University Medical Center, Stanford, California Heart and Heart-Lung Transplantation MICHAEL RUBART M.D. Assistant Scientist, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana Genesis of Cardiac Arrhythmias: Electrophysiological Considerations ROBERT E. SAFFORD M.D., Ph.D. Barbara Woodward Lips Professor of Medicine, Mayo Medical School, Rochester, Minnesota; Consultant in Cardiovascular Diseases, Mayo Clinic, Jacksonville, Florida Comprehensive Rehabilitation of Patients with Coronary Artery Disease SHAUN L. W. SAMUELS M.D. Clinical Assistant Professor, Division of Cardiovascular/Interventional Radiology, Stanford University Hospital, Stanford University, Stanford; Staff Physician, Department of Radiology, Palo Alto VA Medical Center, Palo Alto VA Health Care System, Palo Alto, California Extracardiac Vascular Interventions ANDREW I. SCHAFER M.D. The Bob and Vivian Smith Chair in Medicine and Chairman, Department of Medicine, Baylor College of Medicine; Chief, Internal Medicine Service, The Methodist Hospital, Houston, Texas Hemostasis, Thrombosis, Fibrinolysis, and Cardiovascular Disease FREDERICK J. SCHOEN M.D., Ph.D. Professor of Pathology, Harvard Medical School; Vice-Chairman, Department of Pathology, and Director, Cardiac Pathology, Brigham and Women's Hospital, Boston, Massachusetts Primary Tumors of the Heart ELLEN W. SEELY M.D.

Assistant Professor of Medicine, Harvard Medical School; Director of Clinical Research, Endocrine-Hypertension Division, Brigham and Women's Hospital, Boston, Massachusetts The Heart in Endocrine Disorders NORMAN SILVERMAN M.D., D.Sc. (Med) Professor of Pediatrics and Radiology (Cardiology) and Director of Pediatric and Fetal Echocardiography, University of California, San Francisco, California Congenital Heart Disease in Infancy and Childhood ROBERT SOUFER M.D. Associate Professor of Medicine, Yale University School of Medicine; Attending Physician and Chief, Cardiology, Yale-New Haven Hospital; VA New England Health Care Systems, West Haven, Connecticut Nuclear Cardiology DAVID H. SPODICK M.D. D.Sc. Professor of Medicine, University of Massachusetts Medical School; Director of Clinical Cardiology and Cardiovascular Fellowship Training, Worcester Medical Center/St. Vincent's Hospital, Worcester, Massachusetts Pericardial Diseases ROBERT M. STEINER M.D. Professor of Radiology, Weill Medical College of Cornell University; Attending Radiologist, New York Presbyterian Hospital, New York, New York Radiology of the Heart and Great Vessels RICHARD M. STONE M.D. Associate Professor of Medicine, Harvard Medical School; Clinical Director, Adult Leukemia Program, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts Hematological-Oncological Disorders and Cardiovascular Disease JUDITH THERRIEN M.D. Assistant Professor of Medicine, McGill University; Co-Director of Adult Congenital Heart Disease Clinical, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada

Congenital Heart Disease in Adults FRANS J. TH. WACKERS M.D. Professor of Diagnostic Radiology and Medicine and Director, Cardiovascular Nuclear Imaging and Stress Laboratories, Yale University School of Medicine; Attending Physician, Yale-New Haven Hospital, New Haven, Connecticut Nuclear Cardiology MATTHEW J. WALL JR. M.D. Associate Professor of Surgery, Department of Surgery, Baylor College of Medicine, Houston, Texas Traumatic Heart Disease GARY D. WEBB M.D. Professor of Medicine, University of Toronto; Director, University of Toronto Congenital Cardiac Center for Adults, Toronto General Hospital, Toronto, Ontario, Canada Congenital Heart Disease in Adults GORDON H. WILLIAMS M.D. Professor of Medicine, Harvard Medical School; Director, Clinical Research Center, and Chief, Endocrine-Hypertension Division, Brigham and Women's Hospital, Boston, Massachusetts The Heart in Endocrine Disorders JOSHUA WYNNE M.D., M.B.A. Professor of Medicine, Wayne State University; Attending Physician, Detroit Medical Center, Detroit, Michigan Cardiomyopathies and Myocarditides BARRY L. ZARET M.D. Chief, Cardiovascular Medicine, and Associate Chair for Clinical Affairs, Department of Internal Medicine, Yale University School of Medicine; Medical Director, Heart Center, Yale-New Haven Hospital, New Haven, Connecticut Nuclear Cardiology DOUGLAS P. ZIPES M.D. Distinguished Professor of Medicine, Pharmacology, and Toxicology; Director, Krannert Institute of Cardiology; and Director, Division of Cardiology, Indiana University School of Medicine; Attending Physician, University Hospital, Wishard Memorial Hospital, and

Roudebush Veterans Affairs Hospital, Indianapolis, Indiana Genesis of Cardiac Arrhythmias: Electrophysiological Considerations; Management of the Patient with Cardiac Arrhythmias; Cardiac Pacemakers and Cardioverter-Defibrillators; Specific Arrhythmias: Diagnosis and Treatment; Hypotension and Syncope; Cardiovascular Disease in the Elderly; Neurological Disorders and Cardiovascular Disease




Publisher's Note

We are proud to announce that two distinguished cardiologists, Drs. Douglas P. Zipes and Peter Libby, have joined Dr. Braunwald as editors of the sixth edition. Dr. Zipes is a world-renowned arrhythmologist and clinical electrophysiologist, and Dr. Libby is a leading expert in vascular biology and vascular disease. Both new editors head important Divisions of Cardiology with strong academic and clinical programs.

Preface The accelerating advances in cardiology since the publication of the fifth edition of Heart Disease have required the most extensive changes yet made in any revision. This edition, the first in the new millennium, contains 30 chapters that are new (the most for any revision to date), and the remaining 42 have been extensively revised and updated. The editors warmly welcome 56 authors who are new to this edition. Cardiovascular disease is now, more than ever, a global problem with enormous economic consequences. The various forms of heart disease in different economies and cultures are presented in the new opening chapter by Gaziano, and principles of cost-effective practice are described in a new chapter by Hlatky and Mark. Part II, The Examination of the Patient, begins with the clinical examination and moves

progressively from simple to more sophisticated noninvasive and invasive techniques. All of these approaches are described in detail with many new illustrations. The new chapter "Relative Merits of Cardiovascular Diagnostic Techniques," by Beller, provides a rational approach to the selection among several methods available to image the heart. Heart failure is becoming an increasingly prevalent problem. Bristow has prepared two new chapters on the treatment of this condition, with emphasis on new treatment options based on pathophysiological considerations. There also has been enormous progress in cardiac electrophysiology and arrhythmology. Zipes has enlisted a cadre of talented authors to help update this section, always one of the strongest in Heart Disease. The section on atherosclerosis is entirely new, reflecting greatly expanded information in this field and Libby's expertise in the area. The risk factors for the development of atherosclerosis and methods for its prevention are presented in new chapters. In view of the increasing importance of diabetes as a risk factor for vascular disease, a new chapter on diabetes mellitus and cardiovascular disease has been added. The cardiologist is called upon increasingly to deal with patients with extracardiac vascular disease. In new chapters on this subject, Creager and Libby describe the diagnosis and management of these conditions, and Dake and Samuels describe the extracardiac vascular interventions. The acute coronary syndromes are, by far, the most common diagnoses for cardiovascular patients admitted to the hospital. In a new chapter on unstable angina, Cannon and Braunwald describe the many new diagnostic techniques and therapeutic measures available to care for these patients, and Antman and Braunwald provide a detailed contemporary description of the clinical manifestations and management of acute myocardial infarction. Interventional cardiology has progressed rapidly since the mid-1990s, and Popma and Kuntz have prepared an excellent new chapter on this important subspecialty of cardiology. The sixth edition also focuses on the different manifestations in various populations, with new chapters on acquired heart disease in infancy, congenital heart disease in adults, and heart disease in athletes, in diabetics, in the elderly, and in patients with HIV infection and neoplastic disease, and an updated chapter on coronary artery disease in women. The impact of molecular biology and genetics on cardiovascular disease is growing rapidly. A new chapter, "Principles of Cardiovascular Molecular Biology and Genetics," by Leiden joins the updated chapter "Genetics and Cardiovascular Disease" by Pyeritz in providing clear explanations of this important area. Many cardiovascular diseases result, in part, from coagulation disorders. Schafer and colleagues have prepared an excellent new chapter on hemostasis, thrombosis, and fibrinolysis to equip the cardiologist with the information required to deal effectively with these disorders. Other important new chapters include "Echocardiography," by Armstrong and Feigenbaum, and "Hypotension and Syncope," by Calkins and Zipes. Practice guidelines are increasingly influencing the diagnosis and therapy of heart

disease. Lee provides useful summaries of the most important guidelines developed by authoritative groups and skillfully places them into the perspective of modern patient care. Considerable revisions were made both in galley proofs and page proofs to include information about the most recent advances in the field. Particular emphasis has been placed on ensuring a comprehensive and up-to-date bibliography of more than 18,000 pertinent references, including hundreds of publications that appeared in 2000. Many of the 1700 figures and 546 tables are new to this edition. In order to allow the reader to keep pace with the enormous expansion of cardiovascular knowledge, Heart Disease is supplemented by a number of companion volumes. These include Cardiac Imaging, Cardiovascular Therapeutics, Molecular Basis of Heart Disease, and Clinical Trials in Cardiovascular Disease. These books have been well received, and new editions are in preparation. Companion volumes in other important segments of cardiology are planned. In addition, a Review and Assessment book will again accompany this edition of Heart Disease. It consists of 600 questions based on material discussed in the textbook and provides the answers as well as detailed explanations. The publisher, Harcourt Health Sciences, comprising W.B. Saunders, Mosby, and Churchill Livingstone, is developing a comprehensive website in cardiology: MDConsult-Cardiology. The sixth edition of Heart Disease will serve as the "anchor" of this website, which will be updated continuously. This multipronged educational effort--Heart Disease, the growing number of companion volumes, and the Review and Assessment book, all appearing in print and electronic (CD-ROM) form, as well as the new website--is designed to assist the reader with the awesome task of learning and remaining current in this dynamic field. We hope that this textbook will prove useful to those who wish to broaden their knowledge of cardiovascular medicine. To the extent that it achieves this goal and thereby aids in the care of patients afflicted with heart disease, credit must be given to the many talented and dedicated persons involved in its preparation. Our deepest appreciation goes to our fellow contributors for their professional expertise, knowledge, and devoted scholarship, which are at the very "heart" of this book. At the W.B. Saunders Company, our editor, Richard Zorab, and the production team, Lynne Gery, Frank Polizzano, and Anne Ostroff, were enormously helpful. Our editorial associates, Kathryn Saxon, Janet Hutcheson, and Karen Williams, rendered invaluable and devoted assistance. EUGENE BRAUNWALD DOUGLAS P. ZIPES PETER LIBBY 2001




Adapted from the Preface to the First Edition

Cardiovascular disease is the greatest scourge affecting the industrialized nations. As with previous scourges--bubonic plague, yellow fever, and smallpox--cardiovascular disease not only strikes down a significant fraction of the population without warning but also causes prolonged suffering and disability in an even larger number. In the United States alone, despite recent encouraging declines, cardiovascular disease is still responsible for almost 1 million fatalities each year and more than half of all deaths; almost 5 million persons afflicted with cardiovascular disease are hospitalized each year. The cost of these diseases in terms of human suffering and of material resources is almost incalculable. Fortunately, research focusing on the causes, diagnosis, treatment, and prevention of heart disease is moving ahead rapidly. In order to provide a comprehensive, authoritative text in a field that has become as broad and deep as cardiovascular medicine, I chose to enlist the aid of a number of able colleagues. However, I hoped that my personal involvement in the writing of about half of the book would make it possible to minimize the fragmentation, gaps, inconsistencies, organizational difficulties, and impersonal tone that sometimes plague multiauthored texts. Since the early part of the 20th century, clinical cardiology has had a particularly strong foundation in the basic sciences of physiology and pharmacology. More recently, the

disciplines of molecular biology, genetics, developmental biology, biophysics, biochemistry, experimental pathology, and bioengineering have also begun to provide critically important information about cardiac function and malfunction. Although Heart Disease: A Textbook of Cardiovascular Medicine is primarily a clinical treatise and not a textbook of fundamental cardiovascular science, an effort has been made to explain, in some detail, the scientific bases of cardiovascular diseases. EUGENE BRAUNWALD, 1980

NOTICE Medicine is an ever-changing field. Standard safety precautions must be followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the treating physician, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the Publisher nor the editor assumes any liability for any injury and/or damage to persons or property arising from this publication. THE PUBLISHER




Part I - GENERAL CONSIDERATIONS OF CARDIOVASCULAR DISEASE

1

Chapter 1 - Global Burden of Cardiovascular Disease J. MICHAEL GAZIANO

THE EPIDEMIOLOGICAL TRANSITIONS At the beginning of the 20th century, cardiovascular disease (CVD) accounted for less than 10 percent of all deaths worldwide. At its end, CVD accounted for nearly half of all deaths in the developed world and 25 percent in the developing world.[1] [2] By 2020, CVD will claim 25 million deaths annually and coronary heart disease (CHD) will surpass infectious disease as the world's number one cause of death and disability. This global rise in CVD is the result of a dramatic shift in the health status of individuals

around the world over the course of the 20th century. Equally important, there has been an unprecedented transformation in the dominant disease profile, or the distribution of diseases responsible for the majority of death and debility. Before 1900, infectious diseases and malnutrition were the most common causes of death. These have been gradually supplanted in some (mostly developed) countries by chronic diseases such as CVD and cancer, thanks largely to improved nutrition and public health measures. As this trend spreads to and continues in developing countries, CVD will dominate as the major cause of death by 2020, accounting for at least one in every three deaths.[2] This shift in the diseases that account for the lion's share of mortality and morbidity is known as the epidemiological transition.[3] [4] The epidemiological transition never occurs in isolation but is tightly intertwined with changes in personal and collective wealth (economic transition), social structure (social transition), and demographics (demographic transition). Because the epidemiological transition is linked to the evolution of social and economic forces, it takes place at different rates around the world. Although changes in health status have occurred (and are occurring) in every part of the world, at the beginning of the millennium national health and disease profiles vary widely by country and by region. For example, life expectancy in Japan (80 years) is more than twice that in Sierra Leone (37.5 years).[1] In a similar vein, the Group I diseases defined by Murray and Lopez in their comprehensive analysis of the global burden of disease--communicable, infectious, maternal, perinatal, and nutritional diseases--account for just 6 percent of deaths in so-called developed countries compared with 33 percent in India.[2] The vast differences in burden of disease are readily apparent across three broad economic and geographical sectors of the world (Table 1-1) . These include the established market economies (EstME) of Western Europe, North America, Australia, New Zealand, and Japan; the emerging market economies (EmgME) of the former socialist states of Eastern Europe; and the developing economies (DevE), which can further be subdivided into six geographical regions--China, India, other Asia and islands, sub-Saharan Africa, the Middle Eastern Crescent, and Latin America and the Caribbean. Currently, CVD is responsible for 45 percent of all deaths in the EstME, 55 percent of all deaths in EmgME, and only 23 percent of the deaths in DevE. An excellent model of the epidemiological transition has been developed by Omran.[3] He divides the transition into three basic ages--pestilence and famine, receding pandemics, and degenerative and man-made diseases (Table 1-2) . Olshansky and Ault added a fourth stage, delayed degenerative diseases.[4] Although any specific country or region enters these ages at different times, the progression from one to another tends to proceed in a predictable manner.

2

TABLE 1-1 -- BURDEN OF DISEASE (1990 ESTIMATES) FOR THE THREE ECONOMIC REGIONS OF THE WORLD

REGION POPULATION % OF DEATHS IN THE REGION DUE TO (MILLIONS) (% Cardiovascular Other Communicable Injuries TOTAL Disease Noncommunicable Diseases WORLD * Diseases POPULATION) Developed EstME

798 (15.2)

44.6%

42.8%

6.4%

10.7%

EmgME

346 (6.6)

54.6%

29.5%

5.6%

10.3%

4124 (78.3)

23.0%

24.3%

46.9%

6.2%

5267

28.4%

27.4%

34.2%

10.1%

Developing DevE§ Totals

Adapted from Murray CJL, Lopez AD: The Global Burden of Disease. Cambridge, MA, Harvard School of Public Health, 1996. *Includes cancer, diabetes, neuropsychiatric conditions, congenital anomalies, and respiratory, digestive, genitourinary, and musculoskeletal diseases. EstME: Established market economies--United States, Canada, Western Europe, Japan, Australia, and New Zealand. EmgME: Emerging market economies--former socialist states of Russian Federation. §DevE: Developing market economies--China, India, other Asia and islands, sub-Saharan Africa, Middle Eastern Crescent, Latin America and the Caribbean.

The Age of Pestilence and Famine

From the epidemiological standpoint, humans evolved under conditions of pestilence and famine and have lived with them for most of recorded history. This age is characterized by the predominance of malnutrition and infectious disease and by the infrequency of CVD as a cause of death. Infant and child mortality is quite high, necessitating high fertility rates and resulting in a low mean life expectancy, on the order of 30 years or so. In the countries that eventually became today's established market economies, the transition through the age of pestilence and famine was relatively slow, beginning in the late 1700s and developing throughout the 1800s. Competing influences prolonged the transition--improvements in the food supply early in the Industrial Revolution that by themselves would have reduced mortality were offset by increases in communicable disease such as tuberculosis, cholera, dysentery, and influenza that resulted from concentration of the population in urban centers. Although the transition through the age of pestilence and famine occurred much later in

the emerging market economies and the developing economies, it has also taken place more rapidly, driven largely by the transfer of low-cost agricultural products and technologies and well-established, lower-cost public health technologies. Much of the developing world has emerged from the age of pestilence and famine. In sub-Saharan Africa and parts of India, however, malnutrition and infectious disease remain leading causes of death.

TABLE 1-2 -- FOUR TYPICAL STAGES OF THE EPIDEMIOLOGICAL TRANSITION STAGE DESCRIPTION TYPICAL PREDOMINANT PROPORTION TYPES OF CVD OF DEATHS DUE TO CVD (%) Pestilence and famine

Predominance of malnutrition and infectious diseases as causes of death; high rates of infant and child mortality; low mean life expectancy

0.85; normal=0.7) is often associated with adult-onset diabetes and is a high risk factor for coronary artery disease and should also be looked for. The distinctive general appearance of the Marfan syndrome (see Chap. 56) is often apparent: long extremities with an arm span that exceeds the height; a longer lower segment (pubis to foot) than upper segment (head to pubis); and arachnodactyly (spider fingers). In Cushing syndrome, a cause of treatable secondary hypertension (see Chap. 64) , there is truncal obesity and rounding of the face with disproportionately thin extremities. HEAD AND FACE

Examination of the face often aids in the recognition of many disorders that can affect the cardiovascular system. For example, myxedema (see Chap. 64) is characterized by a dull, expressionless face; periorbital puffiness; loss of the lateral eyebrows; a large

tongue; and dry, sparse hair. An earlobe crease occurs more frequently in patients with coronary artery disease than in those without this condition.[8] [9] Bobbing of the head coincident with each heartbeat (de Musset sign) is characteristic of severe aortic regurgitation. Facial edema may be present in patients with tricuspid valve disease or constrictive pericarditis.

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The muscular dystrophies, the cardiac manifestations of which are described in Chapter 71 , also affect facial appearance profoundly. Patients with myotonic dystrophy exhibit a dull, expressionless face, with ptosis due to weakness of the levator muscles. EYES

External ophthalmoplegia and ptosis due to muscular dystrophy of the extraocular muscles occur in the Kearns-Sayre syndrome, which may be associated with complete heart block. Exophthalmos and stare occur in hyperthyroidism, an important cause of high-output cardiac failure (see Chap. 17) . Severe tricuspid regurgitation can also cause pulsation of the eyeballs[10] (pulsatile exophthalmos), as well as of the earlobes.[11] Blue sclerae may be seen in patients with osteogenesis imperfecta,[12] a disorder that may be associated with aortic dilatation, regurgitation, and dissection and with prolapse of the mitral valve (see Chap. 56) . FUNDI.

Examination of the fundi allows classification of arteriolar disease in patients with hypertension (Fig. 4-1 A) and may also be helpful in the recognition of arteriosclerosis. Beading of the retinal artery may be present in patients with hypercholesterolemia (see Fig. 4-1 B). Hemorrhages near the discs with white spots in the center (Roth spots) occur in infective endocarditis (see Fig. 47-7). Embolic retinal occlusions may occur in patients with rheumatic heart disease, left atrial myxoma, and atherosclerosis of the aorta or arch vessels. Papilledema may be present not only in patients with malignant hypertension (see Chap. 28) but also in those with cor pulmonale with severe hypoxia (see Chap. 54) . SKIN AND MUCOUS MEMBRANES

Central cyanosis (due to intracardiac or intrapulmonary right-to-left shunting) involves the entire body, including warm, well-perfused sites such as the conjunctivae and the mucous membranes of the oral cavity. Peripheral cyanosis (due to reduction of peripheral blood flow, such as occurs in heart failure and peripheral vascular disease) is

characteristically most prominent in cool, exposed areas that may not be well perfused, such as the extremities, particularly the nail beds and nose. Polycythemia can often be suspected from inspection of the conjunctivae, lips, and tongue, which are darkly congested in polycythemia and pale in anemia. Bronze pigmentation of the skin and loss of axillary and pubic hair occur in hemochromatosis (which may result in cardiomyopathy owing to iron deposits in the heart [see Chap. 69 ]). Jaundice may be observed in patients after pulmonary infarction as well as in patients with congestive hepatomegaly or cardiac cirrhosis. Lentigines, which are small brown macular lesions on the neck and trunk that begin at about age 6 and do not increase in number with sunlight, are observed in patients with pulmonic stenosis and hypertrophic cardiomyopathy.[13]

Figure 4-1 A, Severe hypertensive retinopathy. The patient was a 43-year-old man with the symptoms of malignant hypertension. He subsequently died of massive cerebral hemorrhage. B, Beading of the retinal artery in a patient with hypercholesterolemia. The patient was a 37-year-old man with a serum cholesterol level of 400 mg/dl. C, Proliferative retinopathy of Takayasu-Ohnishi disease. The patient was a 27-year-old Asian woman with postural amaurosis and hemiplegia. Brachial pulses were unobtainable. D, Roth spots (hemorrhage with white center) in a patient with subacute bacterial endocarditis. (From Cogan DG: Ophthalmic Manifestations of Systemic Vascular Disease. Philadelphia, WB Saunders, 1974, p 52.)

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Figure 4-2 Tendinous xanthomas of the knees in a patient with familial hypercholesterolemia. The patient was a 10-year-old girl with a serum cholesterol level of 665 mg/dl. Several other members of her family had a similar syndrome. (From Cogan DG: Ophthalmic Manifestations of Systemic Vascular Disease. Philadelphia, WB Saunders, 1974, pp 14 and 15.)

Several types of xanthomas (i.e., cholesterol-filled nodules) are found either subcutaneously or over tendons in patients with hyperlipoproteinemia (see Chap. 31) . Premature atherosclerosis frequently develops in these individuals. Tuberoeruptive xanthomas, present subcutaneously or on the extensor surfaces of the extremities, and xanthoma striatum palmare, which produce yellowish, orange, or pink discoloration of the palmar and digital creases, occur most commonly in patients with type III hyperlipoproteinemia. Patients with xanthoma tendinosum (Fig. 4-2) (i.e., nodular swellings of the tendons, especially of the elbows, extensor surfaces of the hands, and Achilles tendons) usually have type II hyperlipoproteinemia. Eruptive xanthomas are tiny yellowish nodules, 1 to 2 mm in diameter on an erythematous base, that may occur anywhere on the body and are associated with hyperchylomicronemia and are therefore often found in patients with type I and type V hyperlipoproteinemia. Hereditary telangiectases are multiple capillary hemangiomas occurring in the skin, lips (Fig. 4-3) , nasal mucosa, and upper respiratory and gastrointestinal tracts and

resemble the spider nevi seen in patients with liver disease. When present in the lung, they are associated with pulmonary arteriovenous fistulas and cause central cyanosis. EXTREMITIES

A variety of congenital and acquired cardiac malformations are associated with characteristic changes in the extremities. Among the congenital lesions, short stature, cubitus valgus, and medial deviation of the extended forearm are characteristic of Turner syndrome (see Chap. 43) . Patients with the Holt-Oram syndrome[14] (i.e., atrial septal defect with skeletal deformities) often have a thumb with an extra

Figure 4-3 Hemorrhagic telangiectasia on the lips of a 25-year-old woman with pulmonary arteriovenous fistulas. (From Perloff JK: The Clinical Recognition of Congenital Heart Disease. 4th ed. Philadelphia, WB Saunders, 1994, p 719.)

Figure 4-4 A, Normal finger. B, Advanced clubbing in a young cyanotic adult. (From Perloff JK: The Clinical Recognition of Congenital Heart Disease. 4th ed. Philadelphia, WB Saunders, 1994, p 7.)

phalanx, a so-called fingerized thumb, which lies in the same plane as the fingers, making it difficult to appose the thumb and fingers. In addition, they may exhibit deformities of the radius and ulna, causing difficulty in supination and pronation. Arachnodactyly is characteristic of Marfan syndrome (see Chap. 56) . Normally, when a fist is made over a clenched thumb the latter does not extend beyond the ulnar side of the hand, but it usually does so in Marfan syndrome. Systolic flushing of the nail beds, which can be readily detected by pressing a flashlight against the terminal digits (Quincke sign), is a sign of aortic regurgitation and of other conditions characterized by a greatly widened pulse pressure. Differential cyanosis, in which the hands and fingers (especially on the right side) are pink and the feet and toes are cyanotic, is indicative of patent ductus arteriosus with reversed shunt due to pulmonary hypertension (see Chap. 53) ; this finding can often be brought out by exercise. On the other hand, reversed differential cyanosis, in which cyanosis of the fingers exceeds that of the toes, suggests Taussig-Bing anomaly with pulmonary vascular disease and reversed flow through a patent ductus arteriosus. Alternatively, it may occur with transposition of the great arteries, pulmonary hypertension, preductal narrowing of the aorta, and reversed flow through a patent ductus arteriosus.[15] CLUBBING OF THE FINGERS AND TOES.

Clubbing of the digits is characteristic of central cyanosis (cyanotic congenital heart disease or pulmonary disease with hypoxia) (Fig. 4-4) .[16] It may also appear within a few weeks of the development of infective endocarditis. The earliest forms of clubbing

are characterized by increased glossiness and cyanosis of the skin at the root of the nail.[17] After obliteration of the normal angle between the base of the nail and the skin, the soft tissue of the pulp becomes hypertrophied, the nail root floats freely, and its loose proximal end can be palpated. In the more severe forms of clubbing, bony changes occur (i.e., hypertrophic osteoarthropathy); these changes involve the terminal digits and in rare instances even the wrists, ankles, elbows, and knees. Unilateral clubbing of the fingers is rare but can occur when an aortic aneurysm interferes with the arterial supply to one arm. Osler nodes are small, tender, purplish erythematous skin lesions due to infected microemboli and occurring most frequently in the pads of the fingers or toes and in the palms of the hands or soles of the feet,[18] whereas Janeway lesions are slightly raised, nontender hemorrhagic lesions in the palms of hands and soles of the feet; both of these lesions as well as petechiae occur in infective endocarditis (see Chap. 47) . When the latter occur under the nail beds, they are termed splinter hemorrhages. EDEMA.

The presence of edema of the lower extremities is a common finding in congestive heart failure (see Chap. 3) [19] ; however, if it is present in only one leg, it is more likely due to obstructive venous or lymphatic disease than to heart failure. Firm pressure on the pretibial region for 10 to 20 seconds may be necessary for the detection of edema. In patients confined to bed, edema appears first in the sacral region. Edema may involve the face in children with heart failure of any etiology and in adults with heart failure associated with marked elevation of systemic venous pressure (e.g., constrictive pericarditis and tricuspid valve disease).

48

CHEST AND ABDOMEN Examination of the thorax should begin with observations of the rate, effort, and regularity of respiration. The shape of the chest is important as well; thus, a barrel-shaped chest with low diaphragm suggests emphysema, bronchitis, and cor pulmonale. Inspection of the chest is an integral part of the cardiac examination (see p. 54 ). It may reveal a bulging to the right of the upper sternum caused by an aortic aneurysm. The latter can also produce a venous collateral pattern caused by obstruction of the superior vena cava. Kyphoscoliosis of any etiology can cause cor pulmonale; this skeletal abnormality, as well as pectus excavatum (funnel chest)[20] [21] [22] and pectus carinatum (pigeon breast), is often present in Marfan syndrome. Left ventricular failure and other causes of elevation of pulmonary venous pressure may cause pulmonary rales; wheezing is sometimes audible in pulmonary edema (cardiac

asthma). Painful enlargement of the liver may be due to venous congestion; the tenderness disappears in long-standing heart failure. Hepatic systolic expansile pulsations occur in patients with severe tricuspid regurgitation, and presystolic pulsations can be felt in patients with tricuspid stenosis and sinus rhythm. Patients with constrictive pericarditis also often have pulsatile hepatomegaly, the contour of the pulsations resembling those of the jugular venous pulse in this condition.[23] When firm pressure over the abdomen causes cervical venous distention, that is, when there is abdominojugular reflux, right-sided heart failure[24] [25] (see later) or tricuspid valve disease is usually present. Ascites is also characteristic of heart failure, but it is especially characteristic of tricuspid valve disease and chronic constrictive pericarditis. Splenomegaly may occur in the presence of severe congestive hepatomegaly, most frequently in patients with constrictive pericarditis or tricuspid valve disease. The spleen may be enlarged and painful in infective endocarditis, as well as after splenic embolization. Splenic infarction is frequently accompanied by an audible friction rub. Both kidneys may be palpably enlarged in patients with hypertension secondary to polycystic disease. Auscultation of the abdomen should be carried out in all patients with hypertension; a systolic bruit secondary to renal artery stenosis may be audible near the umbilicus or in the flank. Atherosclerotic aneurysms of the abdominal aorta are usually readily detected on palpation of the abdomen below the umbilicus (see Chap. 40) , except in markedly obese patients. In patients with coarctation of the aorta, no abdominal pulsations are palpable despite the presence of prominent arterial pulses in the neck and upper extremities; arterial pulses in the lower extremities are reduced or absent. JUGULAR VENOUS PULSE Important information concerning the dynamics of the right side of the heart can be obtained by observation of the jugular venous pulse.[6] [26] [27] [28] [29] The internal jugular vein is ordinarily examined; the venous pulse can usually be analyzed more readily on the right than on the left side of the neck, because the right innominate and jugular veins extend in an almost straight line cephalad to the superior vena cava, thus favoring transmission of hemodynamic changes from the right atrium, while the left innominate vein is not in a straight line and may be kinked or compressed by a variety of normal structures, by a dilated aorta, or by an aneurysm. During the examination the patient should be lying comfortably. Although the head should rest on a pillow, it must not be at a sharp angle from the trunk. The jugular venous pulse may be examined effectively by shining a light tangentially across the neck. Most patients with heart disease are examined most effectively in the 45-degree position, but in patients in whom venous pressure is high, a greater inclination (60 or even 90 degrees) is required to obtain visible pulsations, whereas in those in whom

jugular venous pressure is low, a lesser inclination (30 degrees) is desirable. The internal jugular vein is located deep within the neck, where it is covered by the sternocleidomastoid muscle and is therefore not usually visible as a discrete structure except in the presence of venous hypertension. However, its pulsations are transmitted to the skin of the neck, where they are usually easily visible. Sometimes difficulty may be experienced in differentiating between the carotid and jugular venous pulses in the neck, particularly when the latter exhibits prominent v waves, as occurs in patients with tricuspid regurgitation, in whom the valves in the internal jugular veins may be incompetent. However, there are several helpful clues: 1. The arterial pulse is a sharply localized rapid movement that may not be readily visible but that strikes the palpating fingers with considerable force; in contrast, the venous pulse, whereas more readily visible, often disappears when the palpating finger is placed lightly on or below the pulsating area. 2. The arterial pulse usually exhibits a single upstroke, whereas (in patients in sinus rhythm) the venous pulse has two peaks and two troughs per cardiac cycle. 3. The arterial pulsations do not change when the patient is in the upright position or during respiration, whereas venous pulsations usually disappear or diminish greatly in the upright position and during inspiration, unless the venous pressure is greatly elevated. 4. Compression of the root of the neck does not affect the arterial pulse but usually abolishes venous pulsations, except in the presence of extreme venous hypertension. Two principal observations can usually be made from examination of the neck veins: the level of venous pressure and the type of venous wave pattern. To estimate jugular venous pressure, the height of the oscillating top of the distended proximal portion of the internal jugular vein, which reflects right atrial pressure, should be determined. The upper limit of normal is 4 cm above the sternal angle, which corresponds to a central venous pressure of approximately 9 cm H2 O, since the right atrium is approximately 5 cm below the sternal angle. When the veins in the neck collapse in a subject breathing normally in the horizontal position, it is likely that the central venous pressure is subnormal. When obstruction of veins in the lower extremities is responsible for edema, pressure in the neck veins is not elevated and the abdominal-jugular reflux is negative. ABDOMINAL-JUGULAR REFLUX.

This can be tested by applying firm pressure to the periumbilical region for 10 to 30 seconds with the patient breathing quietly while the jugular veins are observed[24] [25] [30] ; increased respiratory excursions or straining should be avoided. In normal subjects, jugular venous pressure rises less than 3 cm H2 O and only transiently while abdominal pressure is continued, whereas in right or left ventricular failure and/or tricuspid regurgitation the jugular venous pressure remains elevated. In the absence of these conditions, a positive abdominal-jugular reflux suggests an elevated pulmonary artery wedge[26] or central venous pressure.[25]

PATTERN OF THE VENOUS PULSE.

The events of the cardiac cycle, shown in Figure 14-22 , provide an explanation for the details of the jugular venous waveform (Fig. 4-5) . The a wave in the venous pulse results from venous distention due to right atrial systole, whereas the x descent is due to atrial relaxation and descent of the floor of the right atrium during right ventricular systole. The c wave, which occurs simultaneously with the carotid arterial pulse, is an inconstant wave in the jugular venous pulse and/or interruption of the x descent after the peak of the a wave. The continuation of the x descent after the c wave is referred to as the x descent. The v wave results from the rise in right atrial pressure when blood flows into this chamber during ventricular systole when the tricuspid valve is shut, and the y descent (i.e., the downslope of the v wave) is related to the decline in right atrial pressure when the tricuspid valve reopens. After the bottom of the y

49

Figure 4-5 Top, Normal jugular venous pulse: the jugular v wave is built up during systole, and its height reflects the rate of filling and the elasticity of the right atrium. Between the bottom of the y descent (y trough) and beginning of the a wave is the period of relatively slow filling of the "atrioventricle" or diastasis period. The wave built up during diastasis is the H wave. The H wave height also reflects the stiffness of the right atrium. S1 and S2 refer to the first and second heart sounds, respectively. Center, As the degree of tricuspid regurgitation (TR) increases, the x descent is increasingly encroached upon. With severe TR, no x descent is seen, and the jugular pulse wave is said to be "ventricularized." Bottom, Black broken line=normal jugular venous pulse and sinus rhythm; red continuous line=after development of atrial fibrillation. The dominant descent in atrial fibrillation is almost always the y descent; that is, it has the superficial appearance of the pulse wave of TR. (From Constant J: Bedside Cardiology. 4th ed. Boston, Little, Brown & Co, 1994, pp 81 and 89.)

descent (the y trough) and beginning of the a wave is a period of relatively slow filling of the atrium or ventricle, the diastasis period, a wave termed the H wave. Although all or most of these events can usually be recorded, they may not be readily distinguishable on inspection. The descents or downward collapsing movements of the jugular veins are more rapid, produce larger excursions, and are therefore more prominent to the eye than are the ascents (see Fig. 4-5) . The normal dominant jugular venous descent, the x descent, occurs between the first (S1 ) and second (S2 ) heart sounds, whereas the y descent ends well after S2 . With an increase in central venous pressure, the v wave becomes higher and the y collapse becomes more prominent. The a wave occurs just before the first sound or carotid pulse and has a sharp rise and fall. The v wave occurs just after the arterial pulse and has a slower, undulating pattern. ALTERATIONS IN DISEASE.

Elevation of jugular venous pressure reflects an increase in right atrial pressure and occurs in heart failure, reduced compliance of the right ventricle, pericardial disease, hypervolemia, obstruction of the tricuspid orifice, and obstruction of the superior vena cava. During inspiration, the jugular venous pressure normally declines but the amplitude of the pulsations increases. Kussmaul sign is a paradoxical rise in the height of the jugular venous pressure during inspiration, which typically occurs in patients with chronic constrictive pericarditis and sometimes in patients with congestive heart failure and tricuspid stenosis. The a wave is particularly prominent in conditions in which the resistance to right atrial contraction is increased, such as right ventricular hypertrophy, pulmonary hypertension, and tricuspid stenosis (Fig. 4-6 A). The a wave may also be tall in left ventricular hypertrophy when the thickened ventricular septum interferes with right ventricular filling. Tall a waves are present in patients with sinus rhythm and tricuspid stenosis or atresia, right atrial myxoma, or reduced compliance and/or marked hypertrophy of the right ventricle. Cannon (amplified) a waves are noted in patients with AV dissociation when the right atrium contracts against a closed tricuspid valve. In atrial fibrillation, the a wave and x descent disappear and the v wave and y descent (see Fig. 4-5 , bottom) become more prominent. In right ventricular failure and sinus rhythm, there may be increases in prominence of both the a and v waves. A steeply rising H wave (see Fig. 4-5) is observed (or recorded) in restrictive cardiomyopathy, constrictive pericarditis, and right ventricular infarction. The x descent may be prominent in patients with large a waves, as well as in patients with right ventricular volume overload (atrial septal defect). Constrictive pericarditis (see Fig. 4-6 B) is characterized by a rapid and deep y descent followed by a rapid rise to a diastolic plateau (H wave) without a prominent a wave; occasionally, the x descent is prominent in this condition as well, causing a "W"-shaped jugular venous pulse. However, it is in cardiac tamponade that the x descent is most prominent. A prominent v wave or a c-v wave (i.e., fusion of the c and v waves in the absence or attenuation of an x descent) occurs in tricuspid regurgitation, sometimes causing a systolic movement of the earlobe[29] (see Fig. 4-5 , center) and a right-to-left head movement with each ventricular systole. Equal a and v waves are seen in atrial septal defect; the y descent is gradual when right atrial emptying is impeded, as in tricuspid stenosis, and rapid when it is unimpeded, as in tricuspid regurgitation. A steep y descent is seen in any condition in which there is myocardial dysfunction, ventricular dilatation, and an elevated central venous pressure. SPHYGMOMANOMETRIC MEASUREMENT OF ARTERIAL PRESSURE Systolic arterial pressure can be estimated without a sphygmomanometer by gradually compressing the brachial artery while palpating the radial artery; the force required to obliterate

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Figure 4-6 A, Jugular venous pressure (JVP) in mitral stenosis with pulmonary hypertension. The JVP is dominated by a very large a wave resulting from diminished compliance of the right ventricle associated with pulmonary hypertension. The peaked a wave represents a brief period of retrograde flow from right atrium to great veins. B, JVP in constrictive pericarditis. In this severe and long-standing case, the x descent has become very shallow and the y descent is the principal feature, indicating that antegrade flow from the venous system to the right side of the heart is now limited to early diastole. A pericardial knock (K) is seen at approximately the nadir of the y descent. (From Craige E, Smith P: Heart sounds. In Braunwald E [ed]: Heart Disease: A Textbook of Cardiovascular Medicine. 3rd ed. Philadelphia, WB Saunders, 1988, pp 61 and 62.)

the radial pulse represents the systolic blood pressure, and, with practice, one can often estimate this level within 20 mm Hg. Ordinarily, however, a sphygmomanometer is used to obtain an indirect measurement of blood pressure.[31] [32] The cuff should fit snugly around the arm, with its lower edge at least 1 inch above the antecubital space, and the diaphragm of the stethoscope should be placed close to or under the edge of the sphygmomanometer cuff. The width of the cuff selected should be at least 40 percent of the circumference of the limb to be used. The standard size, with a 5-inch-wide cuff, is designed for adults with an arm of average size. When this cuff is applied to a large upper arm or a normal adult thigh, arterial pressure is overestimated, leading to spurious hypertension in the obese (arm circumference >35 cm)[33] [34] ; when it is applied to a small arm, the pressure is underestimated. The cuff width should be approximately 1.5 inches in infants and small children, 3 inches in young children (2 to 5 years), and 8 inches in obese adults. The rubber bag should be long enough to extend at least halfway around the limb (10 inches in adults). In patients with rigid, sclerotic arteries the systolic pressure may also be overestimated, by as much as 30 mm Hg. Mercury manometers are, in general, more accurate and reliable than the aneroid type; the latter should be calibrated at least once yearly. BLOOD PRESSURE IN THE UPPER EXTREMITIES.

To measure arterial pressure in an upper extremity,[35] [36] [37] the patient should be seated or lying comfortably and relaxed, the arm should be slightly flexed and at heart level, and the arm muscles should be relaxed. The cuff should be inflated rapidly to approximately 30 mm Hg above the anticipated systolic pressure. These maneuvers, which diminish the volume of blood in the venous bed, decrease the tissue pressure distal to the cuff and thereby increase the flow into the occluded brachial artery. The cuff is then deflated slowly, no faster than 3 mm Hg/sec; the pressure at which the brachial pulse can be palpated is close to the systolic pressure. The cuff should be deflated rapidly after the diastolic pressure is noted and a full minute allowed to elapse before pressure is remeasured in the same limb. Although excessive pressure on the stethoscope head does not affect systolic pressure, it does erroneously lower diastolic readings. In one study, the anxiety associated with blood pressure measurement was shown to elevate arterial pressure by an average of 27/17 mm Hg [38]

("white coat hypertension," see Chap. 28) . BLOOD PRESSURE IN THE LOWER EXTREMITIES.

To measure pressure in the legs, the patient should lie on the abdomen, an 8-inch-wide cuff should be applied with the compression bag over the posterior aspect of the mid thigh and should be rolled diagonally around the thigh to keep the edges snug against the skin, and auscultation should be carried out in the popliteal fossa. To measure pressure in the lower leg, an arm cuff is placed over the calf and auscultation is carried out over the posterior tibial artery. Regardless of where the cuff is applied, care must be taken to avoid letting the rubber part of the balloon of the cuff extend beyond its covering and to avoid placing the cuff on so loosely that central ballooning occurs. KOROTKOFF SOUNDS.

There are five phases of Korotkoff sounds (i.e., sounds produced by the flow of blood as the constricting blood pressure cuff is gradually released). The first appearance of clear, tapping sound (phase I) represents the systolic pressure. These sounds are replaced by soft murmurs during phase II and by louder murmurs during phase III, as the volume of blood flowing through the constricted artery increases. The sounds suddenly become muffled in phase IV, when constriction of the brachial artery diminishes as arterial diastolic pressure is approached. Korotkoff sounds disappear in phase V, which is usually within 10 mm Hg of phase IV. Diastolic pressure measured directly through an intraarterial needle and external manometer corresponds closely to phase V. In severe aortic regurgitation, however, when the disappearance point is extremely low, sometimes 0 mm Hg, the sound of muffling (phase IV) is much closer to the intraarterial diastolic pressure than is the disappearance point (phase V). When the difference between phases IV and V of the Korotkoff sounds exceeds 10 mm Hg, both pressures should be recorded (e.g., 142/54/10 mm Hg). Korotkoff sounds may be difficult to hear and arterial pressure difficult to measure when arterial pressure rises at a slow rate (as in severe aortic stenosis), when the arteries are markedly constricted (as in shock), and when the stroke volume is reduced (as in severe heart failure). Very soft or inaudible Korotkoff sounds can often be accentuated by dilating the blood vessels simply by opening and closing the fist repeatedly. Sometimes in states of shock, the indirect method of measuring blood pressure is unreliable and arterial pressure should be measured through an intraarterial needle.

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The Auscultatory Gap.

This is a silence that sometimes separates the first appearance of the Korotkoff sounds from their second appearance at a lower pressure. The phenomenon tends to occur

when there is venous distention or reduced velocity of arterial flow into the arm. If the first muffling of sounds is considered to be the diastolic pressure, it will be overestimated. If the second appearance is taken as the systolic pressure, it will be underestimated. On the other hand, sounds transmitted through the arterial tree from prosthetic aortic valves may be responsible for falsely high readings. BLOOD PRESSURE IN THE BASAL CONDITION.

To determine arterial pressure in the basal condition, the patient should have rested in a quiet room for 15 minutes. It is desirable to record the arterial pressure in both arms at the time of the initial examination; differences in systolic pressure between the two arms that exceed 10 mm Hg when measurements are made simultaneously or in rapid sequence[37] suggest obstructive lesions involving the aorta or the origin of the innominate and subclavian arteries or supravalvular aortic stenosis (in which pressure in the right arm exceeds that in the left). In patients with vertebral-basal artery insufficiency, a difference in pressure between the arms may signify that a subclavian "steal" is responsible for the cerebrovascular symptoms. To be certain from physical examination that the systolic pressure is different in the two arms or in the upper and lower extremities, two examiners should measure the pressures simultaneously and then switch extremities and measure the pressures again. ORTHOSTATIC HYPOTENSION.

To determine whether orthostatic hypotension is present, arterial pressure should be determined with the patient in both the supine and the erect positions. However, regardless of the patient's posture, the brachial artery should be at the level of the heart to avoid superimposition of the effects of gravity on the recorded pressure. Normally, the systolic pressure in the legs is up to 20 mm Hg higher than in the arms but the diastolic pressures are usually virtually identical. The recording of a higher diastolic pressure in the legs than in the arms suggests that the thigh cuff is too small. When systolic pressure in the popliteal artery exceeds that in the brachial artery by more than 20 mm Hg (Hill sign), aortic regurgitation is usually present.[39] Blood pressure should be measured in the lower extremities in patients with hypertension to detect coarctation of the aorta or when obstructive disease of the aorta or its immediate branches is suspected. ARTERIAL PULSE The volume and contour of the arterial pulse are determined by a combination of factors, including the left ventricular stroke volume, the ejection velocity, the relative compliance and capacity of the arterial system, and the pressure waves that result from the antegrade flow of blood and reflections of the arterial pressure pulse returning from the peripheral circulation.[39] Bilateral palpation of the carotid, radial, brachial, femoral, popliteal, dorsalis pedis, and posterior tibial pulses should be part of the examination of

all cardiac patients (Fig. 4-7) . Caution should be exercised in bilateral carotid palpation, especially in the elderly. The frequency, regularity, and shape of the pulse wave and the character of the arterial wall should be determined.[40] The carotid pulse (see Fig. 4-7 A) provides the most accurate representation of the central aortic pulse.[41] The

Figure 4-7 A, Technique for evaluating the carotid artery pulsations. B, Technique for timing the femoral and radial arteries. C, Technique for palpation of the dorsalis pedis arteries. D, Technique for palpation of the posterior tibial arteries. (From Swartz MH [ed]: Textbook of Physical Diagnosis: History and Examination. 3rd ed. Philadelphia, WB Saunders, 1998, pp 300, 329, and 330.)

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brachial artery is the vessel ordinarily most suitable for appreciating the rate of rise of the pulse and the contour, volume, and consistency of the peripheral vessels. This artery is located at the medial aspect of the elbow, and it may be helpful to flex the arm to improve palpation; palpation of the artery should be carried out with the thumb exerting pressure on the artery until its maximal movement is detected. A normal rate of rise of the arterial pulse suggests that there is no obstruction to left ventricular outflow, whereas a pulse wave of small amplitude with normal configuration suggests a reduced stroke volume. THE NORMAL PULSE.

The pulse in the ascending aorta normally rises rapidly to a rounded dome (Fig. 4-8) ; this initial rise reflects the peak velocity of blood ejected from the left ventricle. A slight anacrotic notch or pause is frequently recorded, but only occasionally felt, on the ascending limb of the pulse. The descending limb of the central aortic pulse is less steep than is the ascending limb, and it is interrupted by the incisura, a sharp downward deflection related to closure of the aortic valve. Immediately thereafter, the pulse wave rises slightly and then declines gradually throughout diastole. As the pulse wave is transmitted to the periphery, its upstroke becomes steeper, the systolic peak becomes higher, the anacrotic shoulder disappears, and the sharp incisura is replaced by a smoother, later dicrotic notch followed by a dicrotic wave.[42] [43] [44] Normally, the height of this dicrotic wave diminishes with age, hypertension, and arteriosclerosis. In the central arterial pulse (central aorta and innominate and carotid arteries), the rapidly transmitted impact of left ventricular ejection results in a peak in early systole, referred to as the percussion wave; a second, smaller peak, the tidal wave, presumed to represent a reflected wave from the periphery, can often be recorded but is not normally palpable. However, in older subjects, particularly those with increased peripheral resistance, as well as in patients with arteriosclerosis and diabetes, the tidal wave may be somewhat higher than the percussion wave; that is, the pulse reaches a peak in late systole. In peripheral arteries, the pulse wave normally has a single sharp peak.

ABNORMAL PULSES.

When peripheral vascular resistance and arterial stiffness are increased, as in hypertension or with the increased arterial stiffness that accompanies normal aging, there is an elevation in pulse wave velocity and the pulse contour has a more rapid upstroke and greater amplitude. Reduced or unequal carotid arterial pulsations occur in patients with carotid atherosclerosis and with diseases of the aortic arch, including aortic dissection, aneurysm, and Takayasu disease (see Chap. 40) . In supravalvular aortic stenosis, there is a selective streaming of the jet toward the innominate artery, the carotid and brachial arterial pulses are stronger and rise more rapidly on the right than on the left side, and pressures may be higher in the right than in the left arm (see Chap. 43) . The pulses of the upper extremities may be reduced or unequal in a variety of other conditions, including arterial embolus or thrombosis, anomalous origin or aberrant path of the major vessels, and cervical rib or scalenus anticus syndrome. Asymmetry of right and left popliteal pulses is characteristic of iliofemoral obstruction. Weakness or absence of radial, posterior tibial, or dorsalis pedis pulses on one side suggests arterial insufficiency (see Fig. 4-7 C and D). In coarctation of the aorta the carotid and brachial pulses are bounding, rise rapidly, and have large volumes, whereas in the lower extremities, the systolic and pulse pressures are reduced, their rate of rise is slow, and there is a late peak. This delay in the femoral arterial pulses can usually be readily detected by simultaneous palpation of the femoral and brachial arterial pulses (see Fig. 4-7B) . In patients with fixed obstruction to left ventricular outflow (valvular aortic stenosis and congenital fibrous subaortic stenosis), the carotid pulse rises slowly (pulsus tardus) (see Fig. 4-8 B); the upstroke is frequently characterized by a thrill (the carotid shudder); and the peak is reduced, occurs late in systole, and is sustained. There is a notch on the upstroke of the carotid pulse (anacrotic notch) that is so distinct that two separate waves can be palpated in what is termed an anacrotic pulse. Pulsus parvus is a pulse of small amplitude, usually because of a reduction of stroke volume. Pulsus parvus et tardus refers to a small pulse with a delayed systolic peak, which is characteristic of severe aortic stenosis. This type of pulse is more readily appreciated by palpating the carotid rather than a more peripheral artery. Patients with severe aortic stenosis and heart failure usually exhibit simply a reduced pulse amplitude (i.e., pulsus parvus), and the delay in the upstroke is not readily apparent. However, this delay is readily recorded. In elderly patients with inelastic peripheral arteries, the pulse may rise normally despite the presence of aortic stenosis. The carotid arterial pulse may be prominent or exaggerated in any condition in which pulse pressure is increased, including anxiety, the hyperkinetic heart syndrome, anemia, fever, pregnancy, or other high cardiac output states (see Chap. 17) , as well as in bradycardia and

Figure 4-8 Schematic diagrams of the configurational changes in the carotid pulse and their differential diagnosis. Heart sounds are also illustrated. A, Normal. B, Anacrotic pulse with slow initial upstroke. The

peak is close to the second heart sound. These features suggest fixed left ventricular outflow obstruction. C, Pulsus bisferiens with both percussion and tidal waves occurring during systole. This type of carotid pulse contour is most frequently observed in patients with hemodynamically significant aortic regurgitation or combined aortic stenosis and regurgitation with dominant regurgitation. It is rarely observed in mitral valve prolapse or in normal individuals. D, Pulsus bisferiens in hypertrophic obstructive cardiomyopathy. It is rarely appreciated at the bedside by palpation. E, Dicrotic pulse results from an accentuated dicrotic wave and tends to occur in sepsis, severe heart failure, hypovolemic shock, and cardiac tamponade and after aortic valve replacement. S 4 =fourth heart sound; S1 =first heart sound; A 2 =aortic component of the second heart sound; P2 =pulmonic component of the second heart sound. (From Chatterjee K: Bedside evaluation of the heart: The physical examination. In Chatterjee K, et al [eds]: Cardiology: An Illustrated Text/Reference. Philadelphia, JB Lippincott, 1991, pp 3.11-3.51.)

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peripheral arteriosclerosis with reduction in arterial distensibility. In patients with mitral regurgitation or ventricular septal defect, the forward stroke volume (from the left ventricle into the aorta) is usually normal but the fraction ejected during early systole is greater than normal; hence, the arterial pulse is of normal volume (the pulse pressure is normal) but the pulse may rise abnormally rapidly.[45] Exaggerated or bounding arterial pulses may be observed in patients with an elevated stroke volume, with sympathetic hyperactivity, and in patients with a rigid, sclerotic aorta. In aortic regurgitation, there is a very brisk rate of rise with an increased pulse pressure. The Corrigan or water-hammer pulse of aortic regurgitation consists of an abrupt upstroke (percussion wave) followed by rapid collapse later in systole but no dicrotic notch. Corrigan pulse reflects a low resistance in the reservoir into which the left ventricle rapidly discharges an abnormally elevated stroke volume, and it can be exaggerated by raising the patient's arm. In acute aortic regurgitation, the left ventricle may not be significantly dilated and premature closure of the mitral valve may occur and limit the volume of aortic reflux; therefore, the aortic diastolic pressure may not be very low, the arterial pulse not bounding, and the pulse pressure not widened despite a serious abnormality of valve function (see Chap. 46) . Signs characteristic of severe chronic aortic regurgitation include "pistol shot" sounds heard over the femoral artery when the stethoscope is placed on it (Traube sign); a systolic murmur heard over the femoral artery when the artery is gradually compressed proximally; a diastolic murmur when the artery is compressed distally (Duroziez sign[39] ) and Quincke sign (phasic blanching of the nail bed). Of these, Duroziez sign is the most predictive of severe aortic regurgitation. Bounding arterial pulses are also present in patients with patent ductus arteriosus or large arteriovenous fistulas; in hyperkinetic states such as thyrotoxicosis, pregnancy, fever, and anemia; in severe bradycardia; and in arteries proximal to coarctation of the aorta. In Hill sign of aortic regurgitation (or any condition leading to an increased stroke volume or the hyperkinetic circulatory state) the indirectly recorded systolic pressures in the lower extremities exceed that in the arms by more than 20 mm Hg. Other signs of increased pulse pressure include Becker sign (visible pulsations of the retinal arterioles) and Mueller sign (pulsating uvula). In the presence of AV dissociation, when atrial activity is irregularly transmitted to the

ventricles, the strength of the peripheral arterial pulse depends on the time interval between atrial and ventricular contractions. In a patient with rapid heart action, the presence of such variations suggests ventricular tachycardia; with an equally rapid rate, an absence of variation of pulse strength suggests a supraventricular mechanism. BISFERIENS PULSE.

A bisferiens pulse (see Fig. 4-8 C) is characterized by two systolic peaks, the percussion and tidal waves, separated by a distinct midsystolic dip; the peaks may be equal, or either may be larger. This type of pulse is detected most readily by palpation of the carotid and, less commonly, of the brachial arteries. It occurs in conditions in which a large stroke volume is ejected rapidly[46] and is observed most commonly in patients with pure aortic regurgitation or with a combination of aortic regurgitation and stenosis; it may disappear as heart failure supervenes. A bisferiens pulse also occurs in patients with hypertrophic obstructive cardiomyopathy,[46] but the bifid nature may only be recorded, not palpated; on palpation there may merely be a rapid upstroke. In these patients the initial prominent percussion wave is associated with rapid ejection of blood into the aorta during early systole, followed by a rapid decline as obstruction becomes manifest in midsystole and by a tidal (reflected) wave. In some patients with hypertrophic cardiomyopathy with no or little obstruction to left ventricular outflow, the arterial pulse is normal or simply hyperkinetic in the basal state, but obstruction and a bisferiens pulse can be elicited by means of the Valsalva maneuver or inhalation of amyl nitrite. Occasionally, a bisferiens pulse is observed in hyperkinetic circulatory states, and very rarely it occurs in normal individuals. DICROTIC PULSE.

Not to be confused with a bisferiens pulse, in which both peaks occur in systole, is a dicrotic pulse, in which the second peak is in diastole immediately after S2 (see Fig. 4-8 E).[40] [41] [43] [44] The normally small wave that follows aortic valve closure (i.e., the dicrotic notch) is exaggerated and measures more than 50 percent of the pulse pressure on direct pressure recordings and in which the dicrotic notch is low (i.e., near the diastolic pressure). A dicrotic wave may be present in normal hypotensive subjects with reduced peripheral resistance, as occurs in fever, and it may be elicited or exaggerated by inhalation alone or the inhalation of amyl nitrite. Rarely, a dicrotic pulse is noted in healthy adolescents or young adults, but it usually occurs in conditions such as cardiac tamponade, severe heart failure, and hypovolemic shock, in which a low stroke volume is ejected into a soft elastic aorta. In these conditions the dicrotic pulse is due to a reduction of the systolic wave with preservation of the incisura. A dicrotic pulse is rarely present when systolic pressure exceeds 130 mm Hg. PULSUS ALTERNANS (Alternating Strong and Weak Pulses).

Mechanical alternans is a sign of depression of left ventricular function (see Chap. 17) . [47] [48] Although more readily recognized on sphygmomanometry, when the systolic

pressure alternates by more than 20 mm Hg, pulsus alternans can be detected by palpation of a peripheral (femoral or brachial) pulse more frequently than by a more central pulse. Palpation should be carried out with light pressure and with the patient's breath held in mid expiration to avoid the superimposition of respiratory variation on the amplitude of the pulse. Pulsus alternans is generally accompanied by alternation in the intensity of the Korotkoff sounds and occasionally by alternation in intensity of the heart sounds. Rarely, pulsus alternans is so marked that the weak beat is not perceived at all.[49] Aortic regurgitation, systemic hypertension, and reducing venous return by administration of nitroglycerin or by tilting the patient into the upright position all exaggerate pulsus alternans and assist in its detection. Pulsus alternans, which is frequently precipitated by a premature ventricular contraction, is characterized by a regular rhythm and must be distinguished from pulsus bigeminus (see later), which is usually irregular. PULSUS BIGEMINUS.

A bigeminal rhythm is caused by the occurrence of premature contractions, usually ventricular, after every other beat and results in alternation of the strength of the pulse, which can be confused with pulsus alternans. However, in contrast to the latter, in which the rhythm is regular, in pulsus bigeminus the weak beat always follows the shorter interval. In normal persons or in patients with fixed obstruction to left ventricular outflow, the compensatory pause after a premature beat is followed by a stronger-than-normal pulse. However, in patients with hypertrophic obstructive cardiomyopathy, the postpremature ventricular contraction beat is weaker than normal because of increased obstruction to left ventricular outflow[50] (see Chap. 48) . PULSUS PARADOXUS.

This is an exaggerated reduction in the strength of the arterial pulse during normal inspiration due to an exaggerated inspiratory fall in systolic pressure (more than 10 mm Hg during quiet breathing) (see Chap. 50) . When marked (i.e., an inspiratory reduction of pressure greater than 20 mm Hg), the paradoxical pulse can be detected by simple palpation of the brachial arterial pulse[51] ; in severe cases there is inspiratory disappearance of the pulse. Milder degrees of a paradoxical pulse can be readily detected on sphygmomanometry: the cuff is inflated to suprasystolic levels and is deflated slowly at a rate of about 2 mm Hg per heartbeat; the peak systolic pressure during exhalation is noted. The cuff is then deflated even more slowly, and the pressure is again noted when Korotkoff sounds become audible throughout the respiratory cycle. Normally, the difference between the two pressures should not exceed 10 mm Hg during quiet respiration. (Pulsus alternans can also be detected by this maneuver by noting whether peak systolic pressure or the intensity of the Korotkoff sounds alternates when the breath is held.) Pulsus paradoxus represents an exaggeration of the normal decline in systolic arterial pressure with inspiration. It results from the reduced left ventricular stroke volume and

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the transmission of negative intrathoracic pressure to the aorta. It is a frequent, indeed characteristic, finding in patients with cardiac tamponade, occurs less frequently (in about half) in patients with chronic constrictive pericarditis, and is also observed in patients with emphysema and bronchial asthma (who have wide respiratory swings of intrapleural pressure),[52] as well as in hypovolemic shock, pulmonary embolus, pregnancy, and extreme obesity. Aortic regurgitation tends to prevent the development of pulsus paradoxus despite the presence of cardiac tamponade. Reversed pulsus paradoxus (an inspiratory rise in arterial pressure) may occur in hypertrophic obstructive cardiomyopathy.[53] THE ARTERIAL PULSE IN VASCULAR DISEASE.

(See also Chap. 41.) Examination of the arterial pulses is of critical importance in the diagnosis of extracardiac obstructive arterial disease. Systematic bilateral palpation of the common carotid, brachial, radial, femoral, popliteal, dorsalis pedis, and posterior tibial vessels (see Fig. 4-7 C and D), as well as palpation of the abdominal aorta (both above and below the umbilicus), should be part of every examination in patients suspected of having ischemic heart disease. A normal aorta is often palpable above the umbilicus, but a palpable aorta below the umbilicus suggests the presence of an aneurysm of the abdominal aorta. To diminish cold-induced vasoconstriction, peripheral pulses should be palpated after the patient has been in a warm room for at least 20 minutes.[54] Absent or weak peripheral pulses usually signify obstruction. However, the dorsalis pedis and posterior tibial arteries may be absent in approximately 2 percent of normal persons because they pursue an aberrant course. Arterial bruits should be sought at specific anatomical sites. When the lumen diameter is reduced by approximately 50 percent, a soft short systolic bruit is heard; as the obstruction becomes more severe, the bruit becomes high pitched, louder, and longer. With approximately 80 percent diameter reduction the murmur spills into early diastole, but it disappears with more severe stenosis or complete occlusion. Arterial bruits are augmented by elevation of the cardiac output (e.g., as occurs in anemia), by poor development of collaterals, and by increased arterial outflow (as occurs in regional exercise). Auscultation over the spine in the interscapular region in patients with coarctation of the aorta may reveal a systolic or continuous murmur, and a systolic murmur may be heard over the lower abdomen in patients with aortic or iliofemoral obstructions.




The Cardiac Examination INSPECTION The cardiac examination proper should commence with inspection of the chest, which can usually best be accomplished with the examiner standing at the side or foot of the bed or examining table. Respirations--their frequency, regularity, and depth--as well as the relative effort required during inspiration and exhalation, should be noted. Simultaneously, one should search for cutaneous abnormalities, such as spider nevi (seen in hepatic cirrhosis and Osler-Weber-Rendu disease). Dilation of veins on the anterior chest wall with caudal flow suggests obstruction of the superior vena cava, whereas cranial flow occurs in patients with obstruction of the inferior vena cava. Precordial prominence is most striking if cardiac enlargement developed before puberty, but it may also be present, although to a lesser extent, in patients in whom cardiomegaly developed in adult life, after the period of thoracic growth. [55] [56] A heavy muscular thorax, contrasting to less developed lower extremities, may occur in coarctation of the aorta, in which collateral arteries may be visible in the axillae and along the lateral chest wall. The upper portion of the thorax exhibits symmetrical bulging in children with stiff lungs in whom the inspiratory effort is increased. A "shield chest" is a broad chest in which the angle between the manubrium and the body of the sternum is greater than normal and is associated with widely separated nipples; shield chest is frequently observed in Turner and Noonan syndromes (see Chap. 43) . Careful note should be made of other deformities of the thoracic cage, such as kyphoscoliosis, which may be responsible for cor pulmonale (see Chap. 54) ; ankylosing spondylitis, sometimes associated with aortic regurgitation (see Chap. 67) ; and pectus carinatum (pigeon chest), which may be associated with Marfan syndrome but does not directly

affect cardiovascular function. Pectus excavatum,[20] [21] [22] a condition in which the sternum is displaced posteriorly, is commonly observed in Marfan syndrome, homocystinuria, Ehlers-Danlos syndrome, Hunter-Hurler syndrome, and a small fraction of patients with mitral valve prolapse. This thoracic deformity rarely compresses the heart or elevates the systemic and pulmonary venous pressures, and the signs of heart disease are more often apparent rather than real.[57] Displacement of the heart into the left thorax, prominence of the pulmonary artery, and a parasternal midsystolic murmur, all key features of this deformity, may falsely suggest the presence of organic heart disease. Pectus excavatum may be associated with palpitations, tachycardia, fatigue, mild dyspnea, and some impairment of cardiac function.[57] Lack of normal thoracic kyphosis (i.e., the straight back syndrome) is often associated with expiratory splitting of S2 , a parasternal midsystolic murmur, and prominence of the pulmonary artery on radiography. CARDIOVASCULAR PULSATIONS

Cardiovascular pulsations should be looked for on the entire chest but specifically in the regions of the cardiac apex, the left parasternal region, and the third left and second right intercostal spaces. Prominent pulsations in these areas suggest enlargement of the left ventricle, right ventricle, pulmonary artery, and aorta, respectively. A thrusting apex exceeding 2 cm in diameter suggests left ventricular enlargement; systolic retraction of the apex may be visible in constrictive pericarditis. Normally, cardiac pulsations are not visible lateral to the midclavicular line; when present there, they signify cardiac enlargement unless there is thoracic deformity or congenital absence of the pericardium. Shaking of the entire precordium with each heartbeat may occur in patients with severe valvular regurgitation, large left-to-right shunts, especially patent ductus arteriosus, complete AV block, hypertrophic obstructive cardiomyopathy, and various hyperkinetic states (see Chap. 17) . Aortic aneurysms may produce visible pulsations of one of the sternoclavicular joints of the right anterior thoracic wall. PALPATION Pulsations of the heart and great arteries that are transmitted to the chest wall are best appreciated when the examiner is positioned on the right side of a supine patient. To palpate the movements of the heart and great arteries, the examiner should use the fingertips or the area just proximal thereto. Precordial movements should be timed with the simultaneously palpated carotid pulse or auscultated heart sounds.[58] [59] The examination should be carried out with the chest completely exposed and elevated to 30 degrees, both with the patient supine and in the partial left lateral decubitus positions (Fig. 4-9) . [2] Rotating the patient into the left lateral decubitus position with the left arm elevated over the head causes the heart to move laterally and increases the palpability of both normal and pathological thrusts of the left ventricle. The subxiphoid region, which allows palpation of the right ventricle, should be examined with the tip of the index finger during held inspiration. Obese, muscular, emphysematous, and elderly persons may have weak or undetectable cardiac pulsations in the absence of cardiac abnormality, and thoracic deformities (e.g.,

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Figure 4-9 A, Palpation of the anterior wall of the right ventricle by applying the tips of three fingers in the third, fourth, and fifth interspaces, left sternal edge (arrows), during full held exhalation. Patient is supine with the trunk elevated 30 degrees. B, Subxiphoid palpation of the inferior wall of the right ventricle (RV) with the relative position of the abdominal aorta (Ao) shown by the arrow. C, The bell of the stethoscope is applied to the cardiac apex while the patient lies in a partial left lateral decubitus position. The thumb of the examiner's free left hand is used to palpate the carotid artery for timing purposes. D, The soft, high-frequency early diastolic murmur of aortic regurgitation or pulmonary hypertensive regurgitation is best elicited by applying the stethoscopic diaphragm very firmly to the mid-left sternal edge. The patient leans forward with breath held in full exhalation. E, Palpation of the left ventricular impulse with a fingertip (arrow). The patient's trunk is 30 degrees above the horizontal. The examiner's right thumb palpates the carotid pulse for timing purposes. F, Palpation of the liver. The patient is supine with knees flexed to relax the abdomen. The flat of the examiner's right hand is placed on the right upper quadrant just below the expected inferior margin of the liver; the left hand is applied diametrically opposite. (From Perloff JK: Physical Examination of the Heart and Circulation. 2nd ed. Philadelphia, WB Saunders, 1990.)

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kyphoscoliosis, pectus excavatum) can alter the pulsations transmitted to the chest wall. In the course of cardiac palpation, precordial tenderness may be detected; this finding may result from costochondritis (Tietze syndrome) and may be an important indication that chest pain is not due to myocardial ischemia. THE LEFT VENTRICLE.

The left ventricular impulse, also referred to as the cardiac impulse, the apex beat, and the apical thrust, is normally produced by left ventricular contraction and is the lowest and most lateral point on the chest at which the cardiac impulse can be appreciated and is normally above the anatomical apex. Although the left ventricular impulse may also be the point of maximal impulse, this is not necessarily the case, because the pulsations produced by other structures (e.g., an enlarged right ventricle, a dilated pulmonary artery, or an aneurysm of the aorta) may be more powerful than the apex beat. Normally, the left ventricular impulse is medial and superior to the intersection of the left midclavicular line and the fifth intercostal space and is palpable as a single, brief outward motion. Although it may not be palpable in the supine position in as many as half of all normal subjects more than 50 years of age, the left ventricular impulse can usually be felt in the left lateral decubitus position. Displacement of the apex beat lateral to the midclavicular line or more than 10 cm lateral to the midsternal line is a sensitive but not specific indicator of left ventricular enlargement. However, when the patient is in the left lateral decubitus position a palpable apical impulse that has a diameter of more than 3 cm is an accurate sign of left ventricular enlargement.[60] Thoracic deformities--particularly scoliosis, straight back, and pectus excavatum--can result in the lateral displacement of a normal-sized heart.

APEX CARDIOGRAM.

This recording reflects the movement of the chest wall and represents the pulsation of the entire left ventricle. Its contour differs from what is perceived on palpation of the apex or what is recorded by the kinetocardiogram, a device in which the motion of specific points on the chest wall is recorded relative to a fixed point in space[61] and which therefore presents a more faithful graphic registration of the movements of the palpating finger on the chest wall. SYSTOLIC MOTION

During isovolumetric contraction, the heart normally rotates counterclockwise (as one faces the patient), and the lower anterior portion of the left ventricle strikes the anterior chest wall, causing a brief outward motion followed by medial retraction of the adjacent chest wall during ejection. The peak outward motion of the left ventricular impulse occurs simultaneously with, or just after, aortic valve opening; then the left ventricular apex moves inward. In asthenic persons, in patients with mild left ventricular enlargement, and in subjects with a normal left ventricle but an augmented stroke volume, as occurs in anxiety and other hyperkinetic states, and in mitral or aortic regurgitation, the cardiac impulse may be overactive but with a normal contour; that is, the outward thrust during systole is exaggerated in amplitude but it is not sustained during ejection. HYPERTROPHY AND DILATATION.

With moderate or severe left ventricular concentric hypertrophy, the outward systolic thrust persists throughout ejection, often lasting up to the second heart sound, [62] and this motion is accompanied by retraction of the left parasternal region. This rocking motion can often be appreciated by placing the index finger of one hand on the apex beat and that of the other hand in the parasternal region and by palpating the simultaneous outward motion of the former while observing retraction of the latter. The left ventricular heave or lift, which is more prominent in concentric hypertrophy than in left ventricular dilatation without volume overload, is characterized by a sustained outward movement of an area that is larger than the normal apex; that is, it is more than 2 to 3 cm in diameter. In patients with left ventricular enlargement the systolic impulse is displaced laterally and downward into the sixth or seventh interspaces. In patients with ischemic heart disease a sustained apex beat is usually associated with a reduced ejection fraction.[63] In patients with volume overload and/or sympathetic stimulation, the left ventricular impulse is hyperkinetic, that is, it is brisker and larger than normal. It is hypokinetic in patients with reduced stroke volume, especially in acute myocardial infarction or dilated cardiomyopathy. OTHER CONDITIONS.

Left ventricular aneurysm produces a larger-than-normal area of pulsation of the left ventricular apex. Alternatively, it may produce a sustained systolic bulge several centimeters superior to the left ventricular impulse, sometimes termed an ectopic impulse. A double systolic outward thrust of the left ventricle is characteristic of patients with hypertrophic obstructive cardiomyopathy, who may also often exhibit a typical presystolic cardiac expansion, thus resulting in three separate outward movements of the chest wall during each cardiac cycle.[64] Constrictive pericarditis is characterized by systolic retraction of the chest, particularly of the ribs in the left axilla (Broadbent sign). This inward movement results from interference with the descent of the base of the heart and the compensatory exaggerated motion of the free wall of the left ventricle during ventricular ejection. [64] DIASTOLIC MOTION.

The outward motion of the apex characteristic of rapid left ventricular diastolic filling is most readily palpated with the patient in the left lateral decubitus position and in full exhalation. The outward motion is accentuated when the inflow of blood into the left ventricle is accelerated. This occurs in mitral regurgitation, when the volume of the left ventricle is increased or its function is impaired.[56] This motion is the mechanical equivalent of and occurs simultaneously with a third heart sound (S3 ). Prominent early diastolic left ventricular filling in constrictive pericarditis may be palpable. PRESYSTOLIC EXPANSION.

When the atrial contribution to ventricular filling is augmented, as occurs in patients with reduced left ventricular compliance associated with concentric left ventricular hypertrophy, myocardial ischemia, and myocardial fibrosis, a presystolic pulsation (usually accompanying a fourth heart sound [S4 ]) is palpable, resulting in a double outward movement of the left ventricular impulse. This presystolic expansion is most readily discernible during exhalation, when the patient is in the left lateral decubitus position, and it can be confirmed by detecting the motion of the stethoscope placed over the left ventricular impulse or by observing the motion of an X mark over the left ventricular impulse. Presystolic expansion of the left ventricle can be enhanced by sustained handgrip and is usually associated with marked elevation of left ventricular end-diastolic (rather than early diastolic) pressure. In patients with ischemic heart disease, presystolic pulsation is usually associated with a reduction in left ventricular compliance.[63] Presystolic expansion of the right ventricle occurs in right ventricular hypertrophy and pulmonary hypertension and may be appreciated by subxiphoid palpation of the right ventricle during inspiration. RIGHT VENTRICLE

Except in the first few months of life, neither this chamber, nor its motion, is palpable. A palpable anterior systolic movement (replacing systolic retraction) in the left parasternal region, best felt by the proximal palm or fingertips, and with the patient supine, usually represents right ventricular enlargement or hypertrophy. [65] In the absence of associated left ventricular enlargement, the right ventricular impulse is accompanied by reciprocal systolic retraction of the apex. In patients with pulmonary emphysema, even an enlarged right ventricle is not readily palpable at the left sternal edge but is better appreciated in the subxiphoid region. Exaggerated motion of the entire parasternal area (i.e., a hyperdynamic impulse with normal contour) usually reflects increased right ventricular contractility due to augmented stroke volume, as occurs in patients with atrial septal defect or tricuspid regurgitation. A sustained left parasternal outward thrust reflects right ventricular hypertrophy due to pressure overload, as occurs in pulmonary hypertension or pulmonic stenosis. With marked right ventricular enlargement, this chamber occupies the apex because the left ventricle is displaced posteriorly. PULMONARY ARTERY

Pulmonary hypertension and/or increased pulmonary blood flow frequently produce a prominent systolic pulsation of the pulmonary trunk in the second intercostal space just to the left of the sternum. This pulsation is often associated with a prominent left parasternal impulse, reflecting right ventricular enlargement, or with hypertrophy and a palpable shock synchronous with the second heart sound, reflecting forceful closure of the pulmonic valve. LEFT ATRIUM.

An enlarged left atrium or a large posterior left ventricular aneurysm can make right ventricular pulsations more prominent by displacing the right ventricle anteriorly against the left parasternal area; and in severe mitral regurgitation an expanding left atrium may be responsible for marked left parasternal movement, even in the absence of right ventricular hypertrophy. The systolic bulging of the left atrium, which is transmitted through the right ventricle, commences and terminates after the left ventricular thrust. Movement imparted by the systolic expansion of the left atrium can be appreciated by placing the index finger of one hand at the left ventricular apex and the index finger of the other in the left parasternal region in the third intercostal space; the movement of the latter finger begins and ends slightly later than that of the former. AORTA.

Enlargement or aneurysm of the ascending aorta or aortic arch may cause visible or palpable systolic pulsations of the right or left sternoclavicular joint and may also cause a systolic impulse in the suprasternal notch or the first or second right intercostal space.[1]

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THRILLS

The flat of the hand or the fingertips usually best appreciate thrills, which are vibratory sensations that are palpable manifestations of loud, harsh murmurs having low- to medium-frequency components.[66] Because the vibrations must be quite intense before they are felt, far more information can be obtained from the auscultatory than from the palpatory features of heart murmurs. High-pitched murmurs such as those produced by valvular regurgitation, even when loud, are not usually associated with thrills. PERCUSSION

Palpation is far more helpful than is percussion in determining cardiac size. However, in the absence of an apical beat, as in patients with pericardial effusion, or in some patients with dilated cardiomyopathy, heart failure, and marked displacement of a hypokinetic apical beat, the left border of the heart can be approximately outlined by means of percussion. Also, percussion of dullness in the right lower parasternal area may, in some instances, aid in the detection of a greatly enlarged right atrium. Percussion aids materially in determining visceral situs, that is, in ascertaining the side on which the heart, stomach, and liver are located. When the heart is in the right side of the chest but the abdominal viscera are located normally, congenital heart disease is usually present. When both the heart and abdominal viscera are in the opposite side of the chest (situs inversus), congenital heart disease is uncommon. CARDIAC AUSCULTATION Principles and Technique

The modern binaural stethoscope is a well-crafted, airtight instrument with earpieces selected for comfort, with metal tubing joined to single flexible 12-inch-long, thick-walled rubber tubing (internal diameter of 1/8 inch), and with dual chest pieces--diaphragm for high frequencies, bell for low or lower frequencies--designed so that the examiner can readily switch from one chest piece to the other.[67] [68] [69] [70] [71] When the bell is applied with just enough pressure to form a skin seal, low frequencies are accentuated; when the bell is pressed firmly, the stretched skin becomes a diaphragm, damping low frequencies. Variable pressure with the bell provides a range of frequencies from low to medium. Cardiac auscultation is best accomplished in a quiet room with the patient comfortable and the chest fully exposed. Palpation and percussion should precede auscultation to establish visceral and cardiac situs, so that auscultation can be carried out with confidence in the topographical anatomy of the heart. Terms such as "mitral area," "tricuspid area," "pulmonary area," and "aortic area" should be avoided because they assume situs solitus without ventricular inversion and with normally related great arteries. The topographical areas for auscultation (Fig. 4-10) , irrespective of cardiac

situs, are best designated by descriptive terms--cardiac apex, left and right sternal borders interspace by interspace, and subxiphoid. For patients in situs solitus with a left-sided thoracic heart, auscultation should begin at the cardiac apex (best identified in the left lateral decubitus) and contiguous lower left sternal edge (inflow), proceeding interspace by interspace up the left sternal border to the left base and then to the right base (outflow). In addition, the stethoscope should be applied regularly to the axillae, the back, the anterior chest on the opposite side, and above the clavicles. In patients with increased anteroposterior chest dimensions (emphysema), auscultation is often best achieved by applying the stethoscope in the epigastrium (subxiphoid). In auscultation, benefits are derived not only from knowledge of the cardiac situs but also from identification of palpable and visible movements of the ventricles. During auscultation, the examiner is generally on the patient's right; three positions are routinely employed: left lateral decubitus (assuming left thoracic heart), supine, and sitting. Auscultation should begin by applying the stethoscope to the cardiac apex with the patient in the left lateral decubitus position (Fig. 4-11) . If tachycardia makes identification

Figure 4-10 Maximal intensity and radiation of six isolated systolic murmurs. HCM=hypertrophic cardiomyopathy; MR=mitral regurgitation; Pulm=pulmonary; VSD=ventricular septal defect. (From Barlow JB: Perspectives on the Mitral Valve. Philadelphia, FA Davis, 1987, p 140.)

of S1 difficult, timing can be established, with few exceptions, by simultaneous palpation of the carotid artery with the thumb of the free left hand. Once the S 1 is identified, analysis then proceeds by systematic, methodical, sequential attention to early, mid, and late systole, S2 , then early, mid, and late diastole (presystole), and returning to S1 . When auscultation at the apex has been completed, the patient is turned into the supine position. Each topographical area--lower to upper left sternal edge interspace by interspace and then the right base--is interrogated using the same systematic sequence of analysis (Fig. 4-12) . Assessment of pitch or frequency ranging from low to moderately high can be achieved by variable pressure of the stethoscopic bell, whereas for high frequencies the diaphragm should be employed. It is practical to begin by using the stethoscopic bell with varying pressure at the apex and lower left sternal edge, changing to the diaphragm when the base is reached. Low frequencies are best heard by applying the bell just lightly enough to achieve a skin seal. High-frequency events are best elicited with firm pressure of the diaphragm, often with the patient sitting, leaning forward in full held exhalation.

Figure 4-11 The bell of the stethoscope is applied to the cardiac apex while the patient lies in a left lateral decubitus position. The thumb of the examiner's free left hand palpates the carotid artery (arrow) for timing purposes.

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Figure 4-12 The soft, high-frequency early diastolic murmur of aortic regurgitation or pulmonary hypertensive regurgitation is best elicited by applying the diaphragm of the stethoscope very firmly to the mid-left sternal edge (arrow) as the patient sits and leans forward with breath held in full exhalation. The Heart Sounds

Heart sounds are relatively brief, discrete auditory vibrations that can be characterized by intensity (loudness), frequency (pitch), and quality (timbre). S 1 identifies the onset of ventricular systole, and S2 identifies the onset of diastole. These two auscultatory events establish a framework within which other heart sounds and murmurs can be placed and timed.[1] [4] The basic heart sounds are the S1 , S2 , S3 , and S4 (Fig. 4-13 A). Each of these events can be normal or abnormal. Other heart sounds are, with few exceptions, abnormal, either intrinsically so or iatrogenic (e.g., prosthetic valve sounds, pacemaker sounds). A heart sound should first be characterized by a simple descriptive term that identifies where in the cardiac cycle the sound occurs. Accordingly, heart sounds within the framework established by S1 and S2 are designated as "early systolic, midsystolic, late systolic," and "early diastolic, mid-diastolic, late diastolic (presystolic)" (see Fig. 4-13) . [2] The next step is to draw conclusions based on what a sound so identified represents. For example, an early systolic sound might be an ejection sound (aortic or pulmonary) or an aortic prosthetic sound. Mid- and late systolic sounds are typified by the click(s) of mitral valve prolapse but occasionally are "remnants" of pericardial rubs. Early diastolic sounds are represented by opening snaps (usually mitral), an early S3 (constrictive pericarditis, less commonly mitral regurgitation), the opening of a mechanical inflow prosthesis, or the abrupt seating of a pedunculated mobile atrial myxoma ("tumor plop"). Mid-diastolic sounds are generally S3 or summation sounds (synchronous occurrence of S3 and S4 ). Late diastolic or presystolic sounds are almost always S4 sounds, rarely pacemaker sounds. First Heart Sound

S1 consists of two components (see Fig. 4-13 C). The initial component is most prominent at the cardiac apex when the apex is occupied by the left ventricle.[72] The second component, if present, is normally confined to the lower left sternal edge, is less commonly heard at the apex, and is seldom heard at the base. The first major component is associated with closure of the mitral valve and coincides with abrupt arrest of leaflet motion when the cusps--especially the larger and more mobile anterior mitral cusp--reach their fully closed positions. The origin of the second component of S1

has been debated but is generally assigned to closure of the tricuspid valve based on an analogous line of reasoning.[73] Opening of the semilunar valves with ejection of blood into the aortic root or pulmonary trunk usually produces no audible sound in the normal heart, although phonocardiograms sometimes record a low-amplitude sound following the mitral and tricuspid components and coinciding with the maximal opening excursion of the aortic cusps.[1] In complete right bundle branch block, S1 is widely split as a result of delay of the tricuspid component.[74] In complete left bundle branch block, S1 is single as a result of delay of the mitral component.[75] When S1 is split, its first component is normally louder. The softer second component is confined to the lower left sternal edge but may also be heard at the apex. Only the louder first component is heard at the base. The intensity of the S1 , particularly its first major audible component, depends chiefly on the position of the bellies of the mitral leaflets, especially the anterior leaflet, at the time the left ventricle begins to contract and less on the rate of left ventricular contraction.[76] S1 is therefore loudest when the onset of left ventricular systole finds the mitral leaflets maximally recessed into the left ventricular cavity, as in the presence of a rapid heart rate, a short PR interval [77] (Fig. 4-14) , short cycle lengths in atrial fibrillation, or mitral stenosis with a mobile anterior leaflet. When this mobility is lost the intensity of S1 decreases.

Figure 4-13 A, The basic heart sounds consist of the first heart sound (S 1 ), the second heart sound (S2 ), the third heart sound (S 3 ), and the fourth heart sound (S4 ). B, Heart sounds within the auscultatory framework established by S1 and S2 . The additional heart sounds are designated descriptively as early systolic (ES), midsystolic (MS), late systolic (LS), early diastolic (ED), mid-diastolic (MD), and late diastolic (LD) or presystolic. C, Upper tracing illustrates a low-frequency S 4 , and the lower tracing illustrates a split S 1 , the two components of which are of the same quality.

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Figure 4-14 Top, Phonocardiogram and electrocardiogram (lead 2) from a 12-year-old girl with congenital complete heart block. The first heart sound (S 1 ) varies from soft (long PR interval) to loud (short PR interval). There is a grade 2/6 vibratory midsystolic murmur (SM). A soft fourth heart sound (arrow) follows the second P wave. Bottom, Phonocardiogram and electrocardiogram from a 15-year-old boy with congenital complete heart block. Arrows point to independent P waves. The S 1 varies from loud to soft depending on the PR interval. The short diastolic murmurs (DM) are especially prominent when atrial contraction (P wave) coincides with and reinforces the rapid filling phase (shortly after the T wave). Early Systolic Sounds

Aortic or pulmonary ejection sounds are the most common early systolic sounds. [78] [79] "Ejection sound" is preferred to the term ejection "click," with the latter designation best

reserved for the mid- to late systolic clicks of mitral valve prolapse (see Chap. 46) . Ejection sounds coincide with the fully opened position of the relevant semilunar valve, as in congenital aortic valve stenosis (Fig. 4-15 A), bicuspid aortic valve in the left side of the heart, or pulmonary valve stenosis in the right side of the heart.[75] [77] Ejection sounds are relatively high frequency events and, depending on intensity, have a pitch similar to that of S1 . An ejection sound originating in the aortic valve (congenital aortic stenosis or bicuspid aortic valve) or in the pulmonary valve (congenital pulmonary valve stenosis) indicates that the valve is mobile because the ejection sound is caused by abrupt cephalad doming (see Fig. 4-15 B).[80] Less certain is the origin of an ejection sound within a dilated arterial trunk distal to a normal semilunar valve (Fig. 4-16 A). Origin of the sound is assigned either to opening movement of the leaflets that resonate in the arterial trunk or to the wall of the dilated great artery. Aortic ejection sounds do not vary with respiration. Pulmonary ejection sounds often selectively and distinctively decrease in intensity during normal inspiration (Fig. 4-17) . Early systolic sounds accompany mechanical prostheses in the aortic location, especially the Starr-Edwards ball-in-cage valve, less so with a tilting disc valve such as the Bjork-Shiley. Early systolic sounds do not occur with bioprosthetic valves (tissue valves) in either the aortic or pulmonary location.

Figure 4-15 A, Phonocardiogram over the left ventricular impulse in a patient with mild congenital bicuspid aortic valve stenosis. The aortic ejection sound (E) is louder than the first heart sound (S 1 ). A2 =aortic component of the second heart sound. B, Left ventriculogram (LV) in another patient with congenital aortic valve stenosis. The cephalad systolic doming of the stenotic valve (arrows) produces the ejection sound.

Figure 4-16 A, Tracings from a 32-year-old woman with an ostium secundum atrial septal defect, pulmonary hypertension, and a small right-to-left shunt. In the second left intercostal space (2LICS), the first heart sound is followed by a prominent pulmonary ejection sound (E). The second sound remains split. The pulmonic component (P 2 ) is very loud and is transmitted to the apex. CAR=carotid pulse. B, Phonocardiogram recorded in the left lateral decubitus position over the left ventricular impulse in a patient with pure rheumatic mitral stenosis. The first heart sound (S1 ) is loud. The second heart sound (S2 ) is followed by an opening snap (OS). There is a mid-diastolic murmur (MDM). The prominent presystolic murmur (PM) goes up to the subsequent loud S 1 .

Figure 4-17 Phonocardiogram from an 11-year-old girl with tetralogy of Fallot and pulmonary atresia. The upper tracing from the second right intercostal space (2RICS) shows an aortic ejection sound (E) that is prominent during exhalation (EXP) but absent during inspiration (INSP). S 1 =first heart sound.

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Mid- to Late Systolic Sounds

The most common mid- to late systolic sound(s) are associated with mitral valve prolapse[4] [81] (see Chap. 46) . The term "click" is appropriate because these mid- to late systolic sounds are of relatively high frequency. Mid- to late systolic clicks of mitral valve prolapse coincide with maximal systolic excursion of a prolapsed anterior leaflet (or scallop of the posterior leaflet) into the left atrium and are ascribed to sudden tensing of the redundant leaflet(s) and elongated chordae tendineae. Physical or pharmacological interventions that reduce left ventricular volume, such as the Valsalva maneuver, or a change in position from squatting to standing (Fig. 4-18) causes the click(s) to occur earlier in systole.[81] [82] Conversely, physical or pharmacological interventions that increase left ventricular volume, such as squatting or sustained hand grip, delay the click(s). Multiple clicks are thought to arise from asynchronous tensing of different portions of redundant mitral leaflets, especially the triscalloped posterior leaflet. The Second Heart Sound (Table 4-1)

S2 , like S1 , has two components. The first component of the second heart sound is designated "aortic" (A2 ) and the second "pulmonic" (P2 ) (Fig. 4-19) .[83] [84] Each component coincides with the incisura of its great arterial pressure pulse.

Figure 4-18 A midsystolic nonejection sound (C) occurs in mitral valve prolapse and is followed by a late systolic murmur that crescendos to the second heart sound (S 2 ). Standing decreases venous return; the heart becomes smaller; C moves closer to the first heart sound (S 1 ) and the mitral regurgitant murmur has an earlier onset. With prompt squatting, venous return increases; the heart becomes larger; C moves toward S 2 and the duration of the murmur shortens. (From Shaver JA, Leonard JJ, Leon DF: Examination of the Heart, Part IV, Auscultation of the Heart. Dallas, American Heart Association, 1990, p 13. Copyright 1990, American Heart Association.)

TABLE 4-1 -- CAUSES OF SPLITTING OF THE SECOND HEART SOUND NORMAL SPLITTING Delayed Pulmonic Closure Delayed electrical activation of the right ventricle Complete right bundle branch block (proximal type) Left ventricular paced beats Left ventricular ectopic beats Prolonged right ventricular mechanical systole Acute massive pulmonary embolus Pulmonary hypertension with right-sided heart failure

Pulmonic stenosis with intact septum (moderate to severe) Decreased impedance of the pulmonary vascular bed (increased hangout) Normotensive atrial septal defect Idiopathic dilatation of the pulmonary artery Pulmonic stenosis (mild) Atrial septal defect, postoperative (70%) Early Aortic Closure Shortened left ventricular mechanical systole (LVET) Mitral regurgitation Ventricular septal defect REVERSED SPLITTING Delayed Aortic Closure Delayed electrical activation of the left ventricle Complete left bundle branch block (proximal type) Right ventricular paced beats Right ventricular ectopic beats Prolonged left ventricular mechanical systole Complete left bundle branch block (peripheral type) Left ventricular outflow tract obstruction Hypertensive cardiovascular disease Arteriosclerotic heart disease Chronic ischemic heart disease Angina pectoris Decreased impedance of the systemic vascular bed (increased hangout) Poststenotic dilatation of the aorta secondary to aortic stenosis or insufficiency Patent ductus arteriosus Early Pulmonic Closure Early electrical activation of the right ventricle Wolff-Parkinson-White syndrome, type B LVET=left ventricular ejection time. Modified from Shaver JA, O'Toole JD: The second heart sound: Newer concepts. Parts 1 and 2. Mod Concepts Cardiovasc Dis 46:7 and 13, 1977. Inspiratory splitting of S2 is due chiefly to a delay in P2 , less to earlier timing of A2 .[85]

During inspiration, the pulmonary arterial incisura moves away from the descending limb of the right ventricular pressure pulse because of an inspiratory increase in capacitance of the pulmonary vascular bed, delaying P2 .[86] Exhalation has the opposite effect. The earlier inspiratory timing of A2 is attributed to a transient reduction in left ventricular volume coupled with unchanged impedance (capacitance) in the systemic vascular bed. Normal respiratory variations in the timing of S2 are therefore ascribed principally to the variations in impedance characteristics (capacitance) of the pulmonary vascular bed and secondarily to an inspiratory increase in right ventricular volume as originally proposed.[69] [72] When an increase in capacitance of the pulmonary bed is lost because of a rise in pulmonary vascular resistance, inspiratory splitting of S2 narrows and, if present at all, reflects an increase in right ventricular ejection time and/or earlier timing of A2 .[4] The frequency compositions of the aortic and pulmonary components of S2 are similar, but their normal amplitudes differ appreciably, the aortic component being the louder,

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Figure 4-19 Top, Normal physiological splitting. During expiration, the aortic (A 2 ) and pulmonic (P2 ) components of the second heart sound are separated by less than 30 milliseconds and are appreciated as a single sound. During inspiration, the splitting interval widens, and A 2 and P2 are clearly separated into two distinct sounds. Bottom, Audible expiratory splitting. In contrast to normal physiological splitting, two distinct sounds are easily heard during expiration. Wide physiological splitting is caused by a delay in P 2 . Reversed splitting is caused by a delay in A2 , resulting in paradoxical movement; that is, with inspiration P2 moves toward A 2 , and the splitting interval narrows. Narrow physiological splitting occurs in pulmonary hypertension, and both A 2 and P2 are heard during expiration at a narrow splitting interval because of the increased intensity and high-frequency composition of P 2 . (From Shaver JA, Leonard JJ, Leon DF: Examination of the Heart, Part IV, Auscultation of the Heart. Dallas, American Heart Association, 1990, p 17. Copyright 1990, American Heart Association.)

reflecting the differences in systemic (aortic) and pulmonary arterial closing pressures. Splitting of S2 is most readily identified in the second left intercostal space, because the softer P2 is normally confined to that site, whereas the louder A2 is heard at the base, sternal edge, and apex.[4] [83] ABNORMAL SPLITTING OF THE SECOND HEART SOUND.

Three general categories of abnormal splitting are recognized: (1) persistently single, (2) persistently split (fixed or nonfixed), and (3) paradoxically split (reversed). When S2 remains single throughout the respiratory cycle, one component is absent or the two components are persistently synchronous. The most common cause of a single S2 is inaudibility of the P2 in older adults with increased anteroposterior chest dimensions. In

the setting of congenital heart disease, a single S2 due to absence of the pulmonary component is a feature of pulmonary atresia, severe pulmonary valve stenosis, dysplastic pulmonary valve, or complete transposition of the great arteries (pulmonary component inaudible because of the posterior position of the pulmonary trunk). Conversely, a single S2 due to inaudibility of the A2 occurs when the aortic valve is immobile (severe calcific aortic stenosis) or atretic (aortic atresia). A single S 2 due to persistent synchrony of its two components is a feature of Eisenmenger syndrome with nonrestrictive ventricular septal defect, in which the aortic and pulmonary arterial incisurae are virtually identical in timing.[78] Both components of the S2 are sometimes inaudible at all precordial sites. This is likely to be so in older adults in whom fibrocalcific changes limit mobility of the aortic valve, whereas the pulmonary component is inaudible because of a large anteroposterior chest dimension (see earlier). A single semilunar valve, as in truncus arteriosus, does not necessarily generate what is judged on auscultation to be a single S2 . Instead, the S2 may be perceived as "split" because of asynchronous closure of the unequal cusps of a quadricuspid valve.[78] In systemic or pulmonary hypertension, the duration of a single loud S2 may be sufficiently prolonged and slurred (reduplicated) to encourage the mistaken impression of splitting. Persistent Splitting of S2 .

This term applies when the two components remain audible (or recordable) during both inspiration and exhalation (see Fig. 4-19) . Persistent splitting may be due to a delay in P2 , as in simple complete right bundle branch block,[72] or to early timing of the A2 , as occasionally occurs in mitral regurgitation. [87] Normal directional changes in the interval of the split (greater with inspiration, lesser with exhalation) in the presence of persistent audibility of both components defines the split as persistent but not fixed. Fixed Splitting of the S2 .

This term applies when the interval between the A2 and P2 is not only wide and persistent but also remains unchanged during the respiratory cycle.[72] Fixed splitting is an auscultatory hallmark of uncomplicated ostium secundum atrial septal defect (Fig. 4-20 (Figure Not Available) ; see Chaps. 43 and 44) . A2 and P2 are widely separated during exhalation and exhibit little or no change in the degree of splitting during inspiration or with the Valsalva maneuver. The wide splitting is caused by a delay in the P2 because a marked increase in pulmonary vascular capacitance prolongs the interval between the descending limbs of the pulmonary arterial and right ventricular pressure pulses ("hangout"), and therefore delays the pulmonary incisura and the P2 . The capacitance (impedance) of the pulmonary bed is appreciably increased, and the right ventricular stroke volume is not influenced by respiration, so there is little or no additional increase during inspiration and little or no inspiratory delay in the P2 . Phasic changes in systemic venous return during respiration in atrial septal defect are

associated with reciprocal changes in the volume of the left-to-right shunt, minimizing respiratory variations in right ventricular filling. The net effect is the characteristic wide, fixed splitting of the two components of the S2 .[78] Paradoxical (Reversed) Splitting of S2 .

This term refers to a reversed sequence of semilunar valve closure, the P 2 preceding the A2 .[72] Common causes of paradoxical splitting

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Figure 4-20 (Figure Not Available) Simultaneous base and apex phonocardiograms recorded with the carotid pulse during quiet respiration in a young woman with a large atrial septal defect. Wide fixed splitting of the second heart sound (S2 ) is present, and the pulmonic component (P2 ) is easily recorded at the apex. A prominent systolic ejection murmur (SEM) is recorded at the base and is attributable to the large stroke volume across the RV outflow tract. The tricuspid component of S 1 is prominent at the apex. EKG=electrocardiogram. (From Shaver JA: Innocent murmurs. Hosp Med 14:8-35, 1978. Copyright 1999, QUADRANT HEALTHCOM, INC.)

are complete left bundle branch block[88] or a right ventricular pacemaker, both of which are associated with initial activation of the right side of the ventricular septum, and delayed activation of the left ventricle owing to transseptal (right-to-left) depolarization.[89] When the S2 splits paradoxically, its two components separate during exhalation and become single (synchronous) during inspiration (see Fig. 4-19) . Inspiratory synchrony is achieved as the two components fuse because of a delay in the P2 , less to earlier timing of the aortic component. ABNORMAL LOUDNESS (INTENSITY) OF THE TWO COMPONENTS OF S2 .

Assessment of intensity requires that both components be compared when heard simultaneously at the same site. The relative softness of the normal P 2 is responsible for its localization in the second left intercostal space, whereas the relative loudness of the normal A2 accounts for its audibility at all precordial sites (see earlier). An increase in intensity of the A2 occurs with systemic hypertension. The intensity of the A2 also increases when the aorta is closer to the anterior chest wall, owing to root dilatation or transposition of the great arteries or when an anterior pulmonary trunk is small or absent, as in pulmonary atresia.[78] A loud P2 is a feature of pulmonary hypertension, and the loudness is enhanced by dilatation of a hypertensive pulmonary trunk. An accentuated P2 can be transmitted to the mid or lower left sternal edge and, when very loud, throughout the precordium to the apex and right base. A loud P2 in the second left interspace may obscure a closely preceding A2 . In this eventuality, auscultation at other precordial sites often identifies

the transmitted but attenuated P2 and allows detection of splitting. A moderate increase in loudness of the P2 sometimes occurs in the absence of pulmonary hypertension when the pulmonary trunk is dilated, as in ostium secundum atrial septal defect or when there is a decrease in anteroposterior chest dimensions (loss of thoracic kyphosis) that places the pulmonary trunk closer to the chest wall.[90] [91] Early Diastolic Sounds

The opening snap of rheumatic mitral stenosis is the best known early diastolic sound (see Fig. 4-16 B). The diagnostic value derived from the pitch, loudness, and timing of the opening snap in the assessment of rheumatic mitral stenosis was established by Wood in his classic monograph, An Appreciation of Mitral Stenosis.[92] An audible opening snap indicates that the mitral valve is mobile, at least its longer anterior leaflet.[93] The snap is generated when superior systolic bowing of the anterior mitral leaflet is rapidly reversed toward the left ventricle in early diastole in response to high left atrial pressure. The mechanism of the opening snap is therefore a corollary to the loud S1 (see Fig. 4-16 B), which is generated by abrupt superior systolic displacement of a mobile anterior mitral leaflet that was recessed into the left ventricle during diastole by high left atrial pressure until the onset of left ventricular isovolumetric contraction (see earlier). The designation "snap" is appropriate because of the relatively high frequency of the sound. The timing of the opening snap relative to the A2 has important physiological meaning.[4] A short A2 /opening snap interval generally reflects the high left atrial pressure of severe mitral stenosis. However, in older subjects with systolic hypertension, mitral stenosis of appreciable severity can occur without a short A2 /opening snap interval because the elevated left ventricular systolic pressure takes longer to fall below the left atrial pressure. In the presence of atrial fibrillation, the A 2 /opening snap interval varies inversely with cycle length, because (all else being equal) the higher the left atrial pressure (short cycle length), the earlier the stenotic valve opens and vice versa. Early diastolic sounds are not confined to the opening snap of rheumatic mitral stenosis but include the pericardial "knock" of chronic constrictive pericarditis.[94] [95] The term "knock" has also been applied to an early diastolic sound in pure severe mitral regurgitation with reduced left ventricular compliance. Both the "pericardial knock" and the "knock" of mitral regurgitation are rapid filling sounds that are early and loud because a high-pressure atrium rapidly decompresses across an unobstructed mitral valve into a recipient ventricle whose compliance is impaired. Early diastolic sounds are sometimes caused by atrial myxomas[96] (see Chap. 49) . The generation of such a sound, called a tumor "plop," requires a mobile myxoma attached to the atrial septum by a long stalk. The "plop" is believed to result from abrupt diastolic seating of the tumor within the right or left AV orifice.[96] An early diastolic sound can also be generated by the opening movement of a mechanical prosthesis in the mitral position. This opening sound is especially prominent

with a ball-in-cage prosthesis (Starr-Edwards) and less prominent with a tilting disc prosthesis (Bjork-Shiley). Mid-Diastolic and Late Diastolic (Presystolic) Sounds

Mid-diastolic sounds are, for all practical purposes, either normal or abnormal S 3 sounds, and most, if not all, late diastolic or presystolic sounds are S 4 sounds (Fig. 4-21) . Each sound coincides with its relevant diastolic filling phase.[97] In sinus rhythm, the ventricles receive blood during two filling phases. The first phase occurs when ventricular pressure drops sufficiently to allow the AV valve to open; blood then flows from atrium into ventricle. This flow coincides with the y descent of the atrial pressure pulse and is designated the "rapid filling phase," accounting for about 80 percent of normal ventricular filling. The rapid filling phase is not a passive event in which the recipient ventricle merely expands in response to augmented inflow volume. Rather, ventricular relaxation is an active, complex, energy-dependent process (see Chaps. 14 and 15) .

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Figure 4-21 Atrial pressure pulse showing the a wave and x descent and the v wave and y descent. The fourth heart sound (S4 ) coincides with the phase of ventricular filling after atrial contraction. The third heart sound (S 3 ) coincides with the y descent (the phase of rapid ventricular filling). S1 =first heart sound; S 2 =second heart sound.

S3 is generated during the rapid filling phase (see Fig. 4-21) .[98] The second filling phase--diastasis--is variable in duration, usually accounting for less than 5 percent of ventricular filling. The third phase of diastolic filling is in response to atrial contraction, which accounts for about 15 percent of normal ventricular filling. S4 is generated during the atrial filling phase (see Fig. 4-21) . Both S3 and S4 occur within the recipient ventricle as that chamber receives blood. The addition of either an S3 or an S4 to the cardiac cycle produces a triple rhythm. If both S 3 and S4 are present, a quadruple rhythm is produced. When diastole is short or the PR interval is long, S3 and S4 occur simultaneously to form a summation sound. [4] Children and young adults often have a normal (physiological) S3 but do not have a normal S4 .[99] A normal S3 sometimes persists beyond age 40 years, especially in women.[100] After that age, however, especially in men, S3 is likely to be abnormal.[101] An S4 is sometimes heard in healthy older adults without clinical evidence of heart disease, particularly after exercise.[102] Such observations have led to the conclusion, still debated, that such an S4 may be normal in the elderly.

Because an S4 requires active atrial contribution to ventricular filling, the sound disappears when coordinated atrial contraction ceases, as in atrial fibrillation. When the atria and ventricles contract independently as in complete heart block (see Fig. 4-14) , an S4 or summation sound occurs randomly in diastole because the relationship between the P wave and the QRS of the electrocardiogram is random. S3 and S4 are events caused by rapid ventricular filling, so obstruction of an AV valve, by impeding ventricular inflow, removes one of the prime preconditions for the generation of these filling sounds. Accordingly, the presence of an S3 or S4 implies an unobstructed (or relatively unobstructed) AV orifice on the side of the heart in which the sound originates. An S3 or S4 originating from the right ventricle often responds selectively and distinctively to respiration, becoming more prominent during inspiration.[4] The inspiratory increase in right atrial flow is converted into an inspiratory augmentation of both mid-diastolic and presystolic filling. S3 and S4 , either normal or abnormal, are relatively low-frequency events that vary considerably in intensity (loudness), that originate in either the left or right ventricle, and that are best elicited when the bell of the stethoscope is applied with just enough pressure to provide a skin seal. An S3 or S4 originating from the left ventricle should be sought over the left ventricular impulse identified with the patient in the left lateral decubitus position. An S3 or S4 originating from the right ventricle should be sought over the right ventricular impulse (lower left sternal edge, occasionally subxiphoid) with the patient supine. An understanding of these simple principles sets the stage for bedside detection. The same principles can be used with advantage to distinguish an S4 preceding a single S1 from splitting of the two components of the S1 (see Fig. 4-13 C). The two components of S1 are similar in frequency (pitch) although not in intensity (loudness) but differ in pitch from a preceding S4 . Selective pressure with the bell of the stethoscope enhances these distinctions. Audibility of S3 is improved by isotonic exercise that augments venous return and mid-diastolic AV flow. A few sit-ups usually suffice to produce the desired increase in venous return and acceleration in heart rate that increase the rate and volume of AV flow. Venous return can be increased by simple passive raising of both legs with the patient supine. The heart rate is also transiently increased by vigorous coughing. Left ventricular S4 , especially in patients with ischemic heart disease, can be induced or augmented when resistance to left ventricular discharge is increased by sustained hand-grip (isometric exercise, see later). In the presence of sinus tachycardia, atrial contraction may coincide with the rapid filling phase, making it impossible to determine whether a given filling sound is an S3 , an S4 , or a summation sound. Carotid sinus massage transiently slows the heart rate, so the diastolic sound or sounds can be assigned their proper timing in the cardiac cycle.[4] CAUSES OF S3 AND S4 .

The normal S3 is believed to be caused by sudden limitation of longitudinal expansion of the left ventricular wall during brisk early diastolic filling.[103] [104] [105] [106] [107] The majority of abnormal S3 sounds are generated by altered physical properties of the recipient ventricle and/or an increase in the rate and volume of AV flow during the rapid filling phase of the ventricle.[108] An abnormal S4 occurs when augmented atrial contraction generates presystolic ventricular distention (an increase in end-diastolic segment length) so that the recipient chamber can contract with greater force.[109] [110] [111] [112] Typical substrates are the left ventricular hypertrophy of aortic stenosis or systemic hypertension[113] or the right ventricular hypertrophy of pulmonary stenosis or pulmonary hypertension in the right side of the heart.[109] S4 sounds are also common in ischemic heart disease and are almost universal during angina pectoris or acute myocardial infarction because the atrial "booster pump" is needed to assist the relatively stiff ischemic ventricle.[114] A variation on the theme is the presystolic pacemaker sound. A pacemaker electrode in the apex of the right ventricle may produce a presystolic sound that is relatively high pitched and clicking and therefore different in pitch from an S4 . The presystolic pacemaker sound is believed to be extracardiac, resulting from contraction of chest wall muscle after spread of the electrical impulse from the pacemaker site. [115] [116] HEART MURMURS A cardiovascular murmur is a series of auditory vibrations that are more prolonged than a sound and are characterized according to timing in the cardiac cycle, intensity (loudness), frequency (pitch), configuration (shape), quality, duration, and direction of radiation. When these features are established, the stage is set for diagnostic conclusions.[2] [117] The principal causes of heart murmurs are listed in Table 4-2 . Intensity or loudness is graded from 1 to 6, based on the original recommendations of Samuel A. Levine in 1933.[118] A grade 1 murmur is so faint that it is heard only with special effort. A grade 2 murmur is soft but readily detected; a grade 3 murmur is prominent but not loud; a grade 4 murmur is loud (and usually accompanied by a thrill); a grade 5 murmur is very loud. A grade 6 murmur is loud enough to be heard with the stethoscope just removed from contact with the chest wall. Frequency or pitch varies from high to low. The configuration or shape of a murmur is best characterized as crescendo, decrescendo, crescendo-decrescendo (diamond-shaped), plateau (even), or variable

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TABLE 4-2 -- PRINCIPAL CAUSES OF HEART MURMURS A. Organic Systolic Murmurs

1. Midsystolic (ejection) a. Aortic (1) Obstructive (a) Supravalvular--supraaortic stenosis, coarctation of the aorta (b) Valvular--aortic stenosis and sclerosis (c) Infravalvular--HOCM (2) Increased flow, hyperkinetic states, aortic regurgitation, complete heart block (3) Dilatation of ascending aorta, atheroma, aortitis, aneurysm of aorta b. Pulmonary (1) Obstructive (a) Supravalvular--pulmonary arterial stenosis (b) Valvular--pulmonic valve stenosis (c) Infravalvular--infundibular stenosis (2) Increased flow, hyperkinetic states, left-to-right shunt (e.g., ASD, VSD) (3) Dilatation of pulmonary artery 2. Pansystolic (regurgitant) a. Atrioventricular valve regurgitation (MR, TR) b. Left-to-right shunt to ventricular level B. Early Diastolic Murmurs 1. Aortic regurgitation a. Valvular: rheumatic deformity; perforation postendocarditis, posttraumatic, postvalvulotomy b. Dilatation of valve ring: aorta dissection, annuloectasia, cystic medial necrosis, hypertension c. Widening of commissures: syphilis d. Congenital: biscuspid valve, with VSD 2. Pulmonic regurgitation a. Valvular: postvalvulotomy, endocarditis, rheumatic fever, carcinoid b. Dilatation of valve ring: pulmonary hypertension; Marfan syndrome c. Congenital: isolated or associated with tetralogy of Fallot, VSD, pulmonic stenosis C. Mid-Diastolic Murmurs 1. Mitral stenosis 2. Carey-Coombs murmur (mid-diastolic apical murmur in acute rheumatic fever) 3. Increased flow across nonstenotic mitral valve (e.g., MR, VSD, PDA, high-output states, and complete heart block)

4. Tricuspid stenosis 5. Increased flow across nonstenotic tricuspid valve (e.g., TR, ASD, and anomalous pulmonary venous return) 6. Left and right atrial tumors D. Continuous Murmurs 1. PDA 2. Coronary arteriovenous fistula 3. Ruptured aneurysm of sinus of Valsalva 4. Aortic septal defect 5. Cervical venous hum 6. Anomalous left coronary artery 7. Proximal coronary artery stenosis 8. Mammary souffle 9. Pulmonary artery branch stenosis 10. Bronchial collateral circulation 11. Small (restrictive) ASD with mitral stenosis 12. Intercostal arteriovenous fistula A and C, Modified from Oram S (ed): Clinical Heart Disease. London, Heinemann, 1981. D, Modified from Fowler NO (ed): Cardiac Diagnosis and Treatment. Hagerstown, MD, Harper & Row, 1980. HOCM=hypertrophic obstructive cardiomyopathy; ASD=atrial septal defect; VSD=ventricular septal defect; MR=mitral regurgitation; TR=tricuspid regurgitation; PDA=patent ductus arteriosus. From O'Rourke RA: Approach to the patient with a heart murmur. In Goldman L, Braunwald E (eds): Primary Cardiology. Philadelphia, WB Saunders, 1998, pp 155-173. (uneven). The duration of a murmur varies from short to long, with all gradations in between. A loud murmur radiates from its site of maximal intensity, and the direction of radiation is sometimes diagnostically useful. There are three broad categories of murmurs--systolic, diastolic, and continuous. A systolic murmur begins with or after S1 and ends at or before S2 on its side of origin. A diastolic murmur begins with or after S2 and ends before the subsequent S1 . A continuous murmur begins in systole and continues without interruption through the S2 into all or part of diastole. The following classification of murmurs is based on their timing relative to S1 and S2 .

Systolic Murmurs

Systolic murmurs are classified according to their time of onset and termination as midsystolic, holosystolic, early systolic, or late systolic (Fig. 4-22) [119] [120] A midsystolic murmur begins after S1 and ends perceptibly before S2 . The termination of a systolic murmur must be related to the relevant component of S2 . Accordingly, midsystolic murmurs originating in the left side of the heart end before A 2 ; midsystolic murmurs originating in the right side of the heart end before P 2 . A holosystolic murmur begins with S1 , occupies all of systole, and ends with the S2 on its side of origin. Holosystolic murmurs originating in the left side of the heart end with A2 , and holosystolic murmurs originating in the right side of the heart end with P2 . The term "regurgitant systolic murmur," originally applied to murmurs that occupied all of systole,[72] has fallen out of use because "regurgitation" can be accompanied by holosystolic, midsystolic, early systolic, or late systolic murmurs.[2] Similarly, the term "ejection systolic murmur," originally applied to midsystolic murmurs, should be discarded, because midsystolic murmurs are not necessarily due to "ejection."[4]

Figure 4-22 Systolic murmurs as illustrated here are descriptively classified according to their time of onset and termination as midsystolic, holosystolic, early systolic, and late systolic. The termination of the murmur must be related to the component of the second heart sound on its side of origin, that is, the aortic component (A 2 ) for systolic murmurs originating in the left side of the heart and the pulmonic component (P2 ) for systolic murmurs originating in the right side of the heart.

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MIDSYSTOLIC MURMURS.

Midsystolic murmurs occur in five settings: (1) obstruction to ventricular outflow, (2) dilatation of the aortic root or pulmonary trunk, (3) accelerated systolic flow into the aorta or pulmonary trunk, (4) innocent (normal) midsystolic murmurs, and (5) some forms of mitral regurgitation. The physiological mechanism of outflow midsystolic murmurs reflects the pattern of phasic flow across the left or right ventricular outflow tract as originally described by Leatham (Fig. 4-23) .[72] Isovolumetric contraction generates S1 . Ventricular pressure rises, the semilunar valve opens, flow commences, and the murmur begins. As flow proceeds, the murmur increases in crescendo; as flow decreases, the murmur decreases in decrescendo. The murmur ends before ventricular pressure drops below the pressure in the central great artery, at which time the aortic and pulmonary valves close, generating A2 and P2 . Aortic valve stenosis (see Chap. 46) is associated with a midsystolic murmur, which

may have an early systolic peak and a short duration, a relatively late peak and a prolonged duration, or all gradations in between. Whether long or short, however, the murmur retains a symmetrical diamond shape beginning after S 1 (or with an aortic ejection sound), rising in crescendo to a systolic peak, and declining in decrescendo to end before A2 . The high-velocity jet within the aortic root results in radiation of the murmur upward, to the right (second right intercostal space), and into the neck. An important variation occurs in older adults with previously normal trileaflet aortic valves rendered sclerotic or stenotic by fibrocalcific changes. The accompanying murmur in the second right intercostal space is harsh, noisy, and impure, whereas the murmur over the left ventricular impulse is pure and often musical (Fig. 4-24) . These two distinctive midsystolic murmurs--the noisy right basal and the musical apical--were described in 1925 by Gallavardin,[121] and the designation "Gallavardin dissociation" is still used. The impure right basal component of the murmur originates within the aortic root because of turbulence caused by the high-velocity jet. The pure musical component of the murmur heard over the left ventricular impulse originates from periodic high-frequency vibrations of the fibrocalcific aortic cusps. The musical apical midsystolic murmur is sometimes dramatically loud. The high-frequency apical midsystolic murmur of aortic sclerosis or stenosis should be distinguished from the high-frequency apical murmur of mitral regurgitation, a distinction that may be difficult or impossible, especially if A2 is

Figure 4-23 Illustration of the physiological mechanism of a midsystolic murmur generated by phasic flow into aortic root or pulmonary trunk. Ventricular (V) and great arterial (GA) pressure pulses are shown with phonocardiogram. The midsystolic murmur begins after the first heart sound (S 1 ), rises in crescendo to a peak as flow proceeds, then declines in decrescendo as flow diminishes, ending just before the second heart sound (S 2 ) as ventricular pressure falls below the pressure in the great artery.

soft or absent. However, when premature ventricular contractions are followed by pauses longer than the dominant cycle length, the apical midsystolic murmur of aortic stenosis or sclerosis increases in intensity in the beat after the premature contraction, whereas the intensity of the murmur of mitral regurgitation (whether midsystolic or holosystolic) remains relatively unchanged.[115] The same patterns hold after longer cycle lengths in atrial fibrillation. The murmur of pulmonary valve stenosis (see Chaps. 43 and 44) is prototypical of a midsystolic murmur originating in the right side of the heart. [78] The murmur begins after S1 or with a pulmonary ejection sound, rises in crescendo to a peak, then decreases in a slower decrescendo to end before a delayed or soft P2 . The length and configuration of the murmur are useful signs of the severity of obstruction. [78] When the ventricular septum is intact (Fig. 4-25 , left), as obstruction becomes more severe, the murmur lengthens and envelops A2 , and P2 becomes softer. When obstruction to right ventricular outflow is accompanied by a ventricular

Figure 4-24 A, Illustration of "Gallavardin dissociation" of the basal and apical murmurs associated with a fibrocalcific trileaflet aortic valve in older adults. The impure, noisy midsystolic murmur at the right base originates within the aortic root because of turbulence caused by the high-velocity jet. The pure, musical midsystolic murmur at the apex results from high-frequency vibrations originating in the fibrocalcific but mobile aortic cusps and radiates selectively into the left ventricular cavity (LV). B, Left ventricular intracardiac phonocardiogram of an older adult with calcific aortic stenosis on a previously normal trileaflet valve. The pure, musical midsystolic murmur (SM) is recorded over the apex of the left ventricle (LV). A prominent fourth heart sound (S4 ) coincides with presystolic distention of the left ventricle (lower vertical arrow). Upper vertical arrow identifies inaudible low-frequency vibrations preceding S 4 . S1 =first heart sound; S2 =second heart sound.

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Figure 4-25 Left, In valvular pulmonic stenosis with intact ventricular septum, right ventricular systolic ejection becomes progressively longer, with increasing obstruction to flow. As a result, the murmur becomes louder and longer, enveloping the aortic component of the second heart sound (A 2 ). The pulmonic component (P2 ) occurs later, and splitting becomes wider but more difficult to hear because A 2 is lost in the murmur and P2 becomes progressively fainter and lower pitched. As pulmonic diastolic pressure progressively decreases, isometric contraction shortens until the pulmonary valvular ejection sound fuses with the first heart sound (S 1 ). In severe pulmonic stenosis with concentric hypertrophy and decreasing right ventricular compliance, a fourth heart sound appears. Right, In tetralogy of Fallot with increasing obstruction at pulmonic infundibular area, an increasing amount of right ventricular blood is shunted across the silent ventricular septal defect and flow across the obstructed outflow tract decreases. Therefore, with increasing obstruction the murmur becomes shorter, earlier, and fainter. P 2 is absent in severe tetralogy of Fallot. A large aortic root receives almost all cardiac output from both ventricular chambers, and the aorta dilates and is accompanied by a root ejection sound that does not vary with respiration. (From Shaver JA, Leonard JJ, Leon DF: Examination of the Heart, Part 4, Auscultation of the Heart. Dallas, American Heart Association, 1990, p 45. Copyright 1990, American Heart Association.)

septal defect (tetralogy of Fallot), the midsystolic murmur becomes shorter with increased severity of obstruction (see Fig. 4-25 , right). Short, soft midsystolic murmurs originate within a dilated aortic root or dilated pulmonary trunk. Midsystolic murmurs are also generated by rapid ejection into a normal aortic root or pulmonary trunk, as during pregnancy, fever, thyrotoxicosis, or anemia. The pulmonary midsystolic murmur of ostium secundum atrial septal defect results from rapid ejection into a dilated pulmonary trunk (see Fig. 4-22) . Normal (innocent) systolic murmurs are, except for the systolic mammary souffle, all midsystolic. [78] The normal vibratory midsystolic murmur (Still murmur) is short, buzzing, pure, and medium in frequency (Fig. 4-26) and is believed to be generated by low-frequency periodic vibrations of normal pulmonary leaflets at their attachments or periodic vibrations of a left ventricular false tendon.[122] [123] A second type of innocent midsystolic murmur occurs in children, adolescents, and young adults and represents an exaggeration of normal ejection vibrations within the pulmonary trunk. This normal

pulmonary midsystolic murmur is relatively impure and is best heard in the second left intercostal space, in contrast to the vibratory

Figure 4-26 Four vibratory midsystolic murmurs (SM) from healthy children. These murmurs, designated "Still murmur," are pure, medium frequency, relatively brief in duration, and maximal along the lower left sternal border (LSB). The last of the four murmurs was from a 5-year-old girl who was febrile. After defervescence, the murmur decreased in loudness and duration.

midsystolic murmur of Still, which is typically heard between the lower left sternal edge and apex. Normal pulmonary midsystolic murmurs are also heard in patients with diminished anteroposterior chest dimensions (e.g., loss of thoracic kyphosis).[90] The most common form of "innocent" midsystolic murmur in older adults has been designated the "aortic sclerotic" murmur (see earlier). The cause of this functionally benign murmur is fibrous or fibrocalcific thickening of the bases of otherwise normal aortic cusps as they insert into the sinuses of Valsalva.[78] As long as the fibrous or fibrocalcific thickening is confined to the base of the leaflets, the free edges remain mobile. No commissural fusion and no obstruction occur. The Gallavardin dissociation phenomenon associated with such an aortic valve was described earlier. It is not uncommon for mitral regurgitation to generate a midsystolic murmur.[87] [124] The clinical setting is usually ischemic heart disease associated with left ventricular regional wall motion abnormalities. The physiological mechanism responsible for the midsystolic murmur of mitral regurgitation in this setting reflects impaired integrity of the muscular component of the mitral apparatus, with early systolic competence of the valve, and midsystolic incompetence, followed by a late systolic decline in regurgitant flow. These midsystolic murmurs are unrelated to "ejection." HOLOSYSTOLIC MURMURS.

Just as the term "midsystolic" is preferable to "ejection" systolic, the term "holosystolic" is preferable to "regurgitant" because holosystolic murmurs are not necessarily due to regurgitant flow. A holosystolic murmur begins with S1 and occupies all of systole up to the S2 on its side of origin (see Fig. 4-22) . [72] Such murmurs are generated by flow from a vascular bed whose pressure or resistance throughout systole is higher than the pressure or resistance in the vascular bed receiving the flow. Holosystolic murmurs occur in the left side of the heart with mitral regurgitation, in the right side of the

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Figure 4-27 Illustration of great arterial (GA), ventricular (VENT), and atrial pressure pulses with phonocardiogram showing the physiological mechanism of a holosystolic murmur in some forms of mitral

regurgitation and in high-pressure tricuspid regurgitation. Ventricular pressure exceeds atrial pressure at the very onset of systole, so regurgitant flow and murmur commence with the first heart sound (S 1 ). The murmur persists up to or slightly beyond the second heart sound (S 2 ) because regurgitation persists to the end of systole (ventricular pressure still exceeds atrial pressure). V=atrial v wave.

heart with high-pressure tricuspid regurgitation, between the ventricles through a restrictive ventricular septal defect, and between the great arteries through aortopulmonary connections. The timing of holosystolic murmurs reflects the physiological and anatomical mechanisms responsible for their genesis. Figure 4-27 illustrates the mechanism of the holosystolic murmur of mitral regurgitation or high-pressure tricuspid regurgitation. Ventricular pressure exceeds atrial pressure at the very onset of systole (isovolumetric contraction), so regurgitant flow begins with the S1 . The murmur persists up to or slightly beyond the relevant component of the S2 , provided that ventricular pressure at end systole exceeds atrial pressure and provided that the AV valve remains incompetent. Direction of radiation of the intraatrial jet of mitral regurgitation determines the chest wall distribution of the murmur. [87] [125] When the direction of the intraatrial jet is forward and medial against the atrial septum near the origin of the aorta, the murmur radiates to the left sternal edge, to the base, and even into the neck (Fig. 4-28) . When the flow generating the murmur of mitral regurgitation is directed posterolaterally within the left atrial cavity, the murmur radiates to the axilla, to the angle of the left scapula, and occasionally to the vertebral column, with bone conduction from the cervical to the lumbar spine. The murmur of tricuspid regurgitation is holosystolic when there is a substantial elevation of right ventricular systolic pressure, as schematically illustrated in Figure 4-27 . A distinctive and diagnostically important feature of the tricuspid murmur is its selective inspiratory increase in loudness--Carvallo sign.[126] The tricuspid murmur is occasionally audible only during inspiration. The increase in intensity occurs because the inspiratory augmentation in right ventricular volume is converted into an increase in stroke volume and in the velocity of regurgitant flow.[127] When the right ventricle fails, this capacity is lost; thus, Carvallo sign vanishes. The murmur of an uncomplicated restrictive ventricular septal defect (see Chap. 43) is holosystolic because left ventricular systolic pressure and systemic resistance exceed right ventricular systolic pressure and pulmonary resistance from the onset to the end of systole. Holosystolic murmurs are perceived as such in patients with large aortopulmonary connections (aortopulmonary window, patent ductus arteriosus) when a rise in pulmonary vascular resistance abolishes the diastolic portion of the continuous murmur, leaving a murmur that is holosystolic or nearly so.[78] EARLY SYSTOLIC MURMURS.

Murmurs confined to early systole begin with S1 , diminish in decrescendo, and end well

before S2 , generally at or before midsystole (see Fig. 4-22) . Certain types of mitral regurgitation, tricuspid regurgitation, or ventricular septal defects are the substrates. Acute severe mitral regurgitation is accompanied by an early systolic murmur or a holosystolic murmur that is decrescendo, diminishing if not ending before S2 (Fig. 4-29 A).[128] [129] The physiological mechanism responsible for this early systolic decrescendo murmur is acute severe regurgitation into a relatively normal-sized left atrium with limited distensibility. A steep rise in left atrial v wave approaches the left ventricular pressure at end systole; a late systolic decline in left ventricular pressure favors this tendency (see Fig. 4-29 B). The stage is set for regurgitant flow that is maximal in early systole and minimal in late systole.

Figure 4-28 Phonocardiograms illustrating wide radiation of the murmur of mitral regurgitation. A, The holosystolic murmur (SM) radiates from the apex to the second left intercostal space (2LICS) to the second right intercostal space (2RICS) and into the neck. S 1 =first heart sound; A 2 =aortic component of the second sound; P2 =pulmonic component of the second sound; S3 =third heart sound; MDM=mid-diastolic murmur; CAR=carotid pulse; DN=dicrotic notch. B, The murmur of mitral regurgitation radiates to the cervical spine, down the thoracic spine (T4-T5, T10) to the lumbar spine.

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Figure 4-29 A, Phonocardiogram recorded from the cardiac apex of a patient with acute severe mitral regurgitation due to ruptured chordae tendineae. There is an early systolic decrescendo murmur (SM) diminishing if not ending before the aortic component (A 2 ) of the second heart sound. P2 =pulmonic component of the second heart sound; S1 =first heart sound; S 3 =third heart sound. B, Left ventricular (LV) and left atrial (LA) pressure pulses with schematic illustration of the phonocardiogram showing the relationship between the decrescendo configuration of the early systolic murmur and late systolic approximation of the tall left atrial v wave and left ventricular end-systolic pressure. Regurgitant flow diminishes or ceases. The murmur therefore is early systolic and decrescendo, paralleling the hemodynamic pattern of regurgitation.

The systolic murmur parallels this pattern, declining or vanishing before S2 . An early systolic murmur is a feature of tricuspid regurgitation with normal right ventricular systolic pressure.[130] An example is tricuspid regurgitation caused by infective endocarditis in drug abusers. The mechanisms responsible for the timing and configuration of the early systolic murmur of low-pressure tricuspid regurgitation are analogous to those just described for mitral regurgitation. The crest of the right atrial v wave reaches the level of normal right ventricular pressure in latter systole; the regurgitation and murmur are therefore chiefly, if not exclusively, early systolic. These murmurs are of medium frequency because normal right ventricular systolic pressure generates comparatively low-velocity regurgitant flow in contrast to elevated right ventricular systolic pressure that generates a high-frequency holosystolic murmur (see

earlier). Early systolic murmurs also occur through ventricular septal defects, but under two widely divergent anatomical and physiological circumstances. A soft, pure, high-frequency, early systolic murmur localized to the mid- or lower left sternal edge is typical of a very small ventricular septal defect in which the shunt is confined to early systole.[78] A murmur of similar timing and configuration occurs through a nonrestrictive ventricular septal defect when an elevation in pulmonary vascular resistance decreases or abolishes late systolic shunting. LATE SYSTOLIC MURMURS.

The term "late systolic" applies when a murmur begins in mid- to late systole and proceeds up to the S2 (see Fig. 4-22) . The late systolic murmur of mitral valve prolapse is prototypical (see Figs. 4-18 and 4-30) .[131] [131A] One or more mid- to late systolic clicks often introduce the murmur. The responses of the late systolic murmur and clicks to postural maneuvers (see earlier discussion) are illustrated in Figure 4-18 . In response to a diminution in left ventricular volume, best achieved by prompt standing after squatting but also achieved by the Valsalva maneuver, the late systolic murmur becomes longer although softer.[82] In response to an increase in left ventricular volume associated with squatting or with sustained handgrip, the late systolic murmur becomes shorter but louder.[82] Pharmacological interventions that variably alter left ventricular volume, especially amyl nitrite (see Fig. 4-30) , produce analogous effects but are less practical at the bedside. The late systolic murmur of mitral valve prolapse is occasionally replaced by an intermittent, striking, and sometimes disconcerting systolic whoop or honk, either spontaneously or in response to physical maneuvers. The whoop is of high frequency, musical, widely transmitted, and occasionally loud enough to be disturbing to the patient.[132] The musical whoop is thought to arise from mitral leaflets and chordae tendineae set into high-frequency periodic vibration. SYSTOLIC ARTERIAL MURMURS.

Systolic murmurs can originate in anatomically normal arteries in the presence of normal or increased flow or in abnormal arteries because of tortuosity or luminal narrowing. Detection of systolic arterial murmurs requires auscultation at nonprecordial sites. Timing with S1 and S2 is imprecise because the murmurs begin at variable distances from the heart. Nevertheless, the arterial murmurs dealt with here are essentially systolic and tend to have a crescendo-decrescendo configuration that reflects the rise and fall of pulsatile arterial flow.[4] The "supraclavicular systolic murmur," often heard in children and adolescents, is believed to originate at the aortic origins of normal major brachiocephalic arteries. The configuration of these murmurs is crescendo-decrescendo, the onset is abrupt, the duration is brief, and the intensity at times is surprisingly loud with radiation below the clavicles. Normal supraclavicular systolic murmurs decrease or vanish in response to

hyperextension of the shoulders, which is achieved by bringing the elbows back until the shoulder girdle muscles are drawn taut. In older adults, the most common cause of a systolic arterial murmur is atherosclerotic narrowing of a carotid, subclavian, or iliofemoral artery. A variation on this theme is the "compression artifact" that can be induced in the femoral artery in the presence of free aortic regurgitation. When the femoral artery is moderately compressed by the examiner's stethoscopic bell, a systolic arterial murmur is generated. Further compression causes the systolic murmur to continue into diastole, a sign described in 1861 by Duroziez.[78] The eponym is still in use. A systolic "mammary souffle" is sometimes heard over the breasts because of increased flow through normal arteries during late pregnancy or more especially in the postpartum period in lactating women.[78] [133] The murmur begins well after S1 because of the interval between left ventricular ejection and arrival of flow at the artery of origin. A systolic arterial murmur is present in the interscapular region over the site of coarctation of the aortic isthmus.[78] Transient systolic arterial murmurs originating in the pulmonary artery and its branches are occasionally heard in normal neonates because the angulation and disparity in size between the pulmonary trunk and its branches set the stage for turbulent systolic flow. These normal or innocent pulmonary arterial systolic murmurs disappear with maturation of the pulmonary bed, generally within the first few weeks or months of life.[78] [134] Similar if not identical pulmonary arterial systolic murmurs

Figure 4-30 Phonocardiograms illustrating the response of the systolic clicks (C) and late systolic murmur (SM) of mitral valve prolapse to amyl nitrite inhalation. At 20 to 30 seconds, the clicks become earlier and the systolic murmur becomes longer but softer. At 50 seconds, the murmur is holosystolic and louder. M 1 =mitral component of the first heart sound; T 1 =tricuspid component of the first heart sound; A 2 =aortic component of the second heart sound; P2 =pulmonary component of the second sound.

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are generated at sites of congenital stenosis of the pulmonary artery and its branches. Rarely, a pulmonary arterial systolic murmur is caused by luminal narrowing after a pulmonary embolus.[109] Diastolic Murmurs

Diastolic murmurs are classified according to their time of onset as early diastolic, mid-diastolic, or late diastolic (presystolic) (Fig. 4-31) . An early diastolic murmur begins with A2 or P2 , depending on its side of origin. A mid-diastolic murmur begins at a clear

interval after S2 . A late diastolic or presystolic murmur begins immediately before S1 . EARLY DIASTOLIC MURMURS.

An early diastolic murmur originating in the left side of the heart occurs in aortic regurgitation (see Chap. 46) . This murmur is heard best with the diaphragm of the stethoscope, with the patient leaning forward and during a held, deep, exhalation (see Fig. 4-12) . The murmur begins with the aortic component of S2 (Fig. 4-32 A), that is, as soon as left ventricular pressure falls below the aortic incisura. The configuration of the murmur tends to reflect the volume and rate of regurgitant flow. In chronic aortic regurgitation of moderate severity, the aortic diastolic pressure consistently and appreciably exceeds left ventricular diastolic pressure, so the decrescendo is subtle and the murmur is well heard throughout diastole. In chronic severe aortic regurgitation, the decrescendo is more obvious, paralleling the dramatic decline in aortic root diastolic pressure. Selective radiation of the murmur of aortic regurgitation to the right sternal edge implies aortic root dilatation, as in Marfan syndrome. When an inverted cusp is set into high-frequency periodic vibration by aortic regurgitation, the accompanying murmur is musical, early diastolic, and decrescendo (see Fig. 4-32 B). The diastolic murmur of acute severe aortic regurgitation differs importantly from the murmur of chronic severe aortic regurgitation as just described[135] (Fig. 4-33) . When regurgitant flow is both sudden and severe (as may occur in

Figure 4-31 Diastolic murmurs are descriptively classified according to their time of onset as early diastolic, mid-diastolic, or late diastolic (presystolic). Diastolic murmurs originate in either the left or the right side of the heart.

infective endocarditis or aortic dissection), the diastolic murmur is relatively short because the aortic diastolic pressure rapidly equilibrates with the steeply rising diastolic pressure in the unprepared, nondilated left ventricle. The pitch of the murmur is likely to be medium rather than high because the velocity of regurgitant flow is less rapid than in chronic severe aortic regurgitation. This short, medium-frequency diastolic murmur of sudden severe aortic regurgitation may be quite soft (grade 2). These auscultatory features are in contrast to the long, pure, high-frequency,

Figure 4-32 A, Phonocardiogram recorded from the mid-left sternal edge of a patient with chronic pure severe aortic regurgitation. An early diastolic murmur (EDM) proceeds immediately from the aortic component (A2 ) of the second heart sound. The murmur has an early crescendo followed by a late long decrescendo. There is a prominent midsystolic flow murmur (SM) across an unobstructed aortic valve. B, Phonocardiogram in the third left intercostal space (3LICS) records a high-frequency, musical, early diastolic decrescendo murmur (EDM) caused by eversion of an aortic cusp. S 1 =first heart sound; SM=midsystolic murmur; A2 =aortic component of the second sound.

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Figure 4-33 Contrast between the auscultatory findings in chronic and acute aortic regurgitation. In chronic aortic regurgitation, a prominent systolic ejection murmur resulting from the large forward stroke volume is heard at the base and the apex and ends well before the second heart sound (S 2 ). The aortic diastolic regurgitant murmur begins with S 2 and continues in a decrescendo fashion, terminating before the first heart sound (S1 ). At the apex, the early diastolic component of Austin Flint murmur (AF) is introduced by a prominent third heart sound (S 3 ). A presystolic component of the AF is also heard. In acute aortic regurgitation there is a significant decrease in the intensity of the systolic ejection murmur compared with that of chronic aortic regurgitation because of the decreased forward stroke volume. The S 1 is markedly decreased in intensity because of preclosure of the mitral valve, and at the apex the presystolic component of the AF murmur is absent. The early diastolic murmur at the base ends well before S1 because of equilibration of the left ventricle and aortic end-diastolic pressures. Significant tachycardia is usually present. (From Shaver JA: Diastolic murmurs. Heart Dis Stroke 2:100, 1994.)

blowing and often loud (grade 4) early diastolic murmur of chronic severe aortic regurgitation (see Figs. 4-32 and 4-33) . The Graham Steell murmur of pulmonary hypertensive pulmonary regurgitation begins with a loud P2 because the elevated pressure exerted on the incompetent pulmonary valve begins at the moment that right ventricular pressure drops below the pulmonary arterial incisura. The high diastolic pressure generates high-velocity regurgitant flow and results in a high-frequency blowing murmur that may last throughout diastole. Because of the persistent and appreciable difference between pulmonary arterial and right ventricular diastolic pressures, the amplitude of the murmur is usually relatively uniform throughout most, if not all, of diastole. MID-DIASTOLIC MURMURS.

A mid-diastolic murmur begins at a clear interval after S2 (see Figs. 4-31 and 4-34) . The majority of mid-diastolic murmurs originate across mitral or tricuspid valves during the rapid filling phase of the cardiac cycle (AV valve obstruction or abnormal patterns of AV flow) or across an incompetent pulmonary valve in the absence of pulmonary hypertension. The mid-diastolic murmur of rheumatic mitral stenosis is a prime example.[136] [137] The murmur characteristically follows the mitral opening snap (see Fig. 4-16 B). Because the murmur originates within the left ventricular cavity, transmission to the chest wall is maximal over the left ventricular impulse. Care must be taken to place the bell of the stethoscope lightly against the skin precisely over the left ventricular impulse with the patient turned into the left lateral decubitus position (see Fig. 4-11) . Soft mid-diastolic murmurs are reinforced when the heart rate and mitral valve flow are transiently increased by vigorous voluntary coughs or a few sit-ups. In atrial fibrillation, the duration of the mid-diastolic murmur is a useful sign of the degree of obstruction at the mitral

orifice. A murmur that lasts up to S1 even after long cycle lengths indicates that the stenosis is severe enough to generate a persistent gradient even at the end of long diastoles. The mid-diastolic murmur of tricuspid stenosis occurs in the presence of atrial fibrillation. The tricuspid mid-diastolic murmur differs from the mitral mid-diastolic murmur in two important respects: (1) the loudness of the tricuspid murmur increases with inspiration, and (2) the tricuspid murmur is confined to a relatively localized area along the left lower sternal edge. The inspiratory increase in loudness occurs because inspiration is accompanied by an augmentation in right ventricular volume, by a fall in right ventricular

Figure 4-34 Diastolic filling murmur (rumble) in mitral stenosis. In mild mitral stenosis, the diastolic gradient across the valve is limited to the two phases of rapid ventricular filling in early diastole and presystole. The rumble may occur during either period or both periods. As the stenotic process becomes severe, a large pressure gradient exists across the valve during the entire diastolic filling period, and the rumble persists throughout diastole. As the left atrial pressure becomes greater, the interval between A 2 and the opening snap shortens. In severe mitral stenosis, secondary pulmonary hypertension develops and results in a loud P2 and the splitting interval usually narrows. ECG=electrocardiogram. (From Shaver JA, Leonard JJ, Leon DF: Examination of the Heart, Part IV, Auscultation of the Heart. Dallas, American Heart Association, 1990, p 55. Copyright 1990, American Heart Association.)

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Figure 4-35 Phonocardiogram recorded over the left ventricular impulse of a patient with pure mitral regurgitation. When regurgitant flow is augmented in response to a pressor amine, the holosystolic crescendo murmur (SM) becomes more prominent and a mid-diastolic flow murmur (MDM) appears.

diastolic pressure, and by an increase in gradient and flow rate across the stenotic tricuspid valve.[138] The murmur is localized to the lower left sternal edge because it originates within the inflow portion of the right ventricle and is transmitted to the overlying chest wall. Mid-diastolic murmurs across unobstructed AV valves occur in the presence of augmented volume and velocity of flow. Examples in the left side of the heart are the mid-diastolic flow murmur of pure mitral regurgitation (Fig. 4-35) and the mid-diastolic mitral flow murmur that accompanies a large left-to-right shunt through a ventricular septal defect (Fig. 4-36 A). Mid-diastolic murmurs due to augmented flow across unobstructed tricuspid valves are generated by severe tricuspid regurgitation or by a large left-to-right shunt through an atrial septal defect (see Fig. 4-36 B). These mid-diastolic murmurs indicate appreciable AV valve incompetence or large left-to-right shunts and are often preceded by an S3 , especially in the presence of mitral or tricuspid regurgitation.

Short, mid-diastolic AV flow murmurs occur intermittently in complete heart block when atrial contraction coincides with the phase of rapid diastolic filling (see Fig. 4-14) . These murmurs are believed to result from antegrade flow across AV valves that are closing rapidly during filling of the recipient ventricle.[136] A similar mechanism is believed to be responsible for the Austin Flint murmur (see Fig. 4-33) . [139] [140] [141] A mid-diastolic murmur is a feature of pulmonary valve regurgitation, provided that the pulmonary arterial pressure is not elevated (Fig. 4-37 A). The diastolic murmur typically begins at a perceptible interval after P2 is crescendo-decrescendo, ending well before the subsequent S1 . [78] The physiological mechanism responsible for the timing of this

Figure 4-36 A, Phonocardiogram recorded at the apex of a patient with a moderately restrictive ventricular septal defect and increased pulmonary arterial blood flow. The mid-diastolic murmur (DM) results from augmented flow across the mitral valve. SM=holosystolic murmur; S 1 =first heart sound; S 2 =second heart sound. B, Phonocardiogram at the lower left sternal edge of a patient with an ostium secundum atrial septal defect and increased pulmonary arterial blood flow. A mid-diastolic murmur (DM) resulted from augmented flow across the tricuspid valve. SM=midsystolic murmur; A 2 and P2 =aortic and pulmonic components of a conspicuously split S 2 .

murmur is shown in Figure 4-37 B. The diastolic pressure exerted on the incompetent pulmonary valve is negligible at the inception of P2 , so regurgitant flow is minimal. Regurgitation accelerates as right ventricular pressure dips below the diastolic pressure in the pulmonary trunk; at that point the murmur reaches its maximum intensity. Late diastolic equilibration of pulmonary arterial and right ventricular pressures eliminates regurgitant flow and abolishes the murmur before the next S1 . LATE DIASTOLIC OR PRESYSTOLIC MURMURS.

A late diastolic murmur occurs immediately before S1 , that is, in presystole (see Fig. 4-31) . With few exceptions, the late diastolic timing of the murmur coincides with the phase of ventricular filling that follows atrial systole and implies the presence of sinus rhythm and coordinated atrial contraction. Late diastolic or presystolic murmurs usually originate at the mitral or tricuspid orifice because of obstruction, but occasionally because of abnormal patterns of presystolic AV flow. The best known presystolic murmur accompanies rheumatic mitral stenosis in sinus rhythm as AV flow is augmented in response to an increase in the force of left atrial contraction (see Figs. 4-16 B and 4-38A). [92] Presystolic accentuation of a mid-diastolic murmur is occasionally heard

Figure 4-37 A, Phonocardiogram illustrating the mid-diastolic murmur (DM) of low-pressure pulmonary regurgitation in a heroin addict who had pulmonary valve infective endocarditis. The murmur begins well

after the second heart sound (S2 ) and is of medium frequency and mid-diastolic, ending well before the subsequent first heart sound (S1 ). B, Pressure pulses and phonocardiogram illustrate the physiological mechanism of the mid-diastolic murmur of low-pressure pulmonary regurgitation. Because the pressure exerted against the incompetent pulmonary valve is low, the murmur does not begin until well after the right ventricular (RV) and pulmonary arterial (PA) pressure pulses diverge. The murmur is maximal when the diastolic gradient (cross-hatched area) is greatest. After an early diastolic dip in the RV pressure pulse, there is equilibration of the PA and RV pressures in later diastole, so the regurgitant gradient is abolished and the murmur disappears.

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Figure 4-38 A, Phonocardiogram from the cardiac apex of a patient with pure rheumatic mitral stenosis. A presystolic murmur (PM) rises in a crescendo that is interrupted by a loud first heart sound (S 1 ). S2 =second heart sound; OS=mitral opening snap. B, Phonocardiogram from the lower left sternal edge of a patient with rheumatic tricuspid stenosis. The first cycle is during inspiration and is accompanied by a prominent presystolic murmur (PM) that is crescendo-decrescendo, decreasing before the S 1 . During exhalation (second cycle), the presystolic murmur all but vanishes.

in mitral stenosis with atrial fibrillation, especially during short cycle lengths[142] [143] ; but the timing is actually early systolic, and the mechanism differs from the true presystolic murmur as described earlier and as shown in Figure 4-38 A. In tricuspid stenosis with sinus rhythm, a late diastolic or presystolic murmur typically occurs in the absence of a perceptible mid-diastolic murmur (see Fig. 4-38 B). This is so because the timing of tricuspid diastolic murmurs reflects the maximal acceleration of flow and gradient, which is usually negligible until powerful right atrial contraction.[138] The presystolic murmur of tricuspid stenosis is crescendo-decrescendo and relatively discrete, fading before S1 (see Fig. 4-38 B). This is in contrast to the presystolic murmur of mitral stenosis, which tends to rise in a crescendo up to S1 (see Fig. 4-38 A). The most valuable auscultatory sign of tricuspid stenosis in sinus rhythm is the effect of respiration on the intensity of the presystolic murmur (see Figs. 4-38 and 4-39) . Inspiration increases right atrial volume, provoking an increase in right atrial

Figure 4-39 Pressure pulses and phonocardiogram illustrating the physiological mechanism of the respiratory variation in the presystolic murmur of tricuspid stenosis. During inhalation, a fall in intrathoracic pressure and an increase in systemic venous return result in an increase in the right atrial (RA) A wave and a decline in right ventricular (RV) end-diastolic pressure, so the presystolic murmur (PSM) increases in loudness. During exhalation, the right atrial A wave declines, the RV diastolic pressure increases, the tricuspid gradient is at its minimum, and the PSM all but vanishes.

contractile force that coincides with a fall in right ventricular end-diastolic pressure. The result is an increase in the tricuspid gradient, in the velocity of tricuspid flow, and in the intensity of the tricuspid stenotic presystolic murmur (see Fig. 4-39) .[138]

Short, crescendo-decrescendo presystolic murmurs are occasionally heard in complete heart block when atrial contraction falls in late diastole. However, the murmur is usually mid-diastolic, as already described, occurring when atrial contraction coincides with and reinforces the rapid filling phase of the cardiac cycle (see Fig. 4-16) . In 1862, Austin Flint described a presystolic murmur in patients with aortic regurgitation and proposed a mechanism that was astonishingly perceptive.[139] [140] [141] [144] [145] "Now in cases of considerable aortic insufficiency, the left ventricle is rapidly filled with blood flowing back from the aorta as well as from the auricle, before the auricular contraction takes place. The distention of the ventricle is such that the mitral curtains are brought into coaptation; and when the auricular contraction takes place, the mitral direct current passing between the curtains throws them into vibration and gives rise to the characteristic blubbering murmur."[139] Continuous Murmurs

The term "continuous" appropriately applies to murmurs that begin in systole and continue without interruption through S2 into all or part of diastole (Fig. 4-40) . The presence of murmurs throughout both phases of the cardiac cycle (holosystolic followed by holodiastolic) is not the criterion for the designation "continuous." Conversely, a murmur that fades completely before the subsequent S1 may be continuous, provided that the systolic portion of the murmur proceeds without interruption through S 2 . Continuous murmurs are generated by uninterrupted flow from a vascular bed of higher pressure or resistance into a vascular bed of lower pressure or resistance without phasic interruption between systole and diastole. Such murmurs are due chiefly to (1) aortopulmonary connections, (2) arteriovenous connections, (3) disturbances of flow patterns in arteries, and (4) disturbances of flow patterns in veins (Table 4-3) . The best known continuous murmur is associated with the aortopulmonary connection of patent ductus arteriosus (Fig. 4-41) (see Chaps. 43 and 44) . The murmur characteristically peaks just before and after S 2 , which it envelops, decreases in late diastole (often appreciably), and may be soft or even absent before the subsequent first heart sound.[78] George Gibson's description in 1900 was even more precise.[146] "It persists through S2 and dies away gradually during the long pause. The murmur is rough and thrilling. It begins softly and increases in intensity so as to reach its acme just about, or immediately after, the incidence of the second sound, and from that point gradually wanes until its termination" (see Fig. 4-41) .

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Figure 4-40 Comparison of the continuous murmur and the to-fro murmur. During abnormal

communication between high-pressure and low-pressure systems, a large pressure gradient exists through the cardiac cycle, producing a continuous murmur. A classic example is patent ductus arteriosus. At times this type of murmur is confused with a to-fro murmur, which is a combination of systolic ejection murmur and a murmur of semilunar valve incompetence. A classic example of a to-fro murmur is aortic stenosis and regurgitation. A continuous murmur crescendos to around the second heart sound (S 2 ), whereas a to-fro murmur has two components. The midsystolic ejection component decrescendos and disappears as it approaches S 2 . (From Shaver JA, Leonard JJ, Leon DF: Examination of the Heart, Part IV, Auscultation of the Heart. Dallas, American Heart Association, 1990, p 55. Copyright 1990, American Heart Association. ARTERIOVENOUS CONTINUOUS MURMURS.

These can be congenital or acquired and are represented in part by arteriovenous fistulas, coronary arterial fistulas, anomalous origin of the left coronary artery from the pulmonary trunk, and sinus of Valsalva-to-right side of heart communications.[78] The configuration, location, and intensity of arteriovenous continuous murmurs vary considerably among these different lesions. Acquired systemic arteriovenous fistulas are created surgically by forearm shunts for hemodialysis. Congenital arteriovenous continuous murmurs occur when a coronary arterial fistula enters the pulmonary trunk, right atrium, or right ventricle. At the latter site, the continuous murmur can be either softer or louder in systole, depending on the degree of compression exerted on the fistulous coronary artery by right ventricular contraction.[78] Rupture of a congenital aortic sinus aneurysm into the right side of the heart results in a continuous murmur that tends to be louder in either systole or diastole, sometimes creating a to-and-fro impression. [78] ARTERIAL CONTINUOUS MURMURS.

These originate in either constricted or nonconstricted arteries. A common example of a continuous murmur arising in a constricted artery is carotid or femoral arterial atherosclerotic obstruction. Not surprisingly, these murmurs are characteristically louder in systole and more often than not are purely systolic. Disturbances of flow patterns in normal, nonconstricted arteries sometimes produce continuous murmurs. The "mammary souffle" described earlier,[133] an innocent murmur heard during late pregnancy and the puerperium, is an arterial murmur that, when continuous, is typically louder in systole and maximal over either lactating breast. A distinct gap separates the S1 from the onset of the mammary souffle because of the relatively long interval that elapses before blood ejected from the left ventricle arrives at the artery of origin.[78] Light pressure with the stethoscope tends to augment the murmur and bring out its continuous features, whereas firm pressure with the stethoscope or by digital compression adjacent to the site of auscultation often abolishes the murmur. Continuous murmurs in nonconstricted arteries originate in the large systemic-to-pulmonary arterial collaterals in certain types of cyanotic congenital heart disease, typically tetralogy of Fallot with pulmonary atresia. These continuous murmurs are randomly located throughout the thorax because of the random location of the aortopulmonary collaterals.[78]

CONTINUOUS VENOUS MURMURS.

These are well represented by the innocent cervical venous hum (Fig. 4-42) . The hum is by far the most common type of normal continuous murmur, universal in healthy children, and frequently present in healthy young adults, especially during pregnancy. Thyrotoxicosis and anemia, by augmenting cervical venous flow, initiate or reinforce the venous hum. The term "hum" does not necessarily characterize the quality of these cervical venous murmurs, which may be rough and noisy and are occasionally accompanied by a high-pitched whine.[78] The hum is truly continuous, although typically louder in diastole, as is generally the case with venous continuous murmurs. The mechanism of the venous hum is unsettled. Silent laminar flow in the internal jugular vein may be disturbed by deformation of the vessel at the level of the transverse process of the atlas during head rotation designed to elicit the hum.[147] Approach to the Patient with a Heart Murmur

Although a careful physical examination with emphasis on detailed auscultation is useful in establishing a cardiac diagnosis, or excluding serious cardiac disease, echocardiography is decisive in confirming the diagnosis and determining the severity of the condition (Fig. 4-43) . As delineated by O'Rourke,[148] the approach to the patient with a heart murmur depends on its intensity, timing, location, response to maneuvers, and the presence of other cardiac and noncardiac symptoms and signs. Patients with diastolic murmurs, or continuous murmurs that are not cervical venous TABLE 4-3 -- DIFFERENTIAL DIAGNOSIS OF CONTINUOUS THORACIC MURMURS (IN ORDER OF FREQUENCY) DIAGNOSIS KEY FINDINGS Cervical venous hum

Disappears on compression of the jugular vein

Hepatic venous hum

Often disappears with epigastric pressure

Mammary souffle

Disappears on pressing hard with stethoscope

Patent ductus arteriosus

Loudest at second left intercostal space

Coronary arteriovenous fistula

Loudest at lower sternal borders

Ruptured aneurysm of sinus of Valsalva

Loudest at upper right sternal border, sudden onset

Bronchial collaterals

Associated signs of congenital heart disease High-grade coarctation Brachial pedal arterial pressure gradient

Anomalous left coronary artery arising from Electrocardiographic changes of pulmonary artery myocardial infarction Truncus arteriosus Pulmonary artery branch stenosis

Heard outside the area of cardiac dullness

Pulmonary arteriovenous fistula

Same as above

Atrial septal defect with mitral stenosis or atresia

Altered by the Valsalva maneuver

Aortic-atrial fistulas Adapted from Sapira JD: The Art and Science of Bedside Diagnosis. Baltimore, Urban & Schwartzenberg, 1990.

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Figure 4-41 The classic continuous murmur of patent ductus arteriosus recorded from within the main pulmonary artery (upper tracing) and simultaneously on the chest wall at the second left intercostal space (2LICS). The murmur "begins softly and increases in intensity so as to reach its acme just about, or immediately after, the incidence of the second sound, and from that point gradually wanes until its termination," as originally described by Gibson in 1900. [ 146]

hums, or mammary souffles of pregnancy, should ordinarily go to two-dimensional and Doppler echocardiography, and subsequent work-up, including cardiac consultation, is guided by the echocardiographic findings. In general, echocardiography is also advised for patients with systolic murmurs having the following characteristics: (1) loud murmur (i.e., grade 3); (2) holosystolic or late systolic murmur, especially at the left sternal edge or apex; (3) systolic murmurs that become louder or longer during the strain of the Valsalva maneuver (suggesting the diagnosis of hypertrophic obstructive cardiomyopathy or mitral valve prolapse respectively; see p. 76); (4) other systolic murmurs in patients with clinical findings suggesting infective endocarditis (see Chap. 47) , thromboembolism, or syncope; (5) a systolic murmur accompanied by an abnormal electrocardiogram. According to this schema, a large majority of patients with heart murmurs (i.e., patients with grade 1 or grade 2 midsystolic murmurs) without any other clinical manifestations

Figure 4-42 The phonocardiogram shows the continuous murmur of a normal venous hum. The diastolic component is louder (paired arrows). Digital pressure over the right internal jugular vein (vertical arrow) abolishes the murmur. The photographs show maneuvers used to elicit or abolish the venous hum. Left, The bell of the stethoscope is applied to the medial aspect of the right supraclavicular fossa as the examiner's left hand grasps the patient's chin from behind and pulls it tautly to the left and upward,

stretching the neck. Right, The patient's head has returned to a more neutral position, and digital compression of the right internal jugular vein (arrow) abolishes the hum.

of cardiac disease ordinarily do not require extensive work-up. Pericardial Rubs (see Chap. 50)

In sinus rhythm, the typical pericardial rub is triple phased, that is, midsystolic, mid-diastolic, and presystolic. Recognition is simplest when all three phases are present and when the characteristic superficial scratchy, leathery quality is evident. Pericardial rubs may be more readily detected when the patient is on elbows and knees (Fig. 4-44) , a physical maneuver designed to increase the contact

Figure 4-43 An approach to the evaluation of a heart murmur that also uses the results of the electrocardiogram (ECG), chest radiograph, and echocardiogram in asymptomatic patients with soft midsystolic murmurs and no other physical findings. This algorithm is useful in patients older than age 40 years in whom the prevalence of coronary artery disease and aortic stenosis increases as the cause of systolic murmurs. (From O'Rourke RA: Approach to the patient with a heart murmur. In Goldman L, Braunwald E [eds]: Primary Cardiology. Philadelphia, WB Saunders, 1998, pp 155-173.)

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Figure 4-44 A technique for eliciting a pericardial rub. The diaphragm of the stethoscope is firmly applied to the precordium (arrow) while the patient rests on elbows and knees.

of visceral and parietal pericardium (see earlier). The term "rub" is appropriate because the auscultatory sign is generated by abnormal visceral and parietal pericardial surfaces "rubbing" against each other. In the supine position, firm pressure with the stethoscopic diaphragm during full held exhalation reinforces visceral and parietal pericardial contact and accentuates the rub. Apposition of visceral and parietal pericardium can be even better achieved by examination while the patient rests on elbows and knees. Of the three phases of the pericardial rub, the systolic phase is the most consistent, followed by the presystolic phase. In atrial fibrillation, the presystolic component necessarily disappears. The diagnosis of a pericardial rub is least secure when only one phase remains, which is typically the midsystolic. The most common clinical setting in which pericardial rubs are heard is immediately after open heart surgery. However, auscultation often detects instead a "crunch" synchronous with the heartbeat, especially in the left lateral decubitus position. This is not a pericardial rub but is Hamman sign caused by air in the mediastinum.[149] Pericardial rubs are frequently audible in acute pericarditis. They may become softer or even disappear in the presence of a large pericardial effusion.




Dynamic Auscultation Dynamic auscultation refers to the technique of altering circulatory dynamics by a variety of physiological and pharmacological maneuvers and determining the effects of these maneuvers on heart sounds and murmurs.[150] [151] [152] [153] The conditions and interventions most commonly employed in dynamic auscultation include respiration, postural changes, the Valsalva maneuver, premature ventricular contractions, isometric exercise, and one of the vasoactive agents--amyl nitrite, methoxamine, or phenylephrine. The clinical applications of dynamic auscultation are summarized in Table 4-4 . RESPIRATION SECOND HEART SOUND.

The splitting of S2 is most audible along the left sternal border and can usually be appreciated when A2 and P2 are separated by more than 0.02 second. The effects of respiration on the splitting of the second heart sound are discussed on p. 60. DIASTOLIC SOUNDS AND EJECTION SOUNDS.

When S3 and S4 originate from the right ventricle, they are characteristically augmented during inspiration and diminished during exhalation, whereas they exhibit the opposite response when they originate from the left side of the heart. Like other left-sided events, the opening snap of the mitral valve may become softer during inspiration and louder during exhalation owing to respiratory alterations in venous return, whereas the opening snap of the tricuspid valve behaves in the opposite fashion. Inspiration also diminishes

the intensity of ejection sounds in pulmonary valve stenosis because the elevation of right ventricular diastolic pressure causes partial presystolic opening of the pulmonary valve and therefore less upward motion of the valve during systole. On the other hand, respiration does not affect the intensity of aortic ejection sounds, except in tetralogy of Fallot with pulmonary atresia. MURMURS.

Respiration exerts more pronounced and consistent alterations on murmurs originating from the right than from the left side of the heart. During inspiration, the diastolic murmurs of tricuspid stenosis (see Fig. 4-39) and low pressure pulmonary regurgitation, the systolic murmurs of tricuspid regurgitation [154] (Carvallo sign), and the presystolic murmur of Ebstein anomaly may all be accentuated. The inspiratory reduction in left ventricular size in patients with mitral valve prolapse increases the redundancy of the mitral valve and therefore the degree of valvular prolapse; consequently, the midsystolic click and the systolic murmurs occur earlier during systole and may become accentuated.[155] THE VALSALVA MANEUVER.

This maneuver consists of a relatively deep inspiration followed by forced exhalation against a closed glottis for 10 to 20 seconds. The patient should first be instructed on how to perform the maneuver. Simulation by the examiner is a simple means of doing so. The examiner then places the flat of the hand on the abdomen to provide the patient with a force against which to strain and to permit assessment of the degree and duration of the straining effort.[156] [157] [158] The normal response to the Valsalva maneuver consists of four phases. Phase I is associated with a transient rise in systemic arterial pressure as straining commences. Phase II is accompanied by a perceptible decrease in systemic venous return, systolic pressure, and pulse pressure (small pulse) and by reflex tachycardia. Phase III begins promptly with cessation of straining and is associated with an abrupt, transient decrease in arterial pressure. Phase IV is characterized by an overshoot of systemic arterial pressure and reflex bradycardia. During phase II, S3 and S4 are attenuated and the A2 -P2 interval narrows or is abolished (Fig. 4-45) . As stroke volume and systemic arterial pressure fall, the systolic murmurs of aortic and pulmonary stenosis and of mitral and tricuspid regurgitation diminish and the diastolic murmurs of aortic and pulmonary regurgitation and of tricuspid and mitral stenosis soften. As left ventricular volume is reduced, the systolic murmur of hypertrophic obstructive cardiomyopathy amplifies and the click and late systolic murmur of mitral valve prolapse begin earlier. In phase III, the sudden increase in systemic venous return is accompanied by wide splitting of the S2 and by augmentation of murmurs and filling sounds in the right side of the heart. Murmurs and filling sounds in the left side of the heart return to control levels and may transiently increase during the overshoot of phase IV. In patients with atrial septal defect, mitral stenosis, or heart failure, the Valsalva maneuver provokes a "square

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TABLE 4-4 -- RESPONSE OF MURMURS AND HEART SOUNDS TO PHYSIOLOGICAL AND PHARMACOLOGICAL INTERVENTIONS CLINICAL INTERVENTION AND RESPONSE DISORDER Systolic Murmurs Aortic outflow obstruction Valvular aortic stenosis

Louder with passive leg-raising, with sudden squatting, with Valsalva release (after five to six beats), following a pause induced by a premature beat, or after amyl nitrite; fades during Valsalva strain and with isometric handgrip

Hypertrophic obstructive cardiomyopathy

Louder with standing, during Valsalva strain, or with amyl nitrite; fades with sudden squatting, recumbency, or isometric handgrip

Pulmonic stenosis

Midsystolic murmur increases with amyl nitrite except with marked right ventricular hypertrophy; also increases during first few beats after Valsalva release

Mitral regurgitation Rheumatic

Murmur louder with sudden squatting, isometric handgrip, or phenylephrine; softens with amyl nitrite

Mitral valve prolapse Midsystolic click moves toward S1 and late systolic murmur starts earlier with standing, Valsalva strain, and amyl nitrite; click may occur earlier on inspiration; murmur starts later and click moves toward S2 during squatting, with recumbency, and often after pause induced by a premature beat Papillary muscle dysfunction

Late systolic murmur generally softer after a pause induced by a premature beat; response to amyl nitrite variable, depending on acute or chronic nature of this disorder

Tricuspid regurgitation

Murmur increases during inspiration, with passive leg-raising, and with amyl nitrite

Ventricular septal defect Small defect with pulmonary hypertension

Fades with amyl nitrite; increases with isometric handgrip or phenylephrine

Large defect with hyperkinetic pulmonary hypertension

Louder with amyl nitrite; fades with phenylephrine

Large defect with severe pulmonary vascular disease

Little change with any of above interventions

Tetralogy of Fallot

Murmur softens with amyl nitrite

Supraclavicular bruit

Altered by compression of subclavian artery; may be eliminated by extension of ipsilateral shoulder

Diastolic Murmurs Aortic regurgitation

Increases with sudden squatting, isometric handgrip, or phenylephrine

Blowing diastolic murmur Austin Flint murmur Pulmonary regurgitation Congenital

Fades with amyl nitrite Early or mid-diastolic rumble increases on inspiration and with amyl nitrite High-frequency blowing murmur not altered by above interventions

Pulmonary hypertension Mitral stenosis

Mid-diastolic and presystolic murmurs louder with exercise, left lateral position, coughing, isometric handgrip, or amyl nitrite; phenylephrine widens A2 /OS interval; inspiration produces sequence of A2 /P2 /OS

Tricuspid stenosis

Mid-diastolic and presystolic murmurs increase during inspiration, with passive leg-raising, and with amyl nitrite

Continuous Murmurs Patent ductus arteriosus

Diastolic phase amplified with isometric handgrip or phenylephrine; diastolic phase fades with amyl nitrite

Cervical venous hum

Obliterated by direct compression of jugular veins or by Valsalva strain

Added Heart Sounds Gallop rhythm Ventricular gallop (S3 Accentuated by lying flat with passive leg-raising; decreased ) and atrial gallop (S4 by standing or during Valsalva; right-sided gallop sounds usually increase during inspiration; left-sided during expiration )

Summation gallop

Separates into ventricular gallop (S3 ) and atrial gallop (S4 ) sounds when heart rate slowed by carotid sinus massage

Ejection sounds

Ejection sound in pulmonary stenosis fades and occurs closer to the first sound during inspiration

OS=opening snap of mitral valve. From Criscitiello MG: Physiologic and pharmacologic aids in cardiac auscultation. In Fowler NO (ed): Cardiac Diagnosis and Treatment. Hagerstown, MD, Harper & Row, 1980. wave" response, negating the four phases and their auscultatory equivalents. The Valsalva maneuver should not be performed in patients with ischemic heart disease because of the accompanying fall in coronary blood flow. THE MULLER MANEUVER.

This maneuver is the converse of the Valsalva maneuver but is less frequently employed because it is not as useful.[81] In this maneuver the patient forcibly inspires while the nose is held closed and the mouth is firmly sealed for about 10 seconds. The Muller maneuver exaggerates the inspiratory effort, widens the split S2 , and augments murmurs and filling sounds originating in the right side of the heart.

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Figure 4-45 Changes in four left-sided systolic murmurs during the strain phase of the Valsalva maneuver. (From Grewe K, Crawford MH, O'Rourke RA: Differentiation of cardiac murmurs by auscultation. Curr Probl Cardiol 13:669, 1988.)

POSTURAL CHANGES AND EXERCISE (See Fig. 4-46.) Sudden assumption of the lying from the standing or sitting position or sudden passive elevation of both legs results in an increase in venous return, which augments first right ventricular and, several cardiac cycles later, left ventricular stroke volume. The principal auscultatory changes include widening of the splitting of S2 in all phases of respiration and augmentations of right-sided S3 and S4 and, several cardiac cycles later, left-sided S3 and S4 . The systolic murmurs of pulmonic valve stenosis and aortic stenosis, the systolic murmurs of mitral and tricuspid regurgitation and ventricular septal defect, and most functional systolic murmurs are augmented. On the other hand, because left ventricular end-diastolic volume is increased, the systolic murmur of hypertrophic obstructive cardiomyopathy is diminished and the midsystolic click and late systolic murmur associated with mitral valve prolapse are delayed and sometimes attenuated

(see Fig. 4-18 and p. 68). Rapid standing or sitting up from a lying position or rapid standing from a squatting posture has the opposite effect; in patients in whom there is relatively wide splitting of S 2 during exhalation--a finding that may be confused with fixed splitting--the width of the splitting is reduced, so that a normal pattern emerges during the respiratory cycle. No change in splitting occurs in patients with true fixed splitting. The decrease in venous return reduces stroke volume and innocent pulmonary flow murmurs as well as the murmurs of semilunar valve stenosis and of AV valve regurgitation. The auscultatory changes in hypertrophic cardiomyopathy and mitral valve prolapse are opposite to those on assumption of the lying posture just described. SQUATTING.

A sudden change from standing to squatting increases venous return and systemic resistance simultaneously. Stroke volume and arterial pressure rise, and the latter may induce a transient reflex bradycardia. The auscultatory features include augmentation of S3 and S4 (from both ventricles) and as a consequence of an increase in stroke volume, the systolic murmurs of pulmonary and aortic stenosis and the diastolic murmurs of tricuspid and mitral stenosis become louder, with right-sided events preceding left-sided events. Squatting may make audible a previously inaudible murmur of aortic regurgitation. The elevation of arterial pressure increases blood flow through the right ventricular outflow tract of patients with tetralogy of Fallot and increases the volume of mitral regurgitation and of the left-to-right shunt through a ventricular septal defect, thereby increasing the intensity of the systolic murmur in these conditions. Also, the diastolic murmur of aortic regurgitation is augmented consequent to an increase in aortic reflux. The combination of elevated arterial pressure and increased venous return increases left ventricular size, which reduces the obstruction to outflow and thus the intensity of the systolic murmur of hypertrophic obstructive cardiomyopathy, the midsystolic click and the late systolic murmur of mitral valve prolapse are delayed. OTHER POSITIONAL CHANGES.

Assumption of the left lateral recumbent position accentuates the intensity of S1 , S3 , and S4 originating from the left side of the heart; the opening snap and the murmurs associated with mitral stenosis and regurgitation; the midsystolic click and late systolic murmur of mitral valve prolapse; and the Austin Flint murmur associated with aortic regurgitation. Sitting up and leaning forward (see Fig. 4-12) make the diastolic murmurs of aortic and pulmonary regurgitation more readily audible. Hyperextension of the shoulders is an important positional maneuver that assists in assessing supraclavicular systolic murmurs. The mechanism responsible for diminution in the intensity of normal supraclavicular systolic murmurs with hyperextension of the shoulders is apparently related to the effect of the maneuver on the site of origin of the murmurs in the proximal brachiocephalic arteries as they leave the aortic arch.

Stretching the neck to elicit a venous hum is illustrated in Figure 4-42 . Passive elevation of the legs with the patient supine transiently increases venous return and augments S3 . ISOMETRIC EXERCISE.

This can be carried out simply and reproducibly using a calibrated handgrip device or hand ball. (It is useful to carry out isometric exercise bilaterally simultaneously.) Isometric exercise should be avoided in patients with ventricular arrhythmias and myocardial ischemia, both of which can be intensified by this activity. Handgrip should be sustained for 20 to 30 seconds, but a Valsalva maneuver during the handgrip must be avoided. Isometric exercise results in transient but significant increases in systemic vascular resistance, arterial pressure, heart rate, cardiac output, left ventricular filling pressure, and heart size. As a consequence, (1) S3 and S4 originating from the left side of the heart become accentuated, (2) the systolic murmur of aortic stenosis is diminished as a result of reduction of the pressure gradient across the aortic valve,[158] [159] (3) the diastolic murmur of aortic regurgitation and the systolic murmurs of rheumatic mitral regurgitation and ventricular septal defect increase in intensity, (4) the diastolic murmur of mitral stenosis becomes louder consequent to the increase in cardiac output, and (5) the systolic murmur of hypertrophic obstructive cardiomyopathy diminishes and the systolic click and late systolic murmur of mitral valve prolapse are delayed because of the increased left ventricular volume.

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Figure 4-46 Diagrammatic representation of the character of the systolic murmur and of the second heart sound in five conditions. The effects of posture, amyl nitrite inhalation, and phenylephrine injection on the intensity of the murmur are shown. (Modified from Barlow JB: Perspectives on the Mitral Valve. Philadelphia, FA Davis, 1987, p 138.)

PHARMACOLOGICAL AGENTS (See Fig. 4-46.) Inhalation of amyl nitrite is carried out by placing an ampule in gauze near the supine patient's nose and then crushing the ampule. The patient is asked to take three or four deep breaths over 10 to 15 seconds, after which the amyl nitrite is removed. The drug produces marked vasodilatation, resulting in the first 30 seconds in a reduction of systemic arterial pressure and 30 to 60 seconds later in a reflex tachycardia, followed in turn by a reflex increase in cardiac output, velocity of blood flow, and heart rate. [4] [150] [151] [152] [153] [160] The major auscultatory changes occur in the first 30 seconds after inhalation. S1 is augmented, and A2 is diminished. The opening snaps of the mitral and tricuspid valves become louder, and as arterial pressure falls, the A2 /opening snap interval shortens. An S3 originating in either ventricle is augmented, owing to greater rapidity of ventricular filling; but because mitral regurgitation is reduced, the S 3

associated with this lesion is diminished. The systolic murmurs of aortic valve stenosis, pulmonary stenosis, hypertrophic obstructive cardiomyopathy, tricuspid regurgitation, and functional systolic murmurs are all accentuated. In patients with tetralogy of Fallot, the reduction of arterial pressure increases the right-to-left shunt and decreases the blood flow from the right ventricle to the pulmonary artery and diminishes the midsystolic murmur. The increase in cardiac output augments the diastolic murmurs of mitral and tricuspid stenosis and of pulmonary regurgitation and the systolic murmur of tricuspid regurgitation. However, as a result of the fall in systemic arterial pressure, the systolic murmurs of mitral regurgitation and ventricular septal defect, the diastolic murmurs of aortic regurgitation, and the Austin Flint murmur as well as the continuous murmurs of patent ductus arteriosus and of systemic arteriovenous fistula are all diminished.[158] The reduction of cardiac size results in an earlier appearance of the midsystolic click and late systolic murmur of mitral valve prolapse; the intensity of the systolic murmur exhibits a variable response. The response to amyl nitrite is useful in distinguishing (1) the systolic murmur of aortic stenosis (which is augmented) from that of mitral regurgitation (which is diminished),[160] (2) the systolic murmur of tricuspid regurgitation (augmented) from that of mitral regurgitation (diminished), (3) the systolic murmur of isolated pulmonary stenosis (augmented) from that of tetralogy of Fallot (diminished), (4) the diastolic rumbling murmur of mitral stenosis (augmented) from the Austin Flint murmur of aortic regurgitation (diminished), and (5) the early blowing diastolic murmur of pulmonary regurgitation (augmented) from that of aortic regurgitation (diminished). Methoxamine and phenylephrine increase systemic arterial pressure and exert an effect opposite to that of amyl nitrite. In general, methoxamine, 3 to 5 mg intravenously, elevates arterial pressure by 20 to 40 mm Hg for 10 to 20 minutes, but phenylephrine is preferred because of its shorter duration of action; 0.3 to 0.5 mg of phenylephrine administered intravenously elevates systolic pressure by approximately 30 mm Hg for only 3 to 5 minutes. Both drugs cause reflex bradycardia and decreased contractility and cardiac output. They should not be used in the presence of congestive heart failure and systemic hypertension. After administration, the intensity of S1 is usually reduced, and the A2 /mitral opening snap interval becomes prolonged. The responses of S3 and S4 are variable. As a

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result of the increased arterial pressure, the diastolic murmur of aortic regurgitation, the systolic murmurs of mitral regurgitation (see Fig. 4-35) , ventricular septal defect, and tetralogy of Fallot, and the continuous murmurs of patent ductus arteriosus and systemic arteriovenous fistula all become louder. On the other hand, as a consequence of the increase in left ventricular size, the systolic murmur of hypertrophic obstructive cardiomyopathy becomes softer and the click and late systolic murmur of mitral valve prolapse are delayed. The reduction in cardiac output diminishes the systolic murmur of

aortic valve stenosis, functional systolic murmurs, and the diastolic murmur of mitral stenosis. The rumbling diastolic murmurs of mitral regurgitation and the Austin Flint murmur also diminish.




REFERENCES THE GENERAL PHYSICAL EXAMINATION Mangione S, Nieman LZ, Gracely E, et al: The teaching and practice of cardiac auscultation during internal medicine and cardiology training: A nationwide survey. Ann Intern Med 119:47, 1993. 1.

2.

Shaver JA: Cardiac auscultation: A cost-effective diagnostic skill. Curr Probl Cardiol 20:441, 1995.

3.

Marriott HJL: Bedside Cardiac Diagnosis. Philadelphia, JB Lippincott, 1993.

Perloff JK: Physical Examination of the Heart and Circulation. 3rd ed. Philadelphia, WB Saunders, 2000. 4.

5.

Sapira JD: The Art and Science of Bedside Diagnosis. Baltimore, Urban & Schwartzenberg, 1990.

6.

Constant J: Bedside Cardiology. 4th ed. Boston, Little, Brown & Co, 1993.

Swartz MH (ed): Textbook of Physical Diagnosis: History and Examination. 3rd ed. Philadelphia, WB Saunders, 1998. 7.

Brady PM, Zive MA, Goldberg RJ, et al: A new wrinkle to the earlobe crease. Arch Intern Med 147:65, 1987. 8.

Kirkham N, Murrels T, Melcher SH, Morrison EA: Diagonal ear lobe creases and fatal cardiovascular disease: A necropsy study. Br Heart J 61:361, 1989. 9.

10.

Allen SJ, Naylor D: Pulsation of the eyeballs in tricuspid regurgitation. Can Med Assoc J 133:119,

1985. Byrd MD: Lateral systolic pulsation of the earlobe: A sign of tricuspid regurgitation. Am J Cardiol 54:244, 1984. 11.

Criscitiello MG, Ronan JA, Besterman EM, Schoenwetter W: Cardiovascular abnormalities in osteogenesis imperfecta. Circulation 31:255, 1965. 12.

Woywodt A, Welzel J, Haase H, et al: Cardiomyopathic lentiginosis/LEOPARD syndrome presenting as sudden cardiac arrest. Chest 113:1415, 1998. 13.

Basson CT, Cowley GS, Solomon SD, et al: The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome). N Engl J Med 330:885, 1994; erratum, N Engl J Med 330:1627, 1994. 14.

Buckley MJ, Mason DT, Ross J Jr, Braunwald E: Reversed differential cyanosis with equal desaturation of the upper limbs: Syndrome of complete transposition of the great vessels with complete interruption of the aortic arch. Am J Cardiol 15:111, 1965. 15.

16.

Finger clubbing. Lancet 1:1285, 1975.

Lanken PN, Fishman AP: Clubbing and hypertrophic osteoarthropathy. In Fishman AP (ed): Pulmonary Diseases and Disorders. New York, McGraw-Hill, 1980, pp 84-91. 17.

Yee J, McAllister CK: The utility of Osler's nodes in the diagnosis of infective endocarditis. Chest 92:751, 1987. 18.

Braunwald E: Edema. In Braunwald E, et al (eds): Harrison's Principles of Internal Medicine. 15th ed. New York, McGraw-Hill, 2001. 19.

Quigley PM, Haller JA Jr, Jelus KL, et al: Cardiorespiratory function before and after corrective surgery in pectus excavatum. J Pediatr 128:638, 1996. 20.

Willekes CL, Backer CL, Mavroudis C: A 26-year review of pectus deformity repairs, including simultaneous intracardiac repair. Ann Thorac Surg 67:511-518, 1999. 21.

Fonkalsrud EW, Bustorff-Silva J: Repair of pectus excavatum and carinatum in adults. Am J Surg 177:121-124, 1999. 22.

23.

Coralli RJ, Crawley IS: Hepatic pulsations in constrictive pericarditis. Am J Cardiol 58:370, 1986.

Ewy GA: The abdominojugular test: Technique and hemodynamic correlates. Ann Intern Med 109:456, 1988. 24.

Ducas J, Magder S, McGregor M: Validity of the hepatojugular reflux as a clinical test for congestive heart failure. Am J Cardiol 52:1299, 1983. 25.

26.

Swartz MH: Jugular venous pressure pulse: Its value in cardiac diagnosis. Prim Cardiol 8:197, 1982.

Stojnic BB, Brecker SJ, Xiao HB, Gibson DG: Jugular venous "a" wave in pulmonary hypertension: New insights from a Doppler echocardiographic study. Br Heart J 68:187, 1992. 27.

28.

Cook DJ: The clinical assessment of central venous pressure. Am J Med Sci 299:175-178, 1990.

Butman SM, Ewy GA, Standen JR, et al: Bedside cardiovascular examination in patients with severe chronic heart failure: Importance of rest or inducible jugular venous distension. J Am Coll Cardiol 22:968, 1993. 29.

Maisel AS, Atwood JE, Goldberger AL: Hepatojugular reflux: Useful in the bedside diagnosis of tricuspid regurgitation. Ann Intern Med 101:781, 1984. 30.

31.

Petrie JC, et al: Recommendations on blood pressure measurement. BMJ 293:611, 1986.

Frohlich ED, et al: Recommendations for human blood pressure determination by sphygmomanometers: Report of a special task force appointed by the steering committee, American Heart Association. Circulation 77:501a, 1988. 32.

Linfors EW, Feussner JR, Blessing CL, et al: Spurious hypertension in the obese patient: Effect of sphygmomanometer cuff size on prevalence of hypertension. Arch Intern Med 144:1482, 1984. 33.

Manning DM, Kuchirka C, Kaminski J: Miscuffing: Inappropriate blood pressure cuff application. Circulation 68:763, 1983. 34.

35.

Nelson WP, Egbert AM: How to measure blood pressure accurately. Prim Cardiol 10:14, 1984.

Londe S, Klitzner TS: Auscultatory blood pressure measurement: Effect of pressure on the head of the stethoscope. West J Med 141:193, 1984. 36.

Gould BA, Hornung RS, Kieso HA, et al: Is the blood pressure the same in both arms? Clin Cardiol 8:423, 1985. 37.

Mancia G, Grassi G, Pomidossi G, et al: Effects of blood-pressure measurement by the doctor on patient's blood pressure and heart rate. Lancet 2:695, 1983. 38.

Sapira JD: Quincke, de Musset, Duroziez, and Hill: Some aortic regurgitations. South Med J 74:459, 1981. 39.

40.

Schlant RC, Feiner JM: The arterial pulse: Clinical manifestations. Curr Probl Cardiol 1(5), 1976.

Perloff JK: The physiologic mechanisms of cardiac and vascular physical signs. J Am Coll Cardiol 1:184, 1983. 41.

42.

Smith D, Craige E: Mechanism of the dicrotic pulse. Br Heart J 56:531, 1986.

Moriya S, Iga Y, Konishi T: Dicrotic pulse observed in a patient with prolapse of the aortic valve without aortic regurgitation. Heart Vessels 12:250, 1997. 43.

44.

Talley JD: Dicrotism: Examples and review of the dicrotic pulse. J Ark Med Soc 92:507, 1996.

Elkins RC, Morrow AG, Vasko JS, Braunwald E: The effects of mitral regurgitation on the pattern of instantaneous aortic blood flow: Clinical and experimental observations. Circulation 36:45, 1967. 45.

Talley JD: Recognition, etiology, and clinical implications of pulsus bisferiens. Heart Dis Stroke 3:309, 1994. 46.

Morpurgo M, Boutarin J: Right-sided pulsus alternans: A neglected phenomenon. Cardiologia 40:803-806, 1995. 47.

48.

Lab MJ, Seed WA: Pulsus alternans. Cardiovasc Res 27:1407, 1993.

Rosenthal E: Extreme pulsus alternans presenting as 2:1 electromechanical dissociation. Br Heart J 74:695, 1995. 49.

Brockenbrough EC, Braunwald E, Morrow AG: A hemodynamic technic for the detection of hypertrophic subaortic stenosis. Circulation 23:189, 1961. 50.

51.

Fowler NO: Pulsus paradoxus. Heart Dis Stroke 3:68, 1994.

Pearson MG, Spence DP, Ryland I, Harrison BD: Value of pulsus paradoxus in assessing acute severe asthma. BMJ 307:659, 1993. 52.

Massumi RA, Mason DT, Zakauddin V, et al: Reversed pulsus paradoxus. N Engl J Med 289:1272, 1973. 53.

54.

Linhart J: Bedside examination of peripheral vascular disease. Eur Heart J 4:137, 1983.

THE CARDIAC EXAMINATION 55.

Davies H: Chest deformities in congenital heart disease. Br J Dis Chest 53:151, 1959.

Perloff JK: Diagnostic inferences drawn from observation and palpation of the precordium with special reference to congenital heart disease. Adv Cardiopulm Dis 4:13, 1969. 56.

Beiser GD, Epstein SE, Stampfer M, et al: Impairment of cardiac function in patients with pectus excavatum. N Engl J Med 287:267, 1972. 57.

Abrams J: Precordial palpation. In Horwitz LD, Groves BM (eds): Signs and Symptoms in Cardiology. Philadelphia, JB Lippincott, 1985, pp 156-177. 58.

59.

O'Neill TW, Smith M, Barry M, Graham IM: Diagnostic value of the apex beat. Lancet 1:410, 1989.

Eilen SD, Crawford MH, O'Rourke RA: Accuracy of precordial palpation for detecting increased left ventricular volume. Ann Intern Med 99:628, 1983. 60.

Bancroft WH Jr, Eddleman EE Jr, Larkin LN: Methods and physical characteristics of the kineto-cardiographic and apex cardiographic systems for recording low-frequency precordial motion. Am Heart J 73:756, 1967. 61.

Ellen SD et al: Accuracy of precordial palpation for detecting increased left ventricular volume. Ann Intern Med 99:628, 1983. 62.

Ranganathan N, Juma Z, Sivaciyan V: The apical impulse in coronary heart disease. Clin Cardiol 8:20, 1985. 63.

64.

Dressler W: Clinical Aids in Cardiac Diagnosis. New York, Grune & Stratton, 1970.

80

65.

Gillam PMS, et al: The left parasternal impulse. Br Heart J 26:726, 1964.

Counihan TB, Rappaport MB, Sprague HB: Physiologic and physical factors that govern the clinical appreciation of cardiac thrills. Circulation 4:716, 1951. 66.

Kindig JR, Beeson TP, Campbell RW, et al: Acoustical performance of the stethoscope: A comparative analysis. Am Heart J 104:269, 1982. 67.

68.

Kerridge IH: Rene Laennec and the introduction of the stethoscope. Aust NZ J Med 26:407-410, 1996.

69.

Adolph RJ: In defense of the stethoscope. Chest 114:1235-1237, 1998.

70.

Conti CR: The stethoscope: The forgotten instrument in cardiology? Clin Cardiol 20:911-912, 1997.

71.

Prezioso RL: The stethoscope. Lancet 352:1394, 1998.

HEART SOUNDS 72.

Leatham A: Auscultation of the heart. Lancet 2:703, 1958.

O'Toole JD, Reddy PS, Curtiss EL, et al: The contribution of tricuspid valve closure to the first heart sound: An intracardiac micromanometer study. Circulation 53:752, 1976. 73.

Brooks N, Leech G, Leatham A: Complete right bundle branch block: Echophonocardiographic study of the first heart sound and right ventricular contraction times. Br Heart J 41:637, 1979. 74.

Burggraf GW: The first heart sound in left bundle branch block: An echophonocardiographic study. Circulation 63:429, 1981. 75.

76.

Burggraf GW, Craige E: The first heart sound in complete heart block. Circulation 50:17, 1974.

Leech G, Brooks N, Green-Wilkinson A, Leatham A: Mechanism of influence of PR interval on loudness of first heart sound. Br Heart J 43:138, 1980. 77.

Perloff JK: The Clinical Recognition of Congenital Heart Disease. 4th ed. Philadelphia, WB Saunders, 1994. 78.

Waider W, Craige E: The first heart sound and ejection sounds: Echophonocardiographic correlation with valvular events. Am J Cardiol 35:346, 1975. 79.

Mills PG, Brodie B, McLaurin L, et al: Echocardiographic and hemodynamic relationships of ejection sounds. Circulation 56:430, 1977. 80.

81.

Bank AJ, Sharkey SW, Goldsmith SR, et al: Atypical systolic clicks produced by prolapsing mitral valve

masses. Am J Cardiol 69:1491, 1992. Lembo NJ, Dell'Italia JL, Crawford MH, O'Rourke RA: Bedside diagnosis of systolic murmurs. N Engl J Med 318:1572, 1988. 82.

83.

Leatham A: Splitting of the first and second heart sounds. Lancet 2:607, 1954.

Kupari M: Aortic valve closure and cardiac vibrations in the genesis of the second heart sound. Am J Cardiol 52:152, 1983. 84.

Curtiss EI, Matthews DG, Shaver JA: Mechanism of normal splitting of the second heart sound. Circulation 51:157, 1975. 85.

Shaver JA, Nadolny RA, O'Toole JD, et al: Sound-pressure correlates of the second heart sound. Circulation 49:316, 1974. 86.

Perloff JK, Harvey WP: Auscultatory and phonocardiographic manifestations of pure mitral regurgitation. Prog Cardiovasc Dis 5:172, 1962. 87.

Xiao HB, Faiek AH, Gibson DG: Re-evaluation of normal splitting of the second heart sound in patients with classical left bundle branch block. Int J Cardiol 45:163, 1994. 88.

Hultgren HN, Craige E, Nakamura T, Bilisoly J: Left bundle branch block and mechanical events of the cardiac cycle. Am J Cardiol 52:755, 1985. 89.

90.

de Leon AC, Perloff JK, Twigg H, Moyd M: The straight back syndrome. Circulation 32:193, 1965.

Tokushima T, Utsunomiya T, Ogawa T, et al: Contrast-enhanced radiographic computed tomographic findings in patients with straight back syndrome. Am J Card Imaging 10:228-234, 1996. 91.

Wood P: An appreciation of mitral stenosis: I. Clinical features. BMJ 1:1051, 1954; II. Investigations and results. BMJ 1:1113, 1954. 92.

Joyner CR Jr, Dear WE: The motion of the normal and abnormal mitral valve: A study of the opening snap. J Clin Invest 45:1029, 1966. 93.

Connolly DC, Mann RJ: Dominic J. Corrigan (1802-1880) and his description of the pericardial knock. Mayo Clin Proc 55:771, 1980. 94.

Tyberg TI, Goodyer AVN, Langou RA: Genesis of the pericardial knock in constrictive pericarditis. Am J Cardiol 46:570, 1980. 95.

Bass NM, Sharatt GJP: Left atrial myxoma diagnosed by echocardiography with observations on tumor movement. Br Heart J 35:1332, 1973. 96.

Van de Werf F, Minten J, Carmeliet P, et al: Genesis of the third and fourth heart sounds. J Clin Invest 73:1400, 1984. 97.

Van de Werf F, Boel A, Geboers J, et al: Diastolic properties of the left ventricle in normal adults and in patients with third heart sounds. Circulation 69:1070, 1984. 98.

99.

Kupari M, Koskinen P, Virolainen J, et al: Prevalence and predictors of audible physiological third

heart sound in a population sampled aged 36 to 37 years. Circulation 89:1189, 1994. Van de Werf F, Geboers J, Math L, et al: The mechanism of disappearance of the physiologic third heart sound with age. Circulation 73:877, 1986. 100.

Folland ED, Kriegel BJ, Henderson WG, et al: Implications of third heart sounds in patients with valvular heart disease. The Veterans Affairs Cooperative Study on Valvular Heart Disease. N Engl J Med 327:458, 1992. 101.

Aronow WS, Papageorge's NP, Uyeyama RR, Cassidy J: Maximal treadmill stress test correlated with postexercise phonocardiogram in normal subjects. Circulation 43:884, 1971. 102.

Ozawa Y, Smith D, Craige E: Origin of the third heart sound: I. Studies in dogs. Circulation 67:393, 1983. 103.

Ozawa Y, Smith D, Craige E: Origin of the third heart sound: II. Studies in human subjects. Circulation 67:399, 1983. 104.

Drzewiecki GM, Wasicko MJ, Li JK: Diastolic mechanics and the origin of the third heart sound. Ann Biomed Eng 19:651, 1991. 105.

Glower DD, Murrah RL, Olsen CO, et al: Mechanical correlates of the third heart sound. J Am Coll Cardiol 19:450, 1992. 106.

107.

Downes TR, Dunson W, Stewart K, et al: Mechanism of physiologic and pathologic S 3 gallop sounds.

Am Soc Echocardiol 5:211, 1992. Ishimitsu T, Smith D, Berko B, Craige E: Origin of the third heart sound: Comparison of ventricular wall dynamics in hyperdynamic and hypodynamic types. J Am Coll Cardiol 5:268, 1985. 108.

109.

Adolph RJ: The fourth heart sound. Chest 115:1480-1481, 1999.

Baracca E, Scorzoni D, Brunazzi MC, et al: Genesis and acoustic quality of the physiological fourth heart sound. Acta Cardiol 50:23-28, 1995. 110.

Baracca E, Brunazzi MC, Pasqualini M, et al: An estimation of the left ventricular diastolic function from the spectral analysis of the fourth heart sound: A Doppler validated study in hypertrophic cardiomyopathy. Acta Cardiol 50:17-21, 1995. 111.

Ishikawa M, Sakata K, Maki A, et al: Prognostic significance of a clearly audible fourth heart sound detected a month after an acute myocardial infarction. Am J Cardiol 80:619-621, 1997. 112.

113.

Perloff JK: Clinical recognition of aortic stenosis. Progr Cardiovasc Dis 10:323, 1964.

Huggins GS, Gewirtz H: Chronic stable angina; clinical presentation and diagnostic techniques. In Fuster V, Ross R, Topol EJ (eds): Atherosclerosis and Coronary Artery Disease. Philadelphia, Lippincott-Raven, pp 1401-1418. 114.

115.

Cheng TO, Ertem G, Vera Z: Heart sounds in patients with cardiac pacemakers. Chest 62:66, 1972.

116.

Harris A: Pacemaker "heart sound." Br Heart J 29:608, 1967.

HEART MURMURS 117.

Grewe K, et al: Differentiation of cardiac murmurs by auscultation. Curr Probl Cardiol 13:699, 1988.

Freeman AR, Levine SA: The clinical significance of the systolic murmur: A study of 1000 consecutive "non-cardiac" cases. Ann Intern Med 6:1371, 1933. 118.

119.

Lembo NJ, et al: Bedside diagnosis of systolic murmurs. N Engl J Med 318:1572, 1988.

120.

Ecchells E, et al. Does this patient have an abnormal systolic murmur? JAMA 277:564-571, 1997.

Gallavardin L, Pauper-Ravault: Le souffle du retre cissement aortique peut changer de timbre et devenir musical dans se propagation apexienne. Lyon Med 1925, p 523. 121.

122.

Joffe HS: Genesis of Still's innocent systolic murmur. Br Heart J 67:206, 1992

Donnerstein RL, Thomsen VS: Hemodynamic and anatomic factors affecting the frequency content of Still's innocent murmur. Am J Cardiol 74:508-510, 1994. 123.

Burch GE, DePasquale NP, Phillips JH: The syndrome of papillary muscle dysfunction. Am Heart J 75:399, 1968. 124.

Perloff JK, Roberts WC: The mitral apparatus: Functional anatomy of mitral regurgitation. Circulation 46:227, 1972. 125.

Rivero-Carvallo JM: Sitno para el diagnostico de las insuficiencias tricuspideas. Arch Inst Cardiol Mexico 16:531, 1946. 126.

Leon DF, Leonard JJ, Lancaster JF, et al: Effect of respiration on pansystolic regurgitant murmurs as studied by biatrial intracardiac phonocardiography. Am J Med 39:429, 1965. 127.

128.

Sutton GC, Craige E: Clinical signs of acute severe mitral regurgitation. Am J Cardiol 20:141, 1967.

Ronan JA, Steelman RB, DeLeon AC, et al: The clinical diagnosis of acute severe mitral insufficiency. Am J Cardiol 27:284, 1971. 129.

Rios JC, Massumi RA, Breesman WT, Sarin RK: Auscultatory features of acute tricuspid regurgitation. Am J Cardiol 23:4, 1969. 130.

Ronan JA, Perloff JK, Harvey WP: Systolic clicks and the late systolic murmur-intracardiac phonocardiographic evidence of their mitral valve origin. Am Heart J 70:319, 1965. 131.

Fontana ME: Mitral valve prolapse and floppy mitral valve: Physical examination. In Mitral Valve: Floppy Mitral Valve, Mitral Valve Prolapse, Mitral Valvular Regurgitation, 2nd ed. Armouk, NY, Futura, 2000, pp 283-304. 131A.

Osler W: On a remarkable heart murmur, heard at a distance from the chest wall. Med Times Gaz Lond 2:432, 1980. 132.

Grant RP: A precordial systolic murmur of extracardiac origin during pregnancy. Am Heart J 52:944, 1965. 133.

Danilowicz DA, Rudolph AM, Hoffman JIE, Heyman M: Physiologic pressure differences between the main and branch pulmonary arteries in infants. Circulation 45:410, 1972. 134.

Morganroth J, Perloff JK, Zeldis SM, Dunkman WB: Acute severe aortic regurgitation: Pathophysiology, clinical recognition and management. Ann Intern Med 87:223, 1977. 135.

Ross RS, Criley JM: Cineangiocardiographic studies of the origin of cardiovascular physical signs. Circulation 30:255, 1964. 136.

81

Fortuin NJ, Craige E: Echocardiographic studies of genesis of mitral diastolic murmurs. Br Heart J 35:75, 1973. 137.

138.

Perloff JK, Harvey WP: Clinical recognition of tricuspid stenosis. Circulation 22:346, 1960.

139.

Flint A: On cardiac murmurs. Am J Med Sci 44:23, 1862.

140.

Fortuin NJ, Craige E: On the mechanisms of the Austin Flint murmur. Circulation 45:558, 1972.

Landzberg JS, Tflugfelder PW, Cassidy MM, et al: Etiology of the Austin Flint murmur. J Am Coll Cardiol 20:408, 1992. 141.

Criley JM, Hermer HA: Crescendo pre-systolic murmur of mitral stenosis with atrial fibrillation. N Engl J Med 285:1284, 1971. 142.

Criley JM, Feldman JM, Meredith T: Mitral valve closure and the crescendo presystolic murmur. Am J Med 51:456, 1971. 143.

Reddy PS, Curtiss EL, Salerni R: Sound-pressure correlates of the Austin Flint murmur: An intracardiac sound study. Circulation 53:210, 1976. 144.

145.

Berman P: Austin Flint-America's Laennec revisited. Arch Intern Med 148:2053, 1988.

146.

Gibson GA: Persistence of the arterial duct and its diagnosis. Edinb Med J 8:1, 1900.

Cutforth R, Wideman J, Sutherland RD: The genesis of the cervical venous hum. Am Heart J 80:488, 1970. 147.

O'Rourke R: Approach to the patient with a heart murmur. In Goldman L, Braunwald E (eds): Primary Cardiology. Philadelphia, WB Saunders, 1998, pp 155-173. 148.

149.

Hamman L: Mediastinal emphysema. JAMA 128:1, 1945.

DYNAMIC AUSCULTATION 150.

Grewe K, Crawford MH, O'Rourke RA: Differentiation of cardiac murmurs by dynamic auscultation.

Curr Probl Cardiol 13:671, 1988. Lembro NJ, Dell'Italia LJ, Crawford MH, O'Rourke RA: Bedside diagnosis of systolic murmurs. N Engl J Med 318:1572, 1988. 151.

Baragan J, Fernandez F, Thiron JM: Dynamic Auscultation and Phonocardiography. Tavel ME (ed). Baltimore, Charles Press, 1979. 152.

153.

Rothman A, Goldberger AL: Aids to cardiac auscultation. Ann Intern Med 99:346, 1983.

154.

Cha SD, Gooch AS: Diagnosis of tricuspid regurgitation. Arch Intern Med 143:1763, 1983.

155.

Barlow JB: Perspectives on the Mitral Valve, Philadelphia, FA Davis, 1987.

Vrewe K, Crawford MH, O'Rourke RA: Differentiation of cardiac murmurs by dynamic auscultation. Curr Probl Cardiol 13:671, 1988. 156.

Nishimura RA, Tajik AJ: The Valsalva maneuver and response revisited. Mayo Clin Proc 61:211, 1986. 157.

Criscitiello M: Physiologic and pharmacologic aids in cardiac auscultation. In Fowler NO (ed): Cardiac Diagnosis and Treatment. 3rd ed. Hagerstown, MD, Harper & Row, 1980, pp 77-90. 158.

McCraw DB, Siegel W, Stonecipher HK, et al: Response of the heart murmur intensity to isometric (handgrip) exercise. Br Heart J 34:605, 1972. 159.

Barlow J, Shillingford J: The use of amyl nitrite in differentiating mitral and aortic systolic murmurs. Br Heart J 20:162, 1958. 160.




82

Chapter 5 - Electrocardiography DAVID M. MIRVIS ARY L. GOLDBERGER

The electrocardiogram (ECG), as used today, is the product of a series of technological and physiological advances pioneered over the past two centuries.[1] Early demonstrations of the heart's electrical activity reported during the last half of the 19th century, for example, by Marchand and others, were closely followed by direct recordings of cardiac potentials by Waller in 1887. Invention of the string galvanometer by Willem Einthoven in 1901 provided a reliable and direct method for registering electrical activity of the heart. By 1910, use of the string galvanometer had emerged from the research laboratory into the clinic. Subsequent achievements built on the limited, but very solid foundation supplied by the early electrocardiographers. The result has become a widely used and invaluable clinical tool for the detection and diagnosis of a broad range of cardiac conditions, as well as a technique that has contributed to the understanding and treatment of virtually every type of heart disease. Furthermore, the ECG is essential in the management of major metabolic abnormalities such as hyperkalemia and certain other electrolyte disorders, as well as assessing drug effects and toxicities such as caused by digitalis, antiarrhythmic agents, and tricyclic antidepressants. Moreover, it has remained the most direct method for assessing

abnormalities of cardiac rhythm. FUNDAMENTAL PRINCIPLES Use of the ECG for any of these clinically important purposes is the final outcome of a complex series of physiological and technological processes. This sequence is depicted in Figure 5-1 . First, an extracellular cardiac electrical field is generated by ion fluxes across cell membranes and between adjacent cells. These ion currents are synchronized by cardiac activation and recovery sequences to generate a cardiac electrical field in and around the heart that varies with time during the cardiac cycle. This electrical field passes through numerous other structures, including the lungs, blood, and skeletal muscle, before reaching the body surface. These structures--known as transmission factors--differ in their electrical properties and perturb the cardiac electrical field as it passes through them. The potentials reaching the skin are then detected by electrodes placed in specific locations on the extremities and torso and configured to produce leads. The outputs of these leads are amplified, filtered, and displayed by a variety of electronic devices to construct an ECG recording. Finally, diagnostic criteria are applied to these recordings to produce an interpretation. The criteria have statistical characteristics that determine the clinical utility of the findings. Each of these steps influences the final product--the clinical ECG--and will be considered in detail in this chapter to provide a foundation for considering the common abnormalities found in clinical practice and as a basis for further learning. GENESIS OF THE CARDIAC ELECTRICAL FIELD

CARDIAC ELECTRICAL FIELD GENERATION DURING ACTIVATION.

Transmembrane ionic currents are ultimately responsible for the cardiac potentials that are recorded as an ECG. Current may be analyzed as though carried by positively charged or negatively charged ions. Through a purely arbitrary choice, electrophysiological currents are considered to be the movement of positive charge. A positive current moving in one direction is equivalent to a negative current of equal strength moving in the opposite direction. The process of generating the cardiac electrical field during activation can be illustrated by considering the events in a single cardiac fiber that is activated by a stimulus applied to its left-most margin[2] (Fig. 5-2 , left, panel A). Transmembrane potentials (Vm ) are recorded as the difference between intracellular and extracellular potentials (ki and ke , respectively). Figure 5-2 , left, panel B plots Vm along the length of the fiber at the instant during the propagation (to ) at which activation has reached the point designated as X0 . As each site is activated, the polarity of the transmembrane potential is converted from negative to positive. Thus, sites to the left of the point X 0 , which have already undergone excitation, have positive transmembrane potentials (that is, the inside of the cell is positive relative to the outside of the cell), whereas those to the right of X0 (which remain in a resting state) have negative transmembrane potentials. Near

the site undergoing activation (site X0 ), the potentials reverse polarity over a short distance. Figure 5-2 , left, panel C displays the direction and magnitude of transmembrane currents (Im ) along the fiber at the instant (t o ) at which excitation has reached site X0 . Current flow is inwardly directed in fiber regions that have undergone activation (that is, to the left of point X 0 ) and outwardly directed in neighboring zones still at rest (that is, to the right of X0 ). Sites of outward current flow are current sources and those with inward current flow are current sinks. As depicted in this panel, current flow is most intense in each direction near the site of activation X0 . Because the border between inwardly and outwardly directed currents is relatively sharp, we can visualize these currents as though they were limited to the sites of maximal current flow, as depicted in panel D, and separated by distance d that is usually 1.0 mm or less. As activation proceeds along the fiber, the source-sink pair moves to the right at the speed of propagation for the particular type of fiber. Two point sources of equal strength but of opposite polarity located very near each other, such as the current source and the current sink depicted in Figure 5-2 , left, panel D, may be represented as a current dipole (arrow in panel D). Thus, activation of a fiber can be modeled as a current dipole that moves in the direction of propagation of activation. Such a dipole is fully characterized by three parameters--strength or dipole moment, location, and orientation. In this case, the location of the dipole is the site undergoing activation (point X0 ), and its orientation is in the direction of activation (that is, from left to right along the fiber). Dipole moment is proportional to the rate of change of intracellular potential with respect to distance along the fiber, that is, action potential shape. A current dipole produces a characteristic potential field with positive potentials projected ahead of and negative potentials projected behind the moving dipole. The actual potential recorded at any site within this field is directly proportional to the dipole moment, inversely proportional to the square of the distance from the dipole to the recording site, and directly proportional to the cosine of the angle between the axis of the dipole and a line drawn from the dipole to the recording site (Fig. 5-2 , right).

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Figure 5-1 Schematic representation of the factors resulting in recording the electrocardiogram (ECG). The major paths leading to the ECG are marked by solid arrows, while factors influencing or perturbing this path are shown with dotted arrows.

This example from one cardiac fiber can be generalized to the more realistic case in which multiple adjacent fibers are activated in synchrony to produce an activation front. Activation of each fiber creates a dipole oriented in the direction of activation. The net

effect of all the dipoles in this wave front is a single dipole equal to the (vector) sum of the effects of all the simultaneously active component dipoles. Thus, an activation front propagating through the heart can be represented by a single dipole that projects positive potentials ahead of it and negative potentials behind it. This relationship between activation direction, orientation of the current dipole, and polarity of potentials is a critical one in electrocardiography. It describes a fundamental relationship between the polarity of potentials sensed by an electrode and the direction of movement of an activation front--an electrode senses positive potentials when an activation front is moving toward it and negative potentials when the activation front is moving away from it. The dipole model, while useful in describing cardiac fields and understanding clinical electrocardiography, has significant theoretical limitations. These limits derive primarily from the inability of a single dipole to accurately represent more than one wave front that is propagating through the heart at any one instant. As will be discussed, during much of the time of ventricular excitation, more than one wave front is present. One important and commonly used method of estimating the potentials projected to some point away from an activation front is an application of the solid angle theorem.[3] A solid angle is a geometric measure of the size of a region when viewed from a distant site. It equals the area on the surface of a sphere of unit radius constructed around an electrode that is cut by lines drawn from the recording electrode to all points around the boundary of the region of interest. This region may be a wave front, a zone of infarction, or any other region in the heart. The solid angle theorem states that the potential recorded by a remote electrode (Phi) is defined by Phi=( /4pi)(Vm2 - Vm1 )K where is the solid angle, Vm2 - Vm1 is the potential difference across the boundary under study, and K is a constant reflecting differences in intracellular conductivity. This equation indicates that the recorded potential equals the product of two factors. First, the solid angle reflects spatial parameters, such as the size of the boundary of the region under study and the distance from the electrode to that boundary. The potential will rise as the boundary size increases and as the distance to the electrode shrinks. A second set of parameters includes nonspatial factors, such as the potential difference across the surface and intracellular and extracellular conductivity. Nonspatial effects include, as one example, myocardial ischemia, which changes transmembrane action potential shapes and alters conductivity. CARDIAC ELECTRICAL FIELD GENERATION DURING VENTRICULAR RECOVERY.

The cardiac electrical field during recovery (phases 1 through 3 of the action potential) differs in fundamental ways from that described for activation. First, intercellular potential differences and, hence, the directions of current flow during recovery are the opposite of those described for activation. As a cell undergoes recovery, its intracellular potential becomes progressively more negative. Hence, for two adjacent cells, the

intracellular potential of the cell whose recovery has progressed further is more negative than that of an adjacent, less recovered cell. Intracellular currents then flow from the less toward the more recovered cell. An equivalent dipole can then be constructed for recovery, just as for activation. Its orientation, however, points from less to more recovered cells. Thus, the recovery dipole is oriented away from the activation front, that is, in the direction opposite that of the activation dipole. The moment or strength of the recovery dipole also differs from that of the activation dipole. As described previously, the strength of the activation dipole is proportional to the rate of change in transmembrane potential. Rates of change in potential during the recovery phases of the action potential are considerably slower than during activation, so dipole moment at any one instant during recovery is less than that during activation. A third difference between activation and recovery is the rate of movement of the activation and recovery dipoles. Activation, because it is rapid (as fast as 1 millisecond in duration), occurs over only a small distance along the fiber. Recovery, in contrast, lasts 100 milliseconds or longer and occurs simultaneously over extensive portions of the fiber. These features result in characteristic ECG differences between activation and recovery patterns. All other factors being equal (an assumption that is often not true, as described below), ECG waveforms generated during recovery of a linear fiber with uniform recovery properties may be expected to be of opposite polarity, lower amplitude, and longer duration than those due to activation. As will be described, these features are explicitly demonstrated in the clinical ECG. THE ROLE OF TRANSMISSION FACTORS.

These activation and recovery forces exist within a complex three-dimensional physical environment (the volume conductor). The structures within the volume conductor modify the cardiac electrical field in significant ways.[4] They may be called transmission factors to emphasize their effects on transmission of the cardiac electrical field throughout the body and may be grouped into four broad categories--cellular factors, cardiac factors, extracardiac factors, and physical factors. Cellular factors determine the intensity of current fluxes that result from local transmembrane potential gradients and include intracellular and extracellular resistance and the concentration of relevant ions, especially the sodium ion. Lower ion concentrations reduce the intensity of current flow by reducing the equivalent dipole moment and lowering extracellular potentials. Cardiac factors affect the relationship of one cardiac cell to another. Two major factors are (1) anisotropy, that is, the property of cardiac tissue that results in greater current flow and more rapid propagation along the length of a fiber than transversely, and (2) the presence of connective tissue between cardiac fibers that disrupts effective electrical coupling between adjacent fibers. These factors alter the paths of extracellular currents and produce changes in the amplitude and configuration of recorded electrograms. Recording electrodes oriented along the long axis of a cardiac fiber

register larger potentials than do electrodes oriented perpendicular to the long axis, and waveforms recorded from fibers with little or no intervening connective tissue are narrow in width and smooth in contour, whereas those recorded from tissues with abnormal fibrosis are prolonged and heavily fractionated.[5] Extracardiac factors encompass all the tissues and structures that lie between the activation region and the body surface, including the ventricular walls, intracardiac and intrathoracic blood volume, the pericardium, and the lungs, as well as skeletal muscle, subcutaneous fat, and skin. These tissues alter the cardiac field because of differences in the electrical resistivity of adjacent tissues, that is, the presence of electrical inhomogeneities within the torso. For example, intracardiac blood has much lower resistivity (162 -cm) than do the lungs (2150 -cm). When the cardiac field encounters the boundary between two tissues with differing resistivity, the field is altered. Other transmission factors reflect basic laws of physics. First, changes in the distance between the heart and the recording electrode reduce potential magnitudes in accord with the inverse square law, that is, amplitude decreases in proportion to the square of the distance. A related factor is the effect of eccentricity. The heart is located eccentrically within the chest in that it lies closer to the anterior than to the posterior of the torso, so the right ventricle and the anteroseptal aspect of the left ventricle are located closer to the anterior of the chest than are other parts of the left ventricle and the atria. Therefore, ECG potentials will be higher anteriorly than posteriorly, and waveforms projected from the anterior of the left ventricle will be greater than those generated by posterior ventricular regions. As a result of all of these factors, body surface potentials have an amplitude of only 1 percent of the amplitude of transmembrane potentials and are smoothed in detail so that surface potentials have only a general spatial relationship to the underlying cardiac events.

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Figure 5-2 Example of potentials and currents generated by the activation of a single (e.g., ventricular) cardiac fiber. Left, Panel A, Intracellular (Phii ) and extracellular (Phie ) potentials are recorded with a voltmeter (Vm ) from a fiber 20 mm in length. The fiber is stimulated at site X=0, and propagation proceeds from left to right. B, Plot of transmembrane potential (Vm ) at the instant in time at which activation reaches point X 0 as a function of the length of the fiber. Positive potentials are recorded from activated tissue to the left of site X0 , and negative ones are registered from not yet excited areas to the right of site X0 . C, Membrane current (I m ) flows along the length of the fiber at time to . The outward current is the depolarizing current that propagates ahead of activation site X 0 , while an inward one flows behind site X0 . D, Representation of the sites of peak inward and outward current flow as two point sources, a sink (at the site of peak inward current flow) and a source (at the site of peak outward current

flow) separated by distance d. The dipole produced by the source-sink pair is represented by the arrow.(Modified from Barr RC: Genesis of the electrocardiogram. In MacFarlane PW, Lawrie TDV [eds]: Comprehensive Electrocardiography. New York, Pergamon, 1989.) Right, Formula for computing the electrical potential (phi) recorded by an electrode in terms of the distance from an extracellular dipole generated during activation of a linear cardiac fiber to the electrode (r=radius), the angle between the radius to the electrode and the dipole (O), the dipole moment (M) and extracellular conductivity (sigma). The direction of activation of the fiber is indicated.

The modifying effect of these physical structures is a biophysical one dependent on the physical properties of the structures and the related laws of physics, in contrast to the biological cardiac generators, whose output is dependent on cellular structure and physiological and biochemical processes. Thus, ECG potentials on the body surface are dependent on both biological and biophysical properties.[6] RECORDING ELECTRODES AND LEADS Potentials generated by the cardiac electrical generator and modified by transmission factors are processed by a series of electrical and electronic devices to yield a clinical ECG (Fig. 5-3) . They are first sensed by electrodes placed on the torso that are configured to form various types of leads. ELECTRODE CHARACTERISTICS.

Electrodes used to sense the cardiac electrical field are not passive devices that merely detect the field. Rather, they are intricate systems that are affected by the properties of the dermal and epidermal layers of the skin, the electrolytic paste applied to the skin, the electrode itself, and the mechanical contact between the electrode and skin. The net effect is a complex electrical circuit that includes the resistance, capacitance, and voltage produced by these different components and the interfaces between them. Each of these factors modifies the cardiac potentials that reach the electrodes themselves before they are displayed as an ECG.[7] BIPOLAR AND UNIPOLAR LEAD CONFIGURATIONS.

ECG leads may be subdivided into two general types--bipolar leads and unipolar leads. A bipolar lead consists of two electrodes placed at two different sites. These leads register the difference in potential between these two sites. The actual potential at either electrode is not known, and only the difference between them is recorded. One electrode is designated as the positive input; the potential at the other, or negative, electrode is subtracted from the potential at the positive electrode to yield the bipolar potential. Unipolar leads, in contrast, measure the absolute electrical potential at one site. To do so requires a reference site, that is, a site at which the potential is deemed to be zero. The reference site may be a location far away from the active electrode (as in an experimental

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Figure 5-3 Components used in the recording and processing of an electrocardiogram. (From Mirvis DM: Electrocardiography: A Physiologic Approach. St Louis, Mosby-Year Book, 1993.)

preparation) or, as in clinical electrocardiography, a specially designed electrode configuration such as described below. The unipolar recording is then the potential sensed by a single electrode at one site--the recording or active or exploring electrode--in relation to the designated zero or reference potential. Clinical Electrocardiographic Lead Systems

The standard clinical ECG includes recordings from 12 leads. These 12 leads include three bipolar limb leads (leads I, II, and III), six unipolar precordial leads (leads V1 through V6 ), and three modified unipolar limb leads (the augmented limb leads aVr , aVl , and aVf ). Definitions of the positive and negative inputs for each lead are listed in Table 5-1 . BIPOLAR LIMB LEADS.

Bipolar limb leads record the potential differences between two limbs, as detailed in Table 5-1 and illustrated in Figure 5-4 , top. As bipolar leads, the output is the potential difference between the limbs serving as positive and negative inputs. Lead I represents the potential difference between the left arm (positive electrode) and the right arm (negative electrode), lead II displays the potential difference between the left foot (positive electrode) and the right arm (negative electrode), and lead III represents the potential difference between the left foot (positive electrode) and the left arm (negative electrode). The electrode on the right foot that is not included in these leads serves as a ground connection. The electrical connections for these leads are such that the potential in lead II equals the sum of potentials sensed in leads I and III. That is, I+III=II. This relationship is known as Einthoven's law. UNIPOLAR PRECORDIAL LEADS AND THE WILSON CENTRAL TERMINAL.

The unipolar precordial leads register the potential at each of the six designated torso sites ( Fig. 5-4 , bottom left panel) in relation to a theoretical zero reference potential. To do so, an exploring electrode is placed on each precordial site and connected to the positive input of the recording system ( Fig. 5-4 , bottom right panel). The negative or reference input is composed of a compound electrode (that is, a

configuration of more than one electrode connected electrically) known as the Wilson central terminal. This terminal is formed by combining the output of the left arm, right arm, and left leg electrodes through 5000resistances (Fig. 5-4 , bottom right panel). The result is that each precordial lead registers the potential at a precordial site with reference to the average potential on three limbs. The potential recorded by the Wilson central terminal remains relatively constant during the cardiac cycle, so the output of a precordial lead is determined TABLE 5-1 -- LOCATION OF ELECTRODES AND LEAD CONNECTIONS FOR THE STANDARD 12-LEAD ELECTROCARDIOGRAM AND ADDITIONAL LEADS LEAD TYPE, POSITIVE INPUT NEGATIVE INPUT LEAD BIPOLAR LIMB LEADS Lead I

Left arm

Right arm

Lead II

Left leg

Right arm

Lead III

Left leg

Left arm

AUGMENTED UNIPOLAR L IMB LEADS aVr

Right arm

Left arm + left leg

aVl

Left arm

Right arm + left leg

aVf

Left leg

Left arm + left arm

PRECORDIAL L EADS* V1

Right sternal margin,4th intercostal space Wilson central terminal

V2

Left sternal margin,4th intercostal space

Wilson central terminal

V3

Midway between V2 and V4


V4

Left midclavicular line,5th intercostal space


V5

Left anterior axillary line


V6

Left midaxillary line


V7

Posterior axillary line


V8

Posterior scapular line


V9

Left border of spine


*The right-sided precordial leads V 3 R to V 6 R are taken in mirror image positions on the right side of the chest: V1 R ¬ V2 ; V2 R ¬ V1 . Leads V 5 to V 9 are taken in the same horizontal plane as V4 .QT interval (corrected) DURATION (msec)

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Figure 5-4 Top, Electrode connections for recording the three bipolar limb leads I, II, and III. R, L, and F indicate locations of electrodes on the right arm, the left arm, and the left foot, respectively. Bottom, Electrode locations and electrical connections for recording a unipolar precordial lead. Left, The positions of the exploring electrode (V) for the six precordial leads. Right, Connections to form the Wilson central terminal for recording a precordial (V) lead. (From Goldberger AL: Clinical Electrocardiography: A Simplified Approach. 6th ed. St Louis, CV Mosby, 1999.)

predominantly by changes in the potential at the precordial site. AUGMENTED UNIPOLAR LIMB LEADS.

The three augmented limb leads aVr , aVl , and aVf are modified or augmented unipolar leads. The exploring electrode (Fig. 5-5) is the right arm electrode for lead aVr , the left arm electrode for lead aVl , and the left foot electrode for aVf . It is the reference electrode that is modified. Instead of consisting of a full Wilson central terminal composed of the output from three limb electrodes, the reference potential is

Figure 5-5 Electrode locations and electrical connections for recording the three augmented unipolar leads aVr , aV l , and aVf . Dotted lines indicate connections to generate the reference electrode potential.

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Figure 5-6 Lead vectors for the three bipolar limb leads, the three augmented unipolar limb leads (left), and the six unipolar precordial leads (right).

the mean of the potentials sensed by only two of the three limb electrodes; the electrode used for the exploring electrode is excluded from the reference electrode. For lead aVl , for example, the exploring electrode is on the left arm and the reference electrode is the

mean output of the electrodes on the right arm and the left foot. Similarly, for lead aVf , the reference potential is the mean of the output of the two arm electrodes. This modified reference system was designed to increase the amplitude of the output. The output of the limb leads without augmentation tended to be small, in part because the same electrode potential was included in both the exploring and reference potential input. Eliminating this duplication results in a theoretical increase in amplitude of 50 percent. OTHER LEAD SYSTEMS.

Other lead systems may be used for specific purposes. For example, additional unipolar right precordial leads may be used to assess right ventricular lesions, and locations posterior to V6 may be used to detect posterior infarctions [8] [8A] [8B] (see Table 5-1) . Such posterior locations include lead V7 with the exploring electrode at the left posterior axillary line at the level of V6 , lead V8 with the exploring electrode on the left midscapular line, lead V4 R with the exploring electrode on the right midclavicular line in the 4th intercostal space, and so forth. A vertical parasternal bipolar pair may facilitate detection of P waves for diagnosing arrhythmias.[9] Precordial and anterior-posterior thoracic electrode arrays of up to 150 (or more) electrodes may be used to display the spatial distribution of body surface potentials as body surface isopotential maps.[10] Modified lead systems are also used in ambulatory ECG recording and exercise stress testing, as described elsewhere, and for bedside cardiac monitoring.[11] Other lead systems that have had clinical utility include those designed to record a vectorcardiogram (VCG). The VCG depicts the orientation and strength of a single cardiac dipole or vector at each instant during the cardiac cycle. Lead systems for recording the VCG are referred to as orthogonal systems because they record the three orthogonal or mutually perpendicular components of the dipole moment--the horizontal (x axis), frontal (y axis) and sagittal or anteroposterior (z axis) axes. Clinical use of the VCG has waned in recent years. However, the VCG may be useful in certain situations,[12] and as described below, vectorial principles remain essential to understanding the physiology and pathology of ECG waveform genesis. LEAD VECTORS AND HEART VECTORS

A lead can be represented as a vector (the lead vector). For simple bipolar leads, such as leads I, II, and III, the lead vectors are directed from the negative electrode toward the positive one (see Fig. 5-6 , left). For unipolar leads such as the augmented limb and precordial leads, the origin of the lead vectors lies on the axis connecting the electrodes that make up the compound electrode. That is, for lead aVl , the vector points from the midpoint of the axis connecting the right arm and left leg electrodes toward the left arm (see Fig. 5-6 , left). For the precordial leads, the lead vector points from the center of the torso to the precordial electrode site ( Fig. 5-6 , right). Instantaneous cardiac activity may also be approximated as a single dipole representing

the vector sum of the various active wave fronts (the heart vector). Its location, orientation, and intensity vary from instant to instant because of the changing pattern of cardiac activation. The amplitude and polarity of the potentials sensed in a lead equal the length of the projection of the heart vector on the lead vector multiplied by the length of the lead vector: VL =(H)(cos O) (L) where L and H are the length of the lead and heart vectors, respectively, and O is the angle between the two vectors, as illustrated in Figure 5-7 . If the projection of the heart vector on the lead vector points toward the positive pole of the lead axis, the lead will record a positive potential. If the projection is directed away from the positive pole of the lead axis, the potential will be negative. The lead axes of the six frontal plane leads can be overlaid to produce the hexaxial reference system. As depicted in Figure 5-8, the six lead axes divide the frontal plane into 12 segments subtending 30 degrees.

Figure 5-7 The heart vector H and its projections on the lead axes of leads I and III. Voltages recorded in lead I will be positive whereas potentials in lead III will be negative.

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Figure 5-8 The hexaxial reference system composed of the lead axes of the six frontal plane leads. The lead axes of the six frontal plane leads have been rearranged so that their centers overlay one another. These axes divide the plane into 12 segments, each subtending 30 degrees. Positive ends of each axis are labeled with the name of the lead. The Electrical Axis

The concepts of the heart vector and the lead vector allow calculation of the mean electrical axis of the heart. The process for computing the axis of the mean force during activation (the mean electrical axis) is illustrated in Figure 5-9 and is the reverse of that used to compute potential magnitudes in the leads from the orientation and moment of the heart vector. The mean force during activation is represented by the area under the QRS waveform measured as millivolt-milliseconds. Areas above the baseline are assigned a positive polarity and those below the baseline have a negative polarity; the overall area equals the sum of the positive and the negative areas. The area in each lead (typically two are chosen) is represented as a vector oriented

along the appropriate lead axis in the hexaxial reference system (see Fig. 5-8) , and the

Figure 5-9 Calculation of the mean electrical axis during the QRS complex from the areas under the QRS complex in leads I and III. Magnitudes of the areas of the two leads are plotted as vectors on the appropriate lead axes, and the mean QRS axis is the sum of these two vectors.(From Mirvis DM: Electrocardiography: A Physiologic Approach. St Louis, Mosby-Year Book, 1993.)

mean electrical axis equals the resultant or the sum of the two vectors. An axis directed toward the positive end of the lead axis of lead I, that is, oriented horizontally away from the right arm and toward the left arm, is designated as an axis of zero degrees. Axes oriented in a clockwise direction from this zero level are assigned positive values and those oriented in a counterclockwise direction are assigned negative values. The mean electrical axis in the horizontal plane can be computed in an analogous manner by using the areas and the lead axes of the six precordial leads (see Fig. 5-6 , right). A horizontal plane axis located along the lead axis of lead V6 is assigned a value of zero degrees, and those directed more anteriorly have positive values. This process can be applied to compute the mean electrical axis for other phases of cardiac activity. Thus, the mean force during atrial activation will be represented by the areas under the P wave, and the mean force during ventricular recovery will represented by the areas under the ST-T wave. In addition, the instantaneous electrical axis can be computed at each instant during ventricular activation by using voltages or amplitudes at a specific point in time rather than using areas to calculate the axis. The orientation of the mean electrical axis represents the direction of the activation front (or recovery direction) in an "average" cardiac fiber. The direction of the front, in turn, is determined by the interaction of three factors--the anatomical position of the heart in the chest, the properties of the cardiac conduction system, and the activation and recovery properties of the myocardium. Differences in the anatomical position of the heart within the chest would be expected to change the relationship between cardiac regions and the lead axes and would thus change recorded voltages. Similarly, changes in conduction patterns, even of minor degree, can significantly alter relationships between activation (or recovery) of various cardiac areas and, hence, the direction of instantaneous as well as mean electrical force. In practice, differences in anatomy contribute relatively little to shifts in axis[13] ; the major influences on the mean electrical axis are the properties of the conduction system and cardiac muscle. ELECTROCARDIOGRAPHIC DISPLAY SYSTEMS

Another group of factors that determines ECG waveforms includes the characteristics of the electronic systems used to amplify, filter, and digitize the sensed signals. ECG amplifiers are differential amplifiers, that is, they amplify the difference between two inputs. For bipolar leads, the differential output is the difference between the two active leads; for unipolar leads, the difference is between the exploring electrode and the reference electrode. This differential configuration significantly reduces the electrical

noise that is sensed by both inputs and hence is canceled. The standard amplifier gain for routine electrocardiography is 1000 but may vary from 500 (half-standard) to 2000 (double standard). Amplifiers respond differently to the range of signal frequencies included in an electrophysiological signal. The bandwidth of an amplifier defines the frequency range over which the amplifier accurately amplifies the input signals. Waveform components with frequencies above or below the bandwidth may be artifactually reduced or increased in amplitude. In addition, recording devices include high- and low-pass filters that intentionally reduce the amplitude of specific frequency ranges of the signal. Such reduction in amplitude may be done, for example, to reduce the effect of body motion or line voltage frequencies, that is, 60-Hz interference. For routine electrocardiography, the standards of the American Heart Association require a bandwidth of 0.05 to 100 Hz. Amplifiers for routine electrocardiography include a capacitor stage between the input and the output terminals; that is, they are capacitor coupled. This configuration blocks direct-current (DC) voltage while permitting flow of alternating-current (AC) signals. Because the ECG waveform may be viewed as an AC signal (which accounts for the waveform shape) that is superimposed on a DC baseline (which determines the actual voltage levels of the recording), this coupling has significant effects on the recording process. First, unwanted DC potentials, such as those produced by the electrode interfaces, are eliminated. Second, elimination of the DC potential from the final product means that ECG potentials are not calibrated against an external reference level. ECG potentials must be measured in relation to an internal standard. Thus, amplitudes of waves are measured in millivolts or microvolts relative to another portion of the waveform. The TP segment, which begins at the end of the T wave of one cardiac cycle and ends with onset of the P wave of the next cycle, is usually the most appropriate internal ECG baseline. An additional issue is the digitizing or sampling rate for computerized systems. Too low a sampling rate will miss brief signals such as

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notches in QRS complexes or brief bipolar spikes and reduce the precision and accuracy of waveform morphologies. Too fast a sampling rate may introduce artifacts, including high-frequency noise, and requires excessive digital storage capacity.[14] In general, the sampling rate should be at least twice the frequency of the highest frequencies of interest in the signal being recorded. Standard electrocardiography is most commonly performed with a sampling rate of 500 Hz, with each sample representing a 2-millisecond period. Cardiac potentials may be processed for display in numerous formats. The most common of these formats is the classic scalar ECG. Scalar recordings depict the potentials recorded from one lead as a function of time. For standard electrocardiography, amplitude is displayed on a scale of 1 mV to 10-mm vertical

displacement and time as 200 msec/cm on the horizontal scale. Other display formats are used for ambulatory electrocardiography, as described in Chapter 23 , and for bedside ECG monitoring.[11] THE NORMAL ELECTROCARDIOGRAM The heart is activated with each cardiac cycle in a very characteristic manner determined by the anatomy and physiology of working cardiac muscle and the specialized cardiac conduction systems. The waveforms and intervals that make up the standard ECG are displayed in the diagram in Figure 5-10 , and a normal 12-lead ECG is shown in Figure 5-11 . The P wave is generated by activation of the atria, the PR segment represents the duration of atrioventricular (AV) conduction, the QRS complex is produced by activation of both ventricles, and the ST-T wave reflects ventricular recovery. Table 5-2 includes normal values for the various intervals and waveforms of the ECG. Atrial Activation and the P Wave

Atrial activation[15] begins with impulse generation in the atrial pacemaker complex in or near the sinoatrial (SA) node. The rate of discharge of the SA node and, hence, the heart rate is dependent on parasympathetic and sympathetic tone, as well as the intrinsic properties of the SA node, extrinsic factors such as mechanical stretch, [16] and various pharmacological effects (see Chap. 22) . Increasing attention is being directed at the beat-to-beat changes in heart rate, termed heart rate variability, to gain insight into neuroautonomic control mechanisms and their perturbations with aging, disease, and drug effects. [17] [18] [19] [172A] [178A] [187A] [187B] For example, high-frequency (0.15-0.5 Hz) fluctuations mediated by the vagus nerve occur phasically, with heart

Figure 5-10 The waves and intervals of a normal electrocardiogram. (From Goldberger AL: Clinical Electrocardiography: A Simplified Approach. 6th ed. St Louis, CV Mosby, 1999.)

rate increasing during inspiration and decreasing during expiration. Attenuation of this respiratory sinus arrhythmia is a consistent marker of physiological aging and also occurs with diabetes mellitus, congestive heart failure, and a wide range of other cardiac and noncardiac conditions that alter autonomic tone.[18] [19] [20] [187A] [187B] Lower-frequency (0.05-0.15 Hz) physiological oscillations in heart rate are associated TABLE 5-2 -- NORMAL VALUES FOR DURATIONS OF ELECTROCARDIOGRAPHIC WAVES AND INTERVALS IN ADULTS WAVE/INTERVAL DURATION (msec) P wave duration

3.5 mV RaVl >1.1 mV Romhilt-Estes point score system *

Any limb lead R wave or S wave 2.0 mV

3 points

SV1 or SV2 3.0 mV

3 points

RV5 to RV6 3.0 mV

3 points

ST-T wave abnormality (no digitalis therapy)

3 points

ST-T wave abnormality (digitalis therapy)

1 point

P terminal force in V 1 >4 mV-msec

3 points

Left axis deviation

1 point

Intrinsicoid deflection in V5 or V6 50 msec

1 point

Cornell voltage criteria [54] SV3 +RaVl 2.8 mV (for men) SV3 +RaVl 2.0 mV (for women) Cornell regression equation[54] Risk=1/(1+e-exp ) Where exp=4.558-0.092 (RaV1 +SV3 )-0.306 TV1 - 0.212 QRS-0.278 PTFV1 -0.859 (sex) Where voltages are in mV, QRS is QRS duration in mV, PTF is the area in the P terminal force in lead V1 (in mm-sec), and sex=1 for men and 2 for women; LVH is present if exp is less than -1.55 Cornell voltage-duration measurement[55] QRS duration×Cornell Voltage>2436 QRS duration×sum of voltages in all 12 leads>17,472 Novacode criterion (for men) [56] III

LVMI (gm/m[2] )=-36.4+0.010 RV5 +0.20 SV1 +0.28 S + 0.182 T(neg) V6 -0.148 T(pos) aVr + 1.049 QRSduration

where neg and pos refer to amplitudes of the negative and positive portions of the T waves, respectively; S indicates the amplitude of the S, Q, and QS wave, whichever is larger *Probable left ventricular hypertrophy is diagnosed if 4 points are present and definite left ventricular hypertrophy is diagnosed if 5 or more points are present. LVH=left ventricular hypertrophy; LVMI=left ventricular mass index.R/S in V1 >1 with R >0.5 mV

SENSITIVITY SPECIFICITY

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Several reasons may be suggested for the limited accuracy of these criteria. Many of the clinical studies that were used to define the criteria included a disproportionate number of white men, thus limiting applicability of the tests to other populations; LVH is more common among blacks.[57] In addition, the criteria for dichotomous tests such as the Sokolow-Lyon and Cornell voltage criteria are based on quantitative differences in normally occurring measures, i.e., QRS voltage, between normal and abnormal cohorts; these tests by their nature are limited to detecting only the extreme end of the spectrum of LVH because milder degrees overlap with normal populations.[58] Finally, these voltage measurements are subject to the influence of many noncardiac factors, such as body habitus, which blurs the distinction between normal and abnormal.[59] [59A] CLINICAL SIGNIFICANCE.

The presence of ECG criteria for LVH identify a subset of the general population with a significantly increased risk for cardiovascular morbidity and mortality.[56] [57] [58] [59] [59A] [60] This increased risk is particularly true in women and if ST-T wave abnormalities are present; the relative risk of cardiovascular events for patients with LVH voltage criteria alone is approximately 2.8, whereas the relative risk increases to over 5.0 if ST segment depression is also present.[57] [61] [62] In patients with cardiac disease, the ECG finding of LVH correlates with more severe disease, including higher blood pressure in hypertensives and greater ventricular dysfunction in patients with hypertension or coronary artery disease. [63] In contrast, effective treatment of hypertension reduces ECG evidence of LVH and decreases the associated risk of cardiovascular mortality.[61] Patients with repolarization abnormalities have, on average, more severe degrees of LVH and more commonly have symptoms of left ventricular dysfunction,[64] in addition to a greater risk of cardiovascular events.[61] Right Ventricular Hypertrophy and Enlargement

ECG ABNORMALITIES.

The ECG changes invoked by RVH or right ventricular enlargement are different from those produced by left ventricular enlargement because the right ventricle is considerably smaller than the left ventricle and produces electrical forces that are largely canceled by those generated by the larger left ventricle. Thus, for RVH to be manifested on the ECG, it must be severe enough to overcome the canceling effects of the larger left ventricular forces. In addition, increasing dominance of the right ventricle changes the ECG in fundamental ways, whereas an enlarged left ventricle produces

predominantly quantitative changes in underlying normal waveforms. ECG changes associated with moderate to severe concentric hypertrophy of the right ventricle[65] include abnormally tall R waves in anteriorly and rightward directed leads (leads aVr , V1 , and V2 ) and deep S waves and abnormally small r waves in leftward directed leads (I, aVl , and lateral precordial leads) (see Figs. 5-18 and 5-21) . These changes result in a reversal of normal R wave progression in the precordial leads, a shift in the frontal plane QRS axis to the right, and sometimes the presence of S waves in leads I, II, and III (so-called S1 S2 S3 pattern). Several other ECG patterns of RVH also exist. Less severe hypertrophy, especially when limited to the outflow tract of the right ventricle that is activated late during the QRS complex, produces less marked changes. ECG abnormalities may be limited to an rSr pattern in V1 and persistence of s (or S) waves in the left precordial leads. This pattern is typical of right ventricular volume overload as produced by an atrial septal defect. Chronic obstructive pulmonary disease can induce ECG changes by producing RVH, changes in the position of the heart within the chest, and hyperinflation of the lungs (Fig. 5-22). QRS changes caused by the insulating and positional changes produced by hyperinflation of the lungs include reduced amplitude of the QRS complex, right axis deviation in the frontal plane, and delayed transition in the precordial leads (probably reflecting a vertical and caudal shift in heart position because of hyperinflation and a flattened diaphragm). Evidence of true RVH includes (1) marked right axis deviation (more positive than 110 degrees), (2) deep S waves in the lateral precordial leads,

Figure 5-21 Right ventricular hypertrophy pattern most consistent with severe pressure overload. Note the combination of findings, including (1) a tall R wave in V1 (as part of the qR complex), (2) right axis deviation, (3) T wave inversion in V 1 through V3 , (4) delayed precordial transition zone (rS in V6 ), and (5) right atrial abnormality. An S 1 Q 3 pattern is also present and can occur with acute or chronic right ventricular overload syndrome.

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Figure 5-22 Pulmonary emphysema simulating anterior infarction in a 58-year-old man with no clinical evidence of coronary disease. Note the relative normalization of R wave progression with placement of the chest leads an interspace below their usual position (5V 1 , 5V2 , and so forth). (From Chou TC: Pseudo-infarction (noninfarction Q waves). In Fisch C [ed]: Complex Electrocardiography. Vol 1. Philadelphia, FA Davis, 1973.)

and (3) an S1 Q3 T3 pattern, with an S wave in lead I (as an RS or rS complex), an

abnormal Q wave in lead III, and an inverted T wave in the inferior leads. Finally, acute right ventricular pressure overload such as produced by pulmonary embolism may produce a characteristic ECG pattern (Fig. 5-23) , including (1) a QR or qR pattern in the right ventricular leads; (2) an S 1 Q3 T3 pattern with an S wave in lead I and new or increased Q waves in

Figure 5-23 Acute cor pulmonale secondary to pulmonary embolism simulating inferior and anterior infarction. This tracing exemplifies the classic pseudoinfarct patterns sometimes seen: an S 1 Q 3 T3 , a QR in V1 with poor R wave progression in the right precordial leads ("clockwise rotation"), and right precordial to midprecordial T wave inversion (V1 to V4 ). Sinus tachycardia is also present. The S1 Q 3 pattern is usually associated with a QR or QS complex, but not an rS, in aV r . Furthermore, acute cor pulmonale per se does not cause prominent Q waves in II (only in III and aV f ). (From Goldberger AL: Myocardial Infarction: Electrocardiographic Differential Diagnosis. 4th ed. St Louis, Mosby-Year Book, 1991.)

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TABLE 5-5 -- COMMON DIAGNOSTIC CRITERIA FOR RIGHT VENTRICULAR HYPERTROPHY CRITERION SENSITIVITY(%) SPECIFICITY(%) R in V1 0.7 mV

15 mEq/L).[150] Hypomagnesemia is usually associated with hypocalcemia or hypokalemia. Hypomagnesemia can potentiate certain digitalis toxic arrhythmias (see Chap. 23) . The role of magnesium deficiency in the pathogenesis and treatment of the acquired long QT(U) syndrome with torsades de pointes is discussed in Chapters 23 and 25 . OTHER FACTORS.

Isolated hypernatremia or hyponatremia does not produce consistent effects on the ECG. Acidemia and alkalemia are often associated with hyperkalemia and hypokalemia, respectively. Systemic hypothermia may be associated with the appearance of a distinctive convex elevation at the junction (J point) of the ST segment and QRS complex (J wave or Osborn wave) (Fig. 5-52) . The cellular mechanism of this type of pathological J wave appears to be related to an epicardial-endocardial voltage gradient associated with the localized appearance of a prominent epicardial action potential notch.[151]

Nonspecific QRS and ST-T Changes

Low QRS voltage is said to be present when the total amplitude of the QRS complexes in each of the six extremity leads is 0.5 mV or less or 1.0 mV or less in leads V1 through V6 . Low QRS voltage can relate to a variety of mechanisms (Table 5-12) , including increased insulation of the heart by air (chronic obstructive pulmonary disease) or adipose tissue (obesity); replacement of myocardium, for example, by fibrous tissue (ischemic or nonischemic cardiomyopathy), amyloid, or tumor; or short-circuiting effects (pericardial or pleural effusions). The combination of relatively low limb voltage (QRS voltage 0.8 mV in each of

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Figure 5-52 Systemic hypothermia. The arrows (V 3 through V6 ) point to the characteristic convex J waves, termed Osborn waves. Prominent sinus bradycardia is also present.(From Goldberger AL: Clinical Electrocardiography: A Simplified Approach. 6th ed. St Louis, CV Mosby, 1999.)

the limb leads), relatively prominent QRS voltage in the chest leads (SV1 or SV2 +RV5 or RV6 3.5 mV), and poor R wave progression (R wave less than the S wave in V1 through V4 ) has been reported as a relatively specific, but not sensitive sign of dilated-type cardiomyopathies (ECG-congestive heart failure triad).[152] Multiple factors in addition to ischemia (e.g., postural changes, meals, drugs, hypertrophy, electrolyte and metabolic disorders, central nervous system lesions, infections, pulmonary diseases) can affect the ECG.[85] Ventricular repolarization is particularly sensitive to these effects, which can lead to a variety of nonspecific ST-T changes. The term is usually applied to slight ST depression or T wave inversion or to T wave flattening without evident cause. Care must be taken to not overinterpret such changes, especially in subjects with a low prior probability of heart disease. At the same time, subtle repolarization abnormalities can be markers of coronary or hypertensive heart disease or other types of structural heart disease and probably account for the association of relatively minor but persistent nonspecific ST-T changes with increased cardiovascular mortality in middle-aged men.[153] TABLE 5-12 -- CAUSES OF LOW-VOLTAGE QRS COMPLEXES Adrenal insufficiency AnasarcaArtifactual or spurious, e.g., unrecognized standardization of the electrocardiogram at half the usual gain (i.e., 5 mm/mV)

Cardiac infiltration or replacement (e.g., amyloidosis, tumor) Cardiac transplantation, especially with acute or chronic rejection Cardiomyopathies, idiopathic or secondary* Chronic obstructive pulmonary disease Constrictive pericarditis Hypothyroidism (usually with sinus bradycardia) Left pneumothorax (mid-left chest leads) Myocardial infarction, extensive Myocarditis, acute or chronic Normal variant Obesity Pericardial tamponade (usually with sinus tachycardia) Pleural effusions *Dilated cardiomyopathies may be associated with a combination of relatively low limb lead voltage and prominent precordial voltage.[ 152]

Alternans Patterns

The term alternans applies to conditions characterized by the sudden appearance of a periodic beat-to-beat change in some aspect of cardiac electrical or mechanical behavior. These abrupt changes (AAAA ABAB pattern) are reminiscent of a generic class of subharmonic (period-doubling) bifurcation patterns, well described in perturbed nonlinear control systems. [21] [154] [155] Many different examples of electrical alternans have been described clinically[156] [157] [158] [159] [160] [160A] (Table 5-13) ; a number of others have been reported in the laboratory.[161] Most familiar is total electrical alternans with sinus tachycardia, a specific but not highly sensitive marker of pericardial effusion with tamponade physiology[162] (Fig. 5-53) (see Chap. 50) . This finding is associated with an abrupt transition from a 1:1 to a 2:1 pattern in the "to-fro" swinging motion of the heart in the effusion.[163] Other alternans patterns are due to primary electrical rather than mechanical causes. ST-T alternans has long been recognized as a marker of electrical instability in acute ischemia, where it may precede ventricular tachyarrhythmia[164] (see Fig. 5-39) . Considerable interest has recently been shown in the detection of microvolt T wave (or ST-T) alternans as a noninvasive marker of the risk of ventricular tachyarrhythmia in patients with chronic heart disease[165] [166] [167] [168] [169] (see Chap. 23) . Similarly, TU wave alternans (Fig. 5-54) may be a marker of imminent risk of a ventricular tachyarrhythmia such as torsades de pointes in hereditary or acquired long QT syndromes.[170] [171]

CLINICAL ISSUES IN ELECTROCARDIOGRAPHIC INTERPRETATION These principles and diagnostic ECG guidelines are, finally, subject to appropriate use in the clinical setting. Their effectiveness as a diagnostic tool depends on factors such as the indications for the procedure, the clinical context in which the ECG is used, and proper technique and skills of the ECG reader. INDICATIONS FOR AN ECG.

Little attention has been paid to the indications for an ECG, probably because of its seeming simplicity and low cost. However, the cumulative expense of low-cost tests performed at high volume is significant, and the risk to the patient of false diagnoses of

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TABLE 5-13 -- EXAMPLES OF ALTERNANS PATTERNS IN ECG DIAGNOSIS PATTERN COMMENT P wave alternans

Rarely reported; e.g., in pulmonary embolism [159]

"Total" electrical alternans (P-QRS-T) with sinus tachycardia

Swinging-heart mechanism in pericardial effusion/tamponade* (see Fig. 5-53)

PR interval alternans

Dual AV nodal pathway physiology; alternating bundle branch block (see Fig. 5-29)

ST segment alternans

Can precede ischemic ventricular tachyarrhythmias (see Fig. 5-39)

T wave (or ST-T) alternans

Can precede nonischemic ventricular tachyarrhythmias

TU wave alternans

Can precede torsades de pointes in long QT(U) syndromes, congenital or acquired (see Fig. 5-54)

QRS alternans in supraventricular or ventricular tachycardia

Most common with AV reentrant tachycardia (concealed bypass tract)

R-R (heart rate) alternans

With sinus rhythm, e.g., in congestive heart failure[157] With non-sinus rhythm tachyarrhythmias, e.g., PSVT

Bidirectional tachycardias

Usually ventricular in origin; may be caused by digitalis excess

Intermittent bundle branch/fascicular blocks or Wolff-Parkinson-White patterns

Rarely occur on beat-to-beat basis (see Fig. 5-29)

AV=atrioventricular; PSVT=paroxysmal supraventricular tachycardia. *Also case report of QRS-T alternans with sinus tachycardia in acute pulmonary embolism. [ 160]

cardiac disease can be damaging. Specific indications for the use of ECGs have been proposed and evaluated.[172] [172A] [173] [174] In patients with known cardiac disease, ECGs are warranted as part of a baseline examination; after therapy known to produce ECG changes that correlate with therapeutic responses, progression of disease, or adverse effects; and for intermittent follow-up with changes in signs or symptoms or relevant laboratory findings or after significant intervals (usually 1 year or longer), even in the absence of clinical changes. In patients suspected of having cardiac disease or at high risk for cardiac disease, an ECG is appropriate as part of an initial evaluation in the presence of signs or symptoms suggesting cardiac disease; in patients with important risk factors such as cigarette abuse, diabetes mellitus, peripheral vascular disease, or a family history of cardiac disease (including long QT interval syndromes and ventricular preexcitation); during therapy with cardioactive medications; and during follow-up if clinical events develop or at prolonged intervals (usually 1 year or more) if clinically stable. Preoperative tracings are appropriate for patients with known or suspected cardiac disease, although this application too may be questioned, especially if the cardiac condition is hemodynamically insignificant or the procedure is simple.[174] It has been common practice to include an ECG as part of routine health examinations, before any surgical procedure, and on any admission to a hospital in patients without current evidence of cardiac disease and without major risk factors. These ECGs are assumed to be of value in detecting any unknown abnormalities, serving as a baseline against which to compare later tracings, and assessing future risk of cardiovascular events. There is little evidence to support these practices. The overall sensitivity of the ECG for identifying specific patients who will have future events and the number of therapeutic or diagnostic changes provoked by routine ECG findings are too low to warrant universal screening.[57] [172] In these cases, use of the ECG should be based on clinical judgment rather than rigid protocol

Figure 5-53 Total electrical alternans (P-QRS-T) caused by pericardial effusion with tamponade. This finding, particularly in concert with sinus tachycardia and relatively low voltage, is a highly specific, although not sensitive marker of cardiac tamponade.

122

Figure 5-54 The QT(U) interval is prolonged and measures approximately 600 milliseconds with TU wave alternans. The tracing was recorded in a patient with chronic renal disease shortly following dialysis. This type of repolarization alternans may be a precursor to torsades de pointes. (Courtesy of C. Fisch, M.D.)

requirements. Flexible guidelines for ordering ECGs on general hospital admission and preoperatively have been proposed on the basis of age, gender, medical history, and physical examination.[172] [172A] KNOWLEDGE OF THE CLINICAL CONTEXT AND PRIOR ECG FINDINGS.

Although most ECGs are read without a priori knowledge of the clinical condition of the patient, the accuracy and the value of the interpretation are enhanced by having clinical information about the patient. Such knowledge may include, for example, information about drug therapy, which may be a cause of observed ECG abnormalities, or prior myocardial infarction, which may produce ECG changes mimicking acute ischemia.[175] [176]

Similarly, the availability of prior ECGs can improve the clinical value of the ECG. For example, knowledge of prior ECG patterns can improve diagnostic accuracy and triage decisions for patients with current ECG and clinical evidence of ischemia or infarction, as well as improve the proper interpretation of, for example, bundle branch block in the setting of acute infarction.[177] [178] [178A] TECHNICAL ERRORS AND ARTIFACTS.

Technical errors can lead to significant diagnostic mistakes that can result in false diagnoses that place patients at risk for unneeded and potentially dangerous diagnostic tests and treatments and unnecessarily use limited health care resources. [179] Misplacement of one or more ECG electrodes is a common cause for errors in ECG interpretation. Some misplacements produce ECG patterns that can aid in identification of the error.[180] [181] [182] Reversal of the two arm electrodes, for example, results in an inverted waveform in lead I but not in lead V6 , two leads that would normally be expected to have similar polarities. Others are not as obvious. For example, placing the right precordial electrodes too high on the chest can yield patterns that mimic those produced by anterior myocardial infarction (poor R wave progression) or intraventricular conduction delay (rSr patterns). Electrical or mechanical artifacts such as produced by poor electrode contacts or tremors can simulate life-threatening arrhythmias[179] (Fig. 5-55) , and excessive body motion can cause excessive baseline wander that may simulate an ST segment shift of myocardial ischemia or injury. READING ERRORS.

Errors in interpreting ECGs are common. [182] Studies assessing the accuracy of routine interpretations have demonstrated significant numbers of errors that can lead to clinical mismanagement, including failure to appropriately detect and triage patients with acute

myocardial ischemia and other life-threatening situations.[183] Organizations such as the American College of Cardiology have proposed minimal training and experience standards for electrocardiographers to help reduce these potentially serious errors.[184] A final issue concerns overreliance on computerized interpretations. Computer systems have facilitated storage and retrieval of large numbers of ECGs and, as diagnostic algorithms have become more accurate, have provided important adjuncts to the clinical interpretation of ECGs. However, the current systems are not sufficiently accurate,[185] [186] especially in the presence of rhythm disturbances or complex abnormalities, to be relied on in critical clinical environments without expert review. New analysis techniques based upon artificial intelligence concepts may lead to future improvements,[187] [187A] and new hardware technology may result in expanded deployment of systems for prompt expert interpretation.[187B]

Figure 5-55 Artifacts simulating serious arrhythmias. A, Motion artifact mimicking ventricular tachyarrhythmia. Partly obscured normal QRS complexes (arrows) can be seen with a heart rate of about 100 beats/min. B, Parkinsonian tremor causing baseline oscillations mimicking atrial fibrillation. The regularity of QRS complexes may provide a clue to this artifact.

123

REFERENCES INTRODUCTION AND FUNDAMENTAL PRINCIPLES Fye WB: A history of the origin, evolution, and impact of electrocardiography. Am J Cardiol 73:937-949, 1994. 1.

Barr RC: Genesis of the electrocardiogram. In MacFarlane PW, Lawrie TDV (eds): Comprehensive Electrocardiography: Theory and Practice in Health and Disease. New York, Pergamon, 1989. 2.

Holland RP, Arnsdorf MF: Solid angle theory and the electrocardiogram: Physiologic and quantitative interpretations. Prog Cardiovasc Dis 19:431-457, 1977. 3.

Rudy Y, Plonsey R: A comparison of volume conductor and source geometry effects on body surface and epicardial potentials. Circ Res 46:283-291, 1980. 4.

Spach MS, Dolber PC: Relating extracellular potentials and their derivatives to anisotropic propagation at a microscopic level in human cardiac muscle. Circ Res 58:356-371, 1986. 5.

6.

Mirvis DM: Physiology and biophysics in electrocardiography. J Electrocardiol 29:175-177, 1996.

Zywitz C: Technical aspects of the electrocardiographic recording. In MacFarlane PW, Lawrie TDV (eds): Comprehensive Electrocardiography. New York, Pergamon, 1989. 7.

8.

Casas RE, Marriott HJL, Glancy DL: Value of leads V 7 -V9 in diagnosing posterior wall acute

myocardial infarction and other causes of tall R waves in V 1 -V2 . Am J Cardiol 80:508, 1997. Novak PG, Davies C, Gin KG: Survey of British Columbia cardiologists' and emergency physicians: Practice of using nonstandard ECG leads (V 4 R to V 6 R and V7 to V 9 ) in the diagnosis and treatment of 8A.

acute myocardial infarction. Can J Cardiol 15:967-972, 1999. 8B.

Chia BL, Tan HC, Yip JW, Ang TL: Electrocardiographic patterns in posterior chest leads (V 7 , V8 , V9 )

in normal subjects. Am J Cardiol 85:911-912, 2000. Ott P, Marcus FI, Scott WA, et al: Superiority of a vertical parasternal lead for detection of arrhythmias during ambulatory electrocardiographic monitoring. Am J Cardiol 69:625-627, 1992. 9.

10.

Mirvis DM: Body Surface Electrocardiographic Mapping. Boston, Kluwer, 1988.

Mirvis DM, Berson AS, Goldberger AL, et al: Instrumentation and practice standards for electrocardiographic monitoring in special care units. A report for health professionals by a Task Force of the Council on Clinical Cardiology, American Heart Association. Circulation 79:464-471, 1989. 11.

Kors JA, van Herpen G, Willens JL, et al: Improvement of automated electrocardiographic diagnosis by combination of computer interpretations of the electrocardiogram and the vectorcardiogram. Am J Cardiol 70:96-99, 1992. 12.

Hoekema R, Uijen GJH, van Erning L, et al: Interindividual variability of multilead electrocardiographic recordings. J Electrocardiol 32:137-148, 1999. 13.

Bailey JJ, Berson AS, Garson A, et al: Recommendations and specifications in automated electrocardiography: Bandwidth and digital signal processing. Circulation 81:730-739, 1990. 14.

THE NORMAL ELECTROCARDIOGRAM Chang BC, Scheussler RB, Stone CM, et al: Computerized activation sequence mapping of the human atrial septum. Ann Thorac Surg 49:231, 1990. 15.

Stovut DP, Wenstrom JC, Moeckel RB, et al: Respiratory sinus dysrhythmia persists in transplanted human hearts following autonomic blockade. Clin Exp Pharmacol Physiol 25:322-330, 1998. 16.

Huikuri HV, Makikallio TH, Airaksinen KE, et al: Power-law relationship of heart rate variability as a predictor of mortality in the elderly. Circulation 97:2031-2036, 1998. 17.

18.

Malik M, Camm AJ (eds): Heart Rate Variability. Armonk, NY, Futura, 1995.

Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology: Heart rate variability standards of measurement, physiologic interpretation, and clinical use. Circulation 93:1043-1065, 1996. 19.

Van Ravenswaaij-Arts CMA, Kollee LAA, Hopman JCW, et al: Heart rate variability. Ann Intern Med 118:436-447, 1993. 20.

21.

Goldberger AL: Nonlinear dynamics for clinicians: Chaos theory, fractals, and complexity at the

bedside. Lancet 347:1312-1314, 1996 (see also http://reylab.bidmc.harvard.edu/publications/hrv-refs.html). Debbas NMG, Jackson SHD, de Jonghe D, et al: Human atrial depolarization: Effects of sinus rate, pacing and drugs on the surface electrocardiogram. J Am Coll Cardiol 33:358-365, 1999. 22.

Sapin PM, Koch G, Blauwet MB, et al: Identification of false positive exercise tests with use of electrocardiographic criteria: A possible role for atrial repolarization waves. J Am Coll Cardiol 18:127-135, 1991. 23.

Janse MJ: Propagation of atrial impulses through the atrioventricular node. In Toubol P, Waldo AL (eds): Atrial Arrhythmias. St Louis, Mosby-Year Book, 1990. 24.

Flowers NC, Horan LG, Yang WQ: Application of beat-to-beat techniques. Pacing Clin Electrophysiol 13:2148-2155, 1990. 25.

Durrer D, van Dam RT, Freud GF, et al: Total excitation of the human heart. Circulation 41:899-912, 1970. 26.

Abboud S, Berenfield D, Sadeh D: Simulation of high resolution QRS complex using a ventricular model with a fractal conduction system. Effects of ischemia on high frequency QRS potentials. Circ Res 68:1751-1760, 1991. 27.

Mathew TC, Shankariah L, Spodick DH: Electrocardiographic correlates of absent septal q waves. Am J Cardiol 82:809-811, 1998. 28.

Xiao HB, Gibson DG: Absent septal q wave: A marker of the effects of abnormal activation pattern on left ventricular diastolic function. Br Heart J 72:45-51, 1994. 29.

Goldberger AL: The genesis of indeterminate axis: A quantitative vectorcardiographic analysis. J Electrocardiol 15:221-226, 1982. 30.

Selvester RH, Velasquez DW, Elko PP, Cady LD: Intraventricular conduction defect (IVCD), real or fancied: QRS duration in 1,254 normal adult white males by a multilead automated algorithm. J Electrocardiol 23(Suppl):118-122, 1990. 31.

MacFarlane PW, Lawrie TDV (eds): Comprehensive Electrocardiology: Theory and Practice in Health and Disease. Vol 3. New York, Pergamon, 1989. 32.

Franz MR, Bargheer K, Costartd-Jackle A, et al: Human ventricular repolarization and T wave genesis. Prog Cardiovasc Dis 33:369-384, 1991. 33.

Surawicz B: U wave: Facts, hypotheses, misconceptions, and misnomers. J Cardiovasc Electrophysiol 9:1117-1128, 1998. 34.

Molnar J, Weiss J, Zhang F, et al: Evaluation of five QT correction formulas using a software-assisted method for continuous QT measurements from 24-hour Holter recordings. Am J Cardiol 78:920-926, 1996. 35.

Franz MR: Time for yet another QT correction algorithm? Bazett and beyond. J Am Coll Cardiol 23:1554-1557, 1994. 36.

37.

Day CP, McComb JM, Campbell RWF: QT dispersion: An indicator of arrhythmia risk in patients with

long QT intervals. Br Heart J 63:342-344, 1990. Statters DJ, Malik M, Ward DE, et al: QT dispersion: Problems of methodology and clinical significance. J Cardiovasc Electrophysiol 5:672-685, 1994. 38.

38A. Franz

MR, Zabel M: Electrophysiological basis of QT dispersion measurements. Prog Cardiovasc Dis 47:311-324, 2000. 39.

Macfarlane PW, Lawrie TDV: Comprehensive Electrocardiography. New York, Pergamon, 1989.

Bertolet BD, Boyette AF, Hofmann CA, et al: Prevalence of pseudoischemic ST-segment changes during ambulatory electrocardiographic monitoring. Am J Cardiol 70:818-820, 1992. 40.

Vitelli LL, Crow RS, Shahar E, et al: Electrocardiographic findings in a healthy biracial population. Am J Cardiol 81:453-459, 1998. 41.

42.

Mehta M, Jain AC, Mehta A: Early repolarization. Clin Cardiol 27:59-65, 1999.

42A. Haydar

ZR, Brantley DA, Gittings NS, et al: Early repolarization: An electrocardiographic predictor of enhanced aerobic fitness. Am J Cardiol 85:264-266, 2000. Mirvis DM: Evaluation of normal variations in S-T segment patterns by body surface isopotential mapping: S-T segment elevation in absence of heart disease. Am J Cardiol 50:122-128, 1982. 43.

ATRIAL ABNORMALITIES; VENTRICULAR HYPERTROPHY AND ENLARGEMENT Fitzgerald DM, Hawthorne HR, Crossley GH, et al: P wave morphology during atrial pacing along the atrioventricular ring. J Electrocardiol 29:1-10, 1996. 44.

44A. Pinter

A, Molin F, Savard P, et al: Body surface mapping of retrograde P waves in the intact dog by simulation of accessory pathway re-entry. Can J Cardiol 16:175-182, 2000. Hazen MS, Marwick TH, Underwood DA: Diagnostic accuracy of the resting electrocardiogram in detection and estimation of left atrial enlargement: An echocardiographic correlation in 551 patients. Am Heart J 79:819-828, 1997. 45.

Faggiano P, D'Aloia A, Zanelli E, et al: Contribution of left atrial pressure and dimension to signal-averaged P-wave duration in patients with chronic congestive heart failure. Am J Cardiol 79:219-222, 1997. 46.

Genovese-Ebert A, Marabotti C, Palombo C, et al: Electrocardiographic signs of atrial overload in hypertensive patients: Indexes of abnormality of atrial morphology or function? Am Heart J 121:1113-1118, 1991. 47.

Morris JJ, Estes EH, Whalen RE, et al: P wave analysis in valvular heart disease. Circulation 29:242-252, 1964. 48.

Kaplan JD, Evans GT, Foster E, et al: Evaluation of electrocardiographic criteria for right atrial enlargement by quantitative two-dimensional echocardiography. J Am Coll Cardiol 23:747-752, 1994. 49.

Incalzi RA, Fuso L, De Rosa M, et al: Electrocardiographic signs of cor pulmonale. A negative prognostic finding in chronic obstructive pulmonary disease. Circulation 99:1600-1605, 1999. 50.

Maeda S, Katsua H, Chida K, et al: Lack of correlation between P-pulmonale and right atrial overload in chronic obstructive airways disease. Br Heart J 65:132-136, 1991. 51.

Usui M, Inoue H, Suzuki J, et al: Relationship between distribution of hypertrophic and electrocardiographic changes in hypertrophic cardiomyopathy. Am Heart J 126:177-183, 1993. 52.

Xiao HB, Brecker SJ, Gibson DG: Relative effects of left ventricular mass and conduction disturbance on activation in patients with pathological left ventricular hypertrophy. Br Heart J 71:548-553, 1994. 53.

Casale PN, Devereux RB, Kligfield P, et al: Electrocardiographic detection of left ventricular hypertrophy: Development and prospective validation of improved criteria. J Am Coll Cardiol 6:572-578, 1985. 54.

Molloy TJ, Okin PM, Devereux RB, et al: Electrocardiographic detection of left ventricular hypertrophy by the simple QRS voltage-duration product. J Am Coll Cardiol 20:1180-1186, 1992. 55.

124

Rautaharju PM, Zhou SH, Park LP: Improved ECG models for left ventricular mass adjusted for body size, with specific algorithms for normal conduction, bundle branch block, and old myocardial infarction. J Electrocardiol 29(Suppl):261-269, 1996. 56.

Ashley EA, Raxwal VK, Froelicher VF: The prevalence and prognostic significance of electrocardiographic abnormalities. Curr Probl Cardiol 25:1-72, 2000. 57.

Rautaharju PM, LaCroix AZ, Savage DD, et al: Electrocardiographic estimate of left ventricular mass versus radiographic cardiac size and the risk of cardiovascular disease mortality in the epidemiologic follow-up study of the First National Health and Nutrition Examination Study. Am J Cardiol 62:59-66, 1988. 58.

Rautaharju PM, Park L, Rautaharju FS, et al: A standardized procedure for locating and documenting ECG chest electrode positions: Consideration of the effect of breast tissue on ECG amplitudes of women. J Electrocardiol 31:17-29, 1998. 59.

59A. Okin

PM, Jern S, Devereux RB, et al: Effect of obesity on electrocardiographic left ventricular hypertrophy in hypertensive patients: The losartar intervention for endpoint (LIFE) reduction in hypertension study. Hypertension 35:13-18, 2000. 60.

Mirvis DM: The electrocardiogram as a prognostic tool. ACC Curr Rev J, in press.

Levy D, Salomon M, D'Agostino RB, et al: Prognostic applications of baseline electrocardiographic features and their serial changes in subjects with left ventricular hypertrophy. Circulation 90:1786-1793, 1994. 61.

Menotti A, Seccareccia F: Electrocardiographic Minnesota code findings predicting short-term mortality in asymptomatic subjects. The Italian RIFLE Pooling Project (Risk Factors and Life Expectancy). G Ital Cardiol 27:40-49, 1997. 62.

63.

Kannel WB: Left ventricular hypertrophy as a risk factor: The Framingham experience. J Hypertens

9(Suppl):53-59, 1991. Che J, Okin PM, Roman MJ, et al: Combined rest and exercise electrocardiographic repolarization findings in relation to structural and functional abnormalities in asymptomatic aortic regurgitation. Am Heart J 132:343-347, 1996. 64.

Murphy ML, Thenabadu PN, de Soyza N, et al: Reevaluation of electrocardiographic criteria for left, right and combined cardiac ventricular hypertrophy. Am J Cardiol 53:1140-1147, 1984. 65.

Sreeram N, Cheriex EC, Smeets JL, et al: Value of the 12-lead electrocardiogram at hospital admission in the diagnosis of pulmonary embolism. Am J Cardiol 73:298-303, 1994. 66.

Chen PS, Moser KM, Dembitsky WP, et al: Epicardial activation and repolarization patterns in patients with right ventricular hypertrophy. Circulation 83:104-118, 1991. 67.

67A. Jain

A, Chandna H, Silber EN, et al: Electrocardiographic patterns of patients with echocardiographically determined biventricular hypertrophy. J Electrocardiol 32:269-273, 1999.

INTRAVENTRICULAR CONDUCTION DELAYS AND PREEXCITATION 68.

Rosenbaum MB, Elizari MV, Lazzari JO: The Hemiblocks. Oldsmar, FL, Tampa Tracings, 1970.

Assali A, Scarlovsky S, Herz I, et al: Importance of left anterior hemiblock development in inferior wall acute myocardial infarction. Am J Cardiol 79:672-274, 1997. 69.

Ducceschi V, Sarubbi B, D'Andrea A, et al: Electrophysiologic significance of leftward QRS axis deviation in bifascicular and trifascicular block. Clin Cardiol 21:597-583, 1998. 70.

Mehdirad AA, Nelson SD, Love CJ, et al: QRS duration widening: Reduced synchronization of endocardial activation or transseptal conduction time? Pacing Clin Electrophysiol 21:1589-1564, 1998. 71.

Newby KH, Pisano E, Krucoff MW, et al: Incidence and clinical relevance of the occurrence of bundle branch block in patients with thrombolytic therapy. Circulation 94:2424-2428, 1996. 72.

Parharidis G, Nouskas J, Efthimiadis G, et al: Complete left bundle branch block with left QRS axis deviation: Defining its clinical importance. Acta Cardiol 52:295-303, 1997. 73.

Nikolic G, Marriott HJ: Left bundle branch block with right axis deviation: A marker of congestive cardiomyopathy. J Electrocardiol 18:395-404, 1985. 74.

Xiao HB, Brecker SJ, Gibson DG: Differing effects of right ventricular pacing and left bundle branch block on left ventricular function. Br Heart J 69:166-173, 1993. 75.

Skalidis EI, Kochiadakis GE, Koukouraki SI, et al: Phasic coronary flow pattern and flow reserve in patients with left bundle branch block and normal coronary arteries. J Am Coll Cardiol 33:1338-1346, 1999. 76.

Delonca J, Camenzind E, Meier B, et al: Limits of thallium-201 exercise scintigraphy to detect coronary disease in patients with complete and permanent bundle branch block: A review of 134 cases. Am Heart J 123:1201-1207, 1992. 77.

78.

Vaduganathan P, He Z-X, Raghavan C, et al: Detection of left anterior descending coronary artery

stenosis in patients with left bundle branch block: Exercise, adenosine, or dobutamine imaging? J Am Coll Cardiol 28:543-550, 1996. Ricou F, Nicod P, Gilpin E, et al: Influence of right bundle branch block on short- and long-term survival after acute anterior myocardial infarction. J Am Coll Cardiol 17:858-863, 1991. 79.

Brugada P, Brugada J: Right bundle branch block, persistent ST segment elevation and sudden cardiac death: A distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol 20:1391-1396, 1992. 80.

Brugada J, Brugada P: Further characterization of the syndrome of right bundle branch block, ST segment elevation, and sudden cardiac death. J Cardiovasc Electrophysiol 8:325-331, 1997. 81.

De Leonardis V, Goldstein SA, Lindsay J Jr: Electrocardiographic diagnosis of left ventricular hypertrophy in the presence of complete right bundle branch block. Am J Cardiol 62:590-593, 1988. 82.

Spodick DH: Fascicular blocks: Not interpretable from the electrocardiogram. Am J Cardiol 70:809-810, 1992. 83.

84.

Fisch C: The Electrocardiography of Arrhythmias. Philadelphia, Lea & Febiger, 1990.

MYOCARDIAL ISCHEMIA AND INFARCTION Goldberger AL: Myocardial Infarction: Electrocardiographic Differential Diagnosis. 4th ed. St Louis, Mosby-Year Book, 1991. 85.

86.

Mirvis DM: Electrocardiography: A Physiologic Approach. St Louis, Mosby-Year Book, 1993.

87.

Clements IP (ed): The Electrocardiogram in Acute Myocardial Infarction. Armonk, NY, Futura, 1998.

Kubota I, Yamaki M, Shibata T, et al: Role of ATP-sensitive K+ channel on ECG ST-segment elevation during a bout of myocardial ischemia. Circulation 88:1845-1851, 1993. 88.

89.

Goldberger AL: Hyperacute T waves revisited. Am Heart J 104:888-890, 1982.

Goldberger AL, Erickson R: A subtle ECG sign of myocardial infarction: Prominent reciprocal ST depression with minimal ST elevation. Pacing Clin Electrophysiol 4:709-712, 1981. 90.

Mirvis DM: Physiologic bases for anterior ST segment depression in patients with acute inferior wall myocardial infarction. Am Heart J 116:1308-1322, 1988. 91.

Kracoff OH, Adelman AG, Oettinger M, et al: Reciprocal changes as the presenting electrocardiographic manifestation of acute myocardial ischemia. Am J Cardiol 71:1359-1362, 1993. 92.

Hohnloser SH, Zabel M, Kasper W, et al: Assessment of coronary artery patency after thrombolytic therapy: Accurate prediction utilizing the combined analysis of three noninvasive markers. J Am Coll Cardiol 18:44-49, 1991. 93.

Krucoff MW, Croll MA, Pope JE, et al: Continuous 12-lead ST-segment recovery analysis in the TAMI 7 Study: Performance of a noninvasive method for real-time detection of failed myocardial reperfusion. Circulation 88:437-446, 1993. 94.

94A. de

Lemos JA, Antman EM, Giugliano RP, et al: ST-segment resolution and infarct-related artery patency and flow after thrombolytic therapy. Am J Cardiol 85:299-304, 2000. van't Hof AW, Liem A, de Boer MJ, et al: Clinical value of 12-lead electrocardiogram after successful reperfusion therapy for acute myocardial infarction. Zwolle Myocardial Infarction Study Group. Lancet 350:615-619, 1997. 95.

Mirvis DM, Ingram LA, Ramanathan KB, et al: R and S wave changes produced by experimental nontransmural and transmural myocardial infarction. J Am Coll Cardiol 8:675-681, 1986. 96.

Phibbs B, Marcus F, Marriott HJ, et al: Q-wave versus non-Q-wave myocardial infarction: A meaningless distinction. J Am Coll Cardiol 33:576-582, 1999. 97.

Zema MJ: Electrocardiographic tall R waves in the right precordial leads. Comparison of recently proposed ECG and VCG criteria for distinguishing posterolateral myocardial infarction from prominent anterior forces in normal subjects. J Electrocardiol 23:147-156, 1990. 98.

98A. Bosimini

E, Giannuzzi P, Temporelli PL, et al: Electrocardiographic evolutionary changes and left ventricular remodeling after acute myocardial infarction: Results of the GISSI-3 Echo substudy. J Am Coll Cardiol 35:127-135, 2000. Maeda S, Imai T, Kuboki K, et al: Pathologic implications of restored positive T waves and persistent negative T waves after Q wave myocardial infarction. J Am Coll Cardiol 28:1514, 1996. 99.

Nagase K, Tamura A, Mikuriya Y, et al: Significance of Q-wave regression after anterior wall acute myocardial infarction. Eur Heart J 19:742, 1998. 100.

Wong ND, Levy D, Kannel WB: Prognostic significance of the electrocardiogram after Q wave myocardial infarction. The Framingham Study. Circulation 81:780-789, 1990. 101.

de Zwaan C, Bar FW, Janssen JH, et al: Angiographic and clinical characteristics of patients with unstable angina showing an ECG pattern indicating critical narrowing of the proximal LAD coronary artery. Am Heart J 117:657-665, 1989. 102.

Renkin J, Wijns W, Ladha Z, et al: Reversal of segmental hypokinesis by coronary angioplasty in patients with unstable angina, persistent T wave inversion, and left anterior descending coronary artery stenosis. Additional evidence for myocardial stunning in humans. Circulation 82:913-921, 1990. 103.

Oliva PB, Hammill SC, Edwards WD: Electrocardiographic diagnosis of postinfarction regional pericarditis: Ancillary observations regarding the effect of reperfusion on the rapidity and amplitude of T wave inversion after acute myocardial infarction. Circulation 88:896-904, 1993. 104.

Chikamori T, Kitaoka H, Matsumura Y, et al: Clinical and electrocardiographic profiles producing exercise-induced U-wave inversion in patients with severe narrowing of the left anterior descending coronary artery. Am J Cardiol 80:628-632, 1997. 105.

Jaffe ND, Boden WE: Spontaneous transient, inverted U waves as initial electrocardiographic manifestation of unstable angina. Am Heart J 129:1028-1030, 1995. 106.

125

107.

Hingham PD, Campbell RWF: QT dispersion. Br Heart J 71:508, 1994.

Moreno FL, Villanueva T, Karagounis LA, et al: Reduction of QT interval dispersion by successful thrombolytic therapy in acute myocardial infarction. Circulation 90:94, 1994. 108.

Brezins M, Elyassov S, Elimelech I, et al: Comparison of patients with myocardial infarction with and without ventricular fibrillation. Am J Cardiol 78:948, 1996. 109.

Schneider CA, Voth E, Baer FM, et al: QT dispersion is determined by the extent of viable myocardium in patients with chronic Q-wave myocardial infarction. Circulation 96:3913, 1997. 110.

Sporton SC, Taggart P, Sutton PM, et al: Acute ischemia: A dynamic influence on QT dispersion. Lancet 349:306, 1997. 111.

Hohnloser SH: Effect of coronary ischemia on QT dispersion. Prog Cardiovasc Dis 42:351-358, 2000. 111A.

Dabrowski A, Kramarz E, Piotrowicz R, Kubik L: Predictive power of increased QT dispersion in ventricular extrasystoles and in sinus beats for risk stratification after myocardial infarction. Circulation 101:1693-1697, 2000. 111B.

Kulkarni AU, Brown R, Ayoubi M, et al: Clinical use of posterior electrocardiographic leads: A prospective electrocardiographic analysis during coronary occlusion. Am Heart J 131:736-741, 1996. 112.

Agarwal JB, Khaw K, Aurignac F, et al: Importance of posterior chest leads in patients with suspected myocardial infarction, but nondiagnostic, routine 12-lead electrocardiogram. Am J Cardiol 83:323-326, 1999. 113.

Matetzky S, Freimark D, Chouraqui P, et al: Significance of ST segment elevations in posterior chest leads (V 7 to V 9 ) in patients with acute inferior myocardial infarction: Application for thrombolytic therapy. 114.

J Am Coll Cardiol 31:506-511, 1998. Zimetbaum PJ, Krishnan S, Gold A, et al: Usefulness of ST-segment elevation in lead III exceeding that of lead II for identifying the location of the totally occluded coronary artery in inferior wall myocardial infarction. Am J Cardiol 81:918-919, 1998. 115.

116.

Kinch JW, Ryan TJ: Right ventricular infarction. N Engl J Med 330:1211, 1994.

Zehender M, Kasper W, Kauder E, et al: Right ventricular infarction as an independent predictor of prognosis after acute inferior myocardial infarction. N Engl J Med 328:981, 1993. 117.

Menown IBA, Allen J, Anderson JMcC, et al: Early diagnosis of right ventricular or posterior infarction associated with inferior wall left ventricular acute myocardial infarction. Am J Cardiol 85:934-938, 2000. 117A.

Porter A, Herz I, Strasberg B: Isolated right ventricular infarction presenting as anterior wall myocardial infarction on electrocardiography. Clin Cardiol 20:971-973, 1997. 118.

Mak KH, Chia BL, Tan ATH, et al: Simultaneous ST-segment elevation in lead V 1 and depression in lead V2 : A discordant ECG pattern indicating right ventricular infarction. J Electrocardiol 27:203-207, 119.

1994.

Engelen DJ, Gorgels AP, Cheriex EC, et al: Value of the electrocardiogram in localizing the occlusion site in the left anterior descending coronary artery in acute anterior myocardial infarction. J Am Coll Cardiol 34:389-395, 1999. 120.

Kosuge M, Kimura K, Ishikawa T, et al: New electrocardiographic criteria for predicting the site of coronary artery occlusion in inferior wall acute myocardial infarction. Am J Cardiol 82:1318-1322, 1998. 121.

Kontos MC, Desai PV, Jesse RL, et al: Usefulness of the admission electrocardiogram for identifying the infarct-related artery in inferior wall acute myocardial infarction. Am J Cardiol 79:182-184, 1997. 122.

Shah A, Wagner GS, Green CL, et al: Electrocardiographic differentiation of the ST-segment depression of acute myocardial injury due to the left circumflex artery occlusion from that of myocardial ischemia of nonocclusive etiologies. Am J Cardiol 80:512-513, 1997. 123.

Herz I, Assali AR, Adler Y, et al: New electrocardiographic criteria for predicting either the right or left circumflex artery as the culprit coronary artery in inferior wall acute myocardial infarction. Am J Cardiol 80:1343-1345, 1997. 124.

Assali AR, Sclarovsky S, Herz I, et al: Comparison of patients with inferior wall acute myocardial infarction with versus without ST-segment elevation in leads V 5 and V6 . Am J Cardiol 81:81-83, 1998. 125.

Arbane M, Goy JJ: Prediction of the site of total occlusion in the left anterior descending coronary artery using admission electrocardiogram in anterior wall acute myocardial infarction. Am J Cardiol 85:487-491, 2000. 125A.

Assali A, Sclarovsky S, Herz I, et al: Persistent ST segment depression in precordial leads V5 -V6 after Q-wave anterior wall myocardial infarction is associated with restrictive physiology of the left ventricle. J Am Coll Cardiol 35:352-357, 2000. 125B.

Sapin PM, Musselman DR, Dehmer GJ, Cascio WE: Implications of inferior ST-segment elevation accompanying anterior wall acute myocardial infarction for the angiographic morphology of the left anterior descending coronary artery morphology and site of occlusion. Am J Cardiol 69:860-865, 1992. 126.

Sgarbossa EB, Pinski SL, Barbagelata A, et al: Electrocardiographic diagnosis of evolving acute myocardial infarction in the presence of left bundle-branch block. GUSTO-1 (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries). N Engl J Med 334:481-487, 1996. 127.

Wellens HJ: Acute myocardial infarction and left bundle branch block--can we lift the veil? N Engl J Med 334:528, 1996. 128.

Laham CL, Hammill SC, Gibbons RJ: New criteria for the diagnosis of healed inferior wall myocardial infarction in patients with left bundle branch block. Am J Cardiol 79:19, 1997. 129.

Sgarbossa EB, Pinski SL, Gates KB, et al: Early electrocardiographic diagnosis of acute myocardial infarction in the presence of ventricular paced rhythm. GUSTO-1 investigators. Am J Cardiol 77:423-424, 1996. 130.

Lazar EJ, Goldberger J, Peled H, et al: Atrial infarction: Diagnosis and management. Am Heart J 116:1058-1063, 1988. 131.

132.

Pirwitz MJ, Lange RA, Landau C, et al: Utility of the 12-lead electrocardiogram in identifying

underlying coronary artery disease in patients with depressed left ventricular systolic function. Am J Cardiol 77:1289, 1996. Maron BJ: Q waves in hypertrophic cardiomyopathy: A reassessment. J Am Coll Cardiol 16:375-376, 1990. 133.

Van Gelder IC, Crijns HJ, Van der Laarse A, et al: Incidence and clinical significance of ST segment elevation after electrical cardioversion of atrial fibrillation and atrial flutter. Am Heart J 121:51-56, 1991. 134.

Kok LC, Mitchell MA, Haines DE, et al: Transient ST elevation after transthoracic cardioversion in patients with hemodynamically unstable ventricular tachyarrhythmia. Am J Cardiol 85:878-881, 2000. 134A.

Krishnan SC, Josephson ME: ST segment elevation induced by class IC antiarrhythmic agents: Underlying electrophysiologic mechanisms and insights into drug-induced proarrhythmia. J Cardiovasc Electrophysiol 9:1167-1172, 1998. 135.

Bonnefoy E, Godon P, Kirkorian G, et al: Serum cardiac troponin I and ST-segment elevation in patients with acute pericarditis [Comment]. Eur Heart J 21:832-836, 2000. 135A.

Baljepally R, Spodick DH: PR-segment deviation as the initial electrocardiographic response in acute pericarditis. Am J Cardiol 81:1505-1506, 1998. 136.

Morgera T, De Lenarda A, Dreas L, et al: Electrocardiography of myocarditis revisited: Clinical and prognostic significance of electrocardiographic changes. Am Heart J 124:455-467, 1992. 137.

138.

Samuels MA: Neurogenic heart disease: A unifying hypothesis. Am J Cardiol 60:15J-19J, 1987.

Pollick C, Cujec B, Parker S, et al: Left ventricular wall motion abnormalities in subarachnoid hemorrhage: An echocardiographic study. J Am Coll Cardiol 12:600-605, 1988. 139.

Elrifai AM, Bailes JE, Shih SR, et al: Characterization of the cardiac effects of acute subarachnoid hemorrhage in dogs. Stroke 27:737-741, 1996. 140.

Geller JC, Rosen MR: Persistent T-wave changes after alteration of the ventricular activation sequence: New insights into cellular mechanisms of 'cardiac memory.' Circulation 88:1811-1819, 1993. 141.

Helguera ME, Pinski SL, Sterba R, et al: Memory T waves after radiofrequency catheter ablation of accessory atrioventricular connections in Wolff-Parkinson-White syndrome. J Electrocardiol 27:243-249, 1994. 142.

143.

Walder LA, Spodick DH: Global T wave inversion. J Am Coll Cardiol 17:1479-1485, 1991.

Walder LA, Spodick DH: Global T wave inversion: Long-term follow-up. J Am Coll Cardiol 21:1652-1656, 1993. 144.

DRUG EFFECTS, ELECTROLYTE AND METABOLIC ABNORMALITIES; NONSPECIFIC QRS AND ST-T ABNORMALITIES; ALTERNANS PATTERNS 144A.

Reilly JG, Ayis SA, Ferrier IN, et al: QTc -interval abnormalities and psychotropic drug therapy in

psychiatric patients. Lancet 355:1048-1052, 2000. 145.

Wolfe TR, Caravati EM, Rollins DE: Terminal 40-ms frontal plane QRS axis as a marker for tricyclic

antidepressant overdose. Ann Emerg Med 18:348-351, 1989. Ahmed R, Yano K, Mitsuoka T, et al: Changes in T wave morphology during hypercalcemia and its relation to the severity of hypercalcemia. J Electrocardiol 22:125-132, 1989. 146.

Yu AS: Atypical electrocardiographic changes in severe hyperkalemia. Am J Cardiol 77:906-908, 1996. 147.

Martinez-Vea A, Bardaji A, Garcia C, et al: Severe hyperkalemia with minimal electrocardiographic manifestations: A report of seven cases. J Electrocardiol 32:45-49, 1999. 148.

Goldberger AL: Clinical Electrocardiography: A Simplified Approach. 6th ed. St Louis, CV Mosby, 1999. 149.

Agus ZS, Morad M: Modulation of cardiac ion channels by magnesium. Annu Rev Physiol 53:299-307, 1991. 150.

Yan GX, Antzelevitch C: Cellular basis for the electrocardiographic J wave. Circulation 93:372-379, 1996. 151.

Goldberger AL: A specific ECG triad associated with congestive heart failure. Pacing Clin Electrophysiol 5:593-599, 1982. 152.

Daviglus ML, Liao Y, Greenland P, et al: Association of nonspecific minor ST-T abnormalities with cardiovascular mortality: The Chicago Western Electric Study. JAMA 281:530-536, 1999. 153.

Glass L, Mackey MC: From Clocks to Chaos: The Rhythms of Life. Princeton, NJ, Princeton University Press, 1988. 154.

155.

Kaplan DT, Glass L: Understanding Nonlinear Dynamics. New York, Springer-Verlag, 1995.

Surawicz B, Fisch C: Cardiac alternans: Diverse mechanisms and clinical manifestations. J Am Coll Cardiol 20:483-499, 1992. 156.

157.

Binkley PF, Eaton GM, Nunziata E, et al: Heart rate alternans. Ann Intern Med 122:115-117, 1995.

Fisch C, Mandrola JM, Rardon DP: Electrocardiographic manifestations of dual atrioventricular node conduction during sinus rhythm. J Am Coll Cardiol 29:1015-1022, 1997. 158.

159.

Donato A, Oreto G, Schamroth L: P wave alternans. Am Heart J 116:875-877, 1988.

126

Tighe DA, Chung EK, Park CH: Electric alternans associated with acute pulmonary embolism. Am Heart J 128:188-190, 1994. 160.

Tada H, Nogami A, Shimizu W, et al: ST segment and T wave alternans in a patient with Brugada syndrome. Pacing Clin Electrophysiol 23:413-415, 2000. 160A.

Hall K, Christini DJ, Tremblay M, et al: Dynamic control of cardiac alternans. Phys Rev Lett 78:4518-4521, 1997. 161.

Rigney DR, Goldberger AL: Nonlinear mechanics of the heart's swinging during pericardial effusion. Am J Physiol 257:H1292-H1305, 1989. 162.

Sacks E, Widman LE: Nonlinear heart model predicts range of heart rates for 2:1 swinging in pericardial effusion. Am J Physiol 264:H1716-H1722, 1993. 163.

Laguna P, Moody GB, Garcia J, et al: Analysis of the ST-T complex of the electrocardiogram using the Karhunen-Loeve transform: Adaptive monitoring and alternans detection. Med Biol Eng Comput 37:175-189, 1999. 164.

Nearing BD, Huang AH, Verrier RL: Dynamic tracking of cardiac vulnerability by complex demodulation of the T wave. Science 252:437-440, 1991. 165.

Rosenbaum DS, Jackson LE, Smith JM, et al: Electrical alternans and vulnerability to ventricular arrhythmias. N Engl J Med 330:235-241, 1994. 166.

Verrier RL, Nearing BD: Electrophysiologic basis for T wave alternans as an index of vulnerability to ventricular fibrillation. J Cardiovasc Electrophysiol 5:445-461, 1994. 167.

Hohnloser SH, Klingenheben T, Li YG, et al: T wave alternans as a predictor of recurrent ventricular tachyarrhythmias in ICD recipients: Prospective comparison with conventional risk markers. J Cardiovasc Electrophysiol 9:1258-1268, 1998. 168.

Pastore JM, Girouard SD, Laurita KR, et al: Mechanism linking T-wave alternans to the genesis of cardiac fibrillation. Circulation 99:1385-1384, 1999. 169.

Habbab MA, el-Sherif N: TU alternans, long QTU, and torsade de pointes: Clinical and experimental observations. Pacing Clin Electrophysiol 15:916-931, 1992. 170.

Shimizu W, Antzelevitch C: Cellular and ionic basis for T-wave alternans under long Q-T conditions. Circulation 99:1499-1507, 1999. 171.

CLINICAL ISSUES IN ELECTROCARDIOGRAPHIC INTERPRETATION Goldberger AL, O'Konski M: Utility of the routine electrocardiogram before surgery and on general hospital admission. Ann Intern Med 105:552-557, 1986. 172.

Murdoch CJ, Murdoch DR, McIntyre P, et al: The pre-operative ECG in day surgery: A habit? Anaesthesia 54:907-908, 1999. 172A.

Gold BS, Young ML, Kinman JL, et al: The utility of preoperative electrocardiograms in the ambulatory surgical patient. Arch Intern Med 152:301-305, 1992. 173.

Schlant RC, Adolph RJ, DiMarco JP, et al: Guidelines for electrocardiography. A report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Committee on Electrocardiography). Circulation 85:1221-1228, 1992. 174.

Miller DH, Kligfield P, Schreiber TL, et al: Relationship of prior myocardial infarction to false-positive electrocardiographic diagnosis of acute injury in patients with chest pain. Arch Intern Med 147:257-261, 1987. 175.

Hatala R, Norman GR, Brooks LR: Impact of a clinical scenario on accuracy of electrocardiogram interpretation. J Gen Intern Med 14:126-129, 1999. 176.

Lee TH, Cook F, Weisberg MC, et al: Impact of the availability of a prior electrocardiogram on the triage of a patient with acute chest pain. J Gen Intern Med 5:381-388, 1990. 177.

Ziemba SE, Hubbell FA, Fine MJ: Resting electrocardiograms as baseline tests: Impact on the management of elderly patients. Am J Med 91:576-583, 1991. 178.

Pope JH, Aufderheide TP, Ruthazer R, et al: Missed diagnoses of cardiac ischemia in the emergency department. N Engl J Med 342:1163-1170, 2000. 178A.

Knight BP, Michaud GF, Strickberger SA, et al: Clinical consequences of electrocardiographic artifact mimicking ventricular tachycardia. N Engl J Med 341:1270-1274, 1999. 179.

Peberdy MA, Ornato JP: Recognition of electrocardiographic lead misplacements. Am J Emerg Med 11:403-405, 1993. 180.

Chou T-C, Knilans TK: Electrocardiography in Clinical Practice: Adult and Pediatric. 4th ed. Philadelphia, WB Saunders, 1996. 181.

Hurst JW: Electrocardiographic crotchets or common errors made in the interpretation of the electrocardiogram. Clin Cardiol 21:211-216, 1998. 182.

Jayes RL, Larsen GC, Beshansky JR, et al: Physician electrocardiogram reading in the emergency department--accuracy and effect on triage decisions. J Gen Intern Med 7:387-392, 1992. 183.

Kennedy HL, Goldberger AL, Graboys TB, et al: American College of Cardiology guidelines for training in adult cardiovascular medicine. Task Force 2: Training in electrocardiography, ambulatory electrocardiography, and exercise testing. J Am Coll Cardiol 25:1013, 1995. 184.

Willems JL, Arbeu-Lima C, Arnaud P, et al: The diagnostic performance of computer programs for the interpretation of electrocardiograms. N Engl J Med 325:1767-1773, 1991. 185.

Spodick D: Computer treason: Intraobserver variability of an electrocardiographic computer system. Am J Cardiol 80:102-103, 1997. 186.

Heden B, Ohlin H, Rittner R, et al: Acute myocardial infarction detected in the 12-lead ECG by artificial neural networks. Circulation 96:1798-1802, 1997. 187.

Holst H, Ohlsson M, Peterson C, Edenbrandt L: A confident decision support system for interpreting electrocardiograms. Clin Physiol 19:410-418, 1999. 187A.

Pettis KS, Savona MR, Leibrandt PN, et al: Evaluation of the efficacy of hand-held computer screens for cardiologists' interpretation of 12-lead electrocardiograms. Am Heart J 138:765-770, 1999. 187B.




GUIDELINES ELECTROCARDIOGRAPHY Thomas H. Lee Electrocardiograms (ECGs) are among the most commonly performed tests in medicine and are "the procedure of first choice" in the evaluation of patients with chest pain, syncope, or dizziness. Guidelines published in 1992 by a task force of the American College of Cardiology and American Heart Association (ACC/AHA) described conditions for which it is generally agreed that ECGs are useful (Class I); conditions for which opinion differs with respect to their usefulness (Class II); and conditions for which it is generally agreed that ECGs are of little or no usefulness (Class III).[1] These guidelines addressed categories of patients defined by whether they had known, suspected, or no evidence of cardiovascular disease. For each patient category, the guidelines evaluated use of the ECG as a baseline test, for evaluation of response to therapy, for follow-up, and before surgery ( Table 5-G-1 ). Further discussion of some of the ongoing controversies and disagreements regarding use of the ECG in clinical settings is given in the chapter.

Patients with Known Cardiovascular Disease or Dysfunction The ECG is so critical to the evaluation of all patients with a cardiovascular condition that this test was considered appropriate (Class I) for all patients during the initial evaluation and to evaluate the short- and long-term responses to therapies known to produce ECG changes. The guidelines offer no specific recommendations about the frequency of follow-up ECGs but noted that for several acute cardiovascular problems,

serial ECGs are warranted until the patient has returned to a stable condition. Even in the absence of new symptoms or signs, ECGs were considered appropriate for the follow-up of patients with several conditions, including syncope or near syncope, chest pain, and unexplained fatigue (see Table 5-G-1 ). The ECG was not considered appropriate for patients with mild chronic cardiovascular conditions that were not considered likely to progress (e.g., mild mitral valve prolapse). ECGs at each visit were considered inappropriate for patients with stable heart disease who were seen frequently (e.g., within 4 months) and had no evidence of clinical change. Before cardiac or noncardiac surgery, the ACC/AHA guidelines considered ECGs appropriate for all patients with known cardiovascular disease or dysfunction, except those with insignificant or mild conditions such as mild systemic arterial hypertension.

Patients with Suspected or at High Risk for Cardiovascular Disease The ECG was considered an appropriate baseline test for all patients with suspected cardiovascular conditions and those at high risk for the development of such conditions. It was also considered an appropriate test after the administration of any drug known to influence cardiac

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TABLE 5-5-G-1 -- ACC/AHA GUIDELINES FOR ELECTROCARDIOGRAPHY (1992) Setting Class I (appropriate) Class II (equivocal) Class III (inappropriate) Patients with Known Cardiovascular Disease or Dysfunction Baseline All patients or initial evaluation

None

None

Response Patients in whom to therapy prescribed therapy is known to produce ECG changes that correlate with therapeutic responses or progression of disease

None

Patients receiving pharmacological or nonpharmacological therapy not known to produce ECG changes or to affect conditions that may be associated with such changes

None

Adult patients whose cardiovascular condition is benign and unlikely to progress (e.g., patients with mild mitral prolapse, mild hypertension, or premature contractions in the absence of organic heart disease

Patients in whom prescribed therapy may produce adverse effects that may be predicted from or detected by ECG changes Follow-up

Patients with a change in symptoms, signs, or relevant laboratory findings

Patients with an implanted pacemaker or antitachycardia device Patients with syndromes such as the following conditions, even in the absence of new symptoms of signs, after an interval of time appropriate for the condition or disease: Syncope and near syncope Unexplained change in the usual pattern of angina pectoris Chest pain New or worsening dyspnea Extreme and unexplained fatigue, weakness, and prostration Palpitations New signs of congestive heart failure A new organic murmur

Adult patients with chronic stable heart disease seen at frequent intervals (i.e., 4 mo) and who have no new or unexplained findings

unexplained fatigue, weakness, and prostration Palpitations New signs of congestive heart failure A new organic murmur or pericardial friction rub New findings suggesting pulmonary hypertension Acceleration or poorly controlled systemic arterial hypertension Evidence of a recent cerebrovascular accident Unexplained fever in patients with known valvular disease New onset of cardiac arrhythmis or inappropriate heart rate Chronic known congenital or acquired cardiovascular disease Before surgery

All patients with known cardiovascular disease or dysfunction, except as noted under Class II

Patients with hemodynamically insignificant heart disease, mild systemic arterial hypertension, or infrequent premature complexes in the absence of organic heart disease

None

Patients Suspected of Having or Who Are at Increased Risk for Cardiovascular Disease or Dysfunction Baseline All patients suspected of None or initial having or at increased risk evaluation for cardiovascular disease Patients who may have used cocaine, amphetamines, or other illicit drugs known to have cardiac effects Patients who may have received an overdose of a drug known to have cardiac effects

None

Response To assess therapy with to therapy cardioactive drugs in patients with suspected cardiac disease

To assess the response to administration of any agent known to To assess response to the alter serum electrolyte administration of any concentrations agent known to result in cardiac abnormalities or ECG abnormalities (e.g., antineoplastic drugs, lithium, antidepressant agents)

To assess the response to administration of agents known not to influence cardiac structure or function

Follow-up

The presence of any None change in clinical status or laboratory findings suggesting interval development of cardiac disease or dysfunction

Follow-up ECGs more often than once yearly are not indicated in patients who remain clinically stable, who are not at increased risk for the development of cardiac disease, and who have not been demonstrated to have cardiac disease with previous studies

Periodic follow-up (e.g., every 1--5 yr) of patients known to be at increased risk for heart disease Follow-up of patients after resolution of chest pain Before surgery

As part of the preoperative None evaluation of any patient with suspected or at increased risk for cardiac disease or dysfunction

None

Patients with No Apparent or Suspected Heart Disease or Dysfunction

Baseline Persons aged 40 or more or initial yr undergoing physical evaluation examination Before administration of pharmacological agents known to have a high incidence of cardiovascular effects (e.g., antineoplastic agents)

To evaluate Routine screening or competitive athletes baseline ECGs in asymptomatic persons younger than 40 yr with no risk factors

Before exercise stress testing People of any age who are in special occupations that require very high cardiovascular performance (e.g., fire fighters, police officers) or whose cardiovascular performance is linked to public safety (e.g., pilots, air traffic controllers, critical process operators, bus or truck drivers, and railroad engineers) Response To evaluate patients in to therapy whom prescribed therapy (e.g., doxorubicin) is known to produce cardiovascular effects

None

To assess treatment that is known to not produce any cardiovascular effects

Follow-up

To evaluate asymptomatic None persons > 40 yr of age

To evaluate asymptomatic adults who have had no interval change in symptoms, signs, or risk factors and who have had a normal ECG with the recent past

Before surgery

Patients >40 yr of age Patients being evaluated as a donor for heart transplantation or as a recipient of a noncardiopulmonary transplant

Patients 30--40 yr of Patients younger than 30 age yr with no risk factors for coronary artery disease

Class I: Conditions for which or patients for whom it is generally agreed that electrocardiography is useful (appropriate). Class II: Conditions for which or patients for whom electrocardiography is frequently used but opinion differs with respect to its usefulness (equivocal). Class III: Conditions for which or patients for whom it is generally agreed that electrocardiography is of little or no usefulness (inappropriate). From Schlant RC, Adolph RJ, DiMarco JP, et al: Guidelines for electrocardiography. A report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Committee on Electrocardiography). J Am Coll Cardiol 19:473-481, 1992. Reprinted with permission from the American College of Cardiology. See also Chapter 5 text for further discussion and alternative recommendations. structure or function. Follow-up ECGs more often than once per year were not recommended for patients who remained clinically stable, as long as they had not been previously demonstrated to have cardiac disease. However, for patients known to be at increased risk for the development of heart disease, ECGs every 1 to 5 years were considered appropriate (Class I). ECGs were considered appropriate before cardiac or noncardiac surgery for all patients in this population.

Patients Without Known or Suspected Heart Disease For patients without evidence suggesting cardiovascular disease, ECGs were considered appropriate during the baseline evaluation in the ACC/AHA guidelines for those aged 40 years or older. The ACC/AHA guidelines also recommended ECGs for patients for whom drugs with a high incidence of cardiovascular effects (e.g., chemotherapy) or exercise testing was planned and for people of any age in occupations with high cardiovascular demands or whose cardiovascular status might affect the well-being of many other people (e.g., airline pilot). These guidelines are similar to those of the U.S. Preventive Services Task Force,[2] which suggested ECG screening for those with occupations in which their cardiovascular health might jeopardize the lives of others. Guidelines vary on the performance of baseline ECGs. An American Heart Association panel recommended in 1987 that ECGs be obtained at ages 20, 40, and 60 years in persons with normal blood pressure,[3] while a task force assembled by the Canadian government has discouraged the use of any screening ECGs.[4] Before cardiac or noncardiac surgery, the ACC/AHA guidelines recommend ECGs for all people aged 40 years or older,[1] and ECGs are considered equivocal in appropriateness (Class II) for surgical patients aged 30 to 40 years. Guidelines issued by the American College of Physicians[5] recommend ECGs preoperatively and upon hospital admission for men aged 40 years or older and women aged 50 years or older, as well as all patients having elective intrathoracic, intraperitoneal, or aortic surgery; elective major neurosurgery; or emergency operations under general or regional

anesthesia.

REFERENCES Schlant RC, Adolph RJ, DiMarco JP, et al: Guidelines for electrocardiography. A report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Committee on Electrocardiography). J Am Coll Cardiol 19:473-481, 1992. 1.

US Preventive Task Force: Guide to Clinical Preventive Services. 2nd ed. Baltimore, Williams & Wilkins, 1996. 2.

Grundy SM, Greenland P, Herd A, et al: Cardiovascular and risk factor evaluation of healthy American adults: A statement for physicians by an ad hoc committee appointed by the Steering Committee, American Heart Association. Circulation 75:1340A-1362A, 1987. 3.

Hayward RSA, Steinberg EP, Ford DE, et al: Preventive care guidelines: 1991. Ann Intern Med 114:758-783, 1991. 4.

Goldberger AL, O'Konski MS: Utility of the routine electrocardiogram before surgery and on general hospital admission. Critical review and new guidelines. In Sox HC Jr (ed): Common Diagnostic Tests. Use and Interpretation. 2nd ed. Philadelphia, American College of Physicians, 1990, pp 67-78. 5.




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Chapter 6 - Exercise Stress Testing BERNARD R. CHAITMAN

Exercise is a common physiological stress used to elicit cardiovascular abnormalities not present at rest and to determine adequacy of cardiac function. [1] [2] [3] [4] [5] [6] [7] [8] [9] Exercise electrocardiography (ECG) is one of the most frequent noninvasive modalities used to assess patients with suspected or proven cardiovascular disease. The test is mainly used to estimate prognosis and to determine functional capacity, the likelihood and extent of coronary artery disease (CAD), and the effects of therapy.[5] [6] Hemodynamic and ECG measurements combined with ancillary techniques such as metabolic gas analysis, radionuclide imaging, and echocardiography enhance the information content of exercise testing in selected patients.[9] [10] [11] EXERCISE PHYSIOLOGY (See also Chap. 39) Anticipation of dynamic exercise results in an acceleration of ventricular rate due to vagal withdrawal, increase in alveolar ventilation, and increased venous return primarily as a result of sympathetic venoconstriction. [12] In normal persons, the net effect is to increase resting cardiac output before the start of exercise. The magnitude of hemodynamic response during exercise depends on the severity and amount of muscle mass involved. In the early phases of exercise in the upright position, cardiac output is

increased by an augmentation in stroke volume mediated through the use of the Frank-Starling mechanism and heart rate; the increase in cardiac output in the latter phases of exercise is primarily due to a sympathetic-mediated increase in ventricular rate. At fixed submaximal workloads below anaerobic threshold, steady-state conditions are usually reached after the second minute of exercise, following which heart rate, cardiac output, blood pressure, and pulmonary ventilation are maintained at reasonably constant levels.[7] During strenuous exertion, sympathetic discharge is maximal and parasympathetic stimulation is withdrawn, resulting in vasoconstriction of most circulatory body systems, except for that in exercising muscle and in the cerebral and coronary circulations. Venous and arterial norepinephrine release from sympathetic postganglionic nerve endings, as well as plasma renin levels, is increased; the catecholamine release enhances ventricular contractility. As exercise progresses, skeletal muscle blood flow is increased, oxygen extraction increases by as much as threefold, total calculated peripheral resistance decreases, and systolic blood pressure, mean arterial pressure, and pulse pressure usually increase. Diastolic blood pressure does not change significantly. The pulmonary vascular bed can accommodate as much as a sixfold increase in cardiac output with only modest increases in pulmonary artery pressure, pulmonary capillary wedge pressure, and right atrial pressure; in normal individuals, this is not a limiting determinant of peak exercise capacity. Cardiac output increases by four- to sixfold above basal levels during strenuous exertion in the upright position, depending on genetic endowment and level of training.[12] The maximum heart rate and cardiac output are decreased in older individuals, partly because of decreased beta-adrenergic responsivity.[13] [14] [15] Maximum heart rate can be estimated from the formula 220 - age (years) with a standard deviation of 10 to 12 beats/min. The age-predicted maximum heart rate is a useful measurement for safety reasons. However, the wide standard deviation in the various regression equations used and the impact of drug therapy limit the usefulness of this parameter in estimating the exact age-predicted maximum for an individual patient. In the postexercise phase, hemodynamics return to baseline within minutes of termination. Vagal reactivation is an important cardiac deceleration mechanism after exercise and is accelerated in well-trained athletes but blunted in patients with chronic heart failure.[16] Intense physical work or significant cardiorespiratory impairment may interfere with achievement of a steady state, and an oxygen deficit occurs during exercise. The total oxygen uptake in excess of the resting oxygen uptake during the recovery period is the oxygen debt. PATIENT'S POSITION.

At rest, the cardiac output and stroke volume are higher in the supine than in the upright position. With exercise in normal supine persons, the elevation of cardiac output results almost entirely from an increase in heart rate with little augmentation of stroke volume. In the upright posture, the increase in cardiac output in normal individuals results from a combination of elevations in stroke volume and heart rate. A change from supine to upright posture causes a decrease in venous return, left ventricular end-diastolic volume and pressure, stroke volume, and cardiac index. Renin and norepinephrine levels are increased. End-systolic volume and ejection fraction are not significantly changed. In

normal individuals, end-systolic volume decreases and ejection fraction increases to a similar extent from rest to exercise in the supine and upright positions. The magnitude and direction of change in end-diastolic volume from rest to maximum exercise in both positions are small and may vary according to the patient population studied. The net effect on exercise performance is an approximate 10 percent increase in exercise time, cardiac index, heart rate, and rate pressure product at peak exercise in the upright as compared with the supine position. Cardiopulmonary Exercise Testing

Cardiopulmonary exercise testing involves measurements of respiratory oxygen uptake ( O2 ), carbon dioxide production ( CO2 ), and ventilatory parameters during a symptom-limited exercise test. During testing, the patient usually wears

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a nose clip and breathes through a nonrebreathing valve that separates expired air from room air. Important measurements of expired gas are PO2 , PCO2 , and airflow. Ventilatory measurements include respiratory rate, tidal volume, and minute ventilation ( E) PO2 and P CO2 are sampled breath by breath or by use of a mixing chamber. The O2 and CO2 can be computed on line from ventilatory volumes and differences between inspired and expired gases.[9] Under steady-state conditions, O2 and CO2 measured at the mouth are equivalent to total-body oxygen consumption and carbon dioxide production. The relationship between work output, oxygen consumption, heart rate, and cardiac output during exercise is linear (Fig. 6-1) . O2 max is the product of maximal arterial-venous oxygen difference and cardiac output and represents the largest amount of oxygen a person can use while performing dynamic exercise involving a large part of total muscle mass. The O2 max decreases with age, is usually less in women than in men, and can vary between individuals as a result of genetic factors.[14] [15] O2 max is diminished by degree of cardiovascular impairment and by physical inactivity. In untrained persons, the arterial-mixed venous oxygen difference at peak exercise is relatively constant (14 to 17 vol percent), and O2 max is an approximation of maximum cardiac output. Measured O2 max can be compared with predicted values from empirically derived formulas based on age, sex, weight, and height.[9] [17] Most clinical studies that use exercise as a stress to assess cardiac reserve report peak O2 that is the highest O2 attained during graded exercise testing rather than O2 max. Peak exercise capacity is decreased when the ratio of measured to predicted

max is less than 85 to 90 percent. Oximetry, performed noninvasively, can be used to monitor arterial oxygen saturation, and the value normally does not decrease by more than 5 percent during exercise. Estimates of oxygen saturation during strenuous exercise using pulse oximetry may be unreliable in some patients.[18] O2

ANAEROBIC THRESHOLD.

Anaerobic threshold is a theoretical point during dynamic exercise when muscle tissue switches over to anaerobic metabolism as an additional energy source. All tissues do not shift simultaneously, and there is a brief interval during which exercise muscle tissue shifts from predominantly aerobic to anaerobic metabolism.[9] [12] [17] [19] Lactic acid begins to accumulate when a healthy untrained subject reaches about 50 to 60 percent of the maximal capacity for aerobic metabolism. The increase in lactic acid becomes greater as exercise becomes more intense, resulting in metabolic acidosis. As lactate is formed, it is buffered in the serum by the bicarbonate system, resulting in increased carbon dioxide excretion, which causes reflex hyperventilation. The gas exchange anaerobic threshold is the point at which Eincreases disproportionately relative to O2 and work; it occurs at 40 to 60 percent of [ O2 max in normal, untrained individuals. 9] Below the anaerobic threshold, carbon dioxide production is proportional to oxygen consumption. Above the anaerobic threshold, carbon dioxide is produced in excess of oxygen

Figure 6-1 Cardiopulmonary exercise test in a healthy 53-year-old man using the Bruce protocol. The progressive linear increase in work output, heart rate, and oxygen consumption ( O2 ) is noted, with steady-state conditions reached after 2 minutes in each of the first two stages (top panel). Open arrows indicate the beginning of each new 3-minute stage. The subject completed 7 minutes and 10 seconds of exercise, and peak O2 was 3.08 liters/min. The anaerobic threshold (ATge ), determined by the V-slope method, is the point at which the slope of the relative rate of increase in CO 2 relative to O2 changes; it occurred at a O2 of 1.5 liters/min, or 49 percent of peak O2 , within predicted values for a normal sedentary population (bottom panel). The AT ge determined by the point at which the O2 and CO 2 slopes intersect (1.8 liters/min) (top panel) is slightly greater than the ATge determined by the V-slope method (bottom panel). The V-slope method usually provides a more reproducible estimate of AT ge . PETO2 = end-tidal pressure of oxygen; RER = respiratory exchange ratio; VE/ O2 = ratio ventilation to oxygen uptake.

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consumption. There are several methods to determine anaerobic threshold, which

include (1) the V-slope method, the point at which the rate of increase in CO2 relative to O2 increases (see Fig. 6-1) ; (2) the point at which the O2 and CO2 slopes intersect; and (3) the point at which the ratio of V E/ O2 and end-tidal oxygen tension begins to increase systematically without an immediate increase in the VE/ O2 (see Fig. 6-1) . The anaerobic threshold is a useful parameter because work below this level encompasses most activities of daily living. Anaerobic threshold is often reduced in patients with significant cardiovascular disease. An increase in anaerobic threshold with training can enhance an individual's capacity to perform sustained submaximal activities, with consequent improvement in quality of life and daily living. Changes in anaerobic threshold and peak O2 with repeat testing can be used to assess disease progression, response to medical therapy, and improvement in cardiovascular fitness with training. VENTILATORY PARAMETERS.

In addition to peak O2 , minute ventilation and its relation to CO2 and oxygen consumption are useful indices of cardiac and pulmonary function. The respiratory exchange ratio represents the amount of carbon dioxide produced divided by the amount of oxygen consumed. The respiratory exchange ratio ranges from 0.7 to 0.85 at rest and is partly dependent on the predominant fuel used for cellular metabolism (e.g., respiratory exchange rate for predominant carbohydrate use is 1.0, whereas respiratory exchange ratio for predominant fatty use is 0.7). At high exercise levels, carbon dioxide production exceeds O2 , and a respiratory exchange ratio greater than 1.0 often indicates that the subject has performed at maximal effort. METABOLIC EQUIVALENT.

The current use of the term metabolic equivalent (MET) refers to a unit of sitting, resting oxygen uptake; 1 MET is equivalent to 3.5 ml O2 ·kg-1 ·min-1 of body weight. Measured -1 -1 O2 in ml/min/kg divided by 3.5 ml O2 ·kg ·min determines number of METs associated with activity. Work activities can be calculated in multiples of METs; this measurement is useful to determine exercise prescriptions, assess disability, and standardize the reporting of submaximal and peak exercise workloads when different protocols are used. An exercise workload of 3 to 5 METs is consistent with activities such as raking leaves, light carpentry, golf, and walking at 3 to 4 mph. Workloads of 5 to 7 METs are consistent with exterior carpentry, singles tennis, and light backpacking. Workloads in excess of 9 METs are compatible with heavy labor, handball, squash, and running at 6 to 7 mph. Estimating O2 from work rate or treadmill time in individual patients may lead to misinterpretation of data if exercise equipment is not correctly calibrated, when the patient holds onto the front handrails, if the patient fails to achieve steady state, is obese, or has peripheral

vascular disease, pulmonary vascular disease, or cardiac impairment. O2 does not increase linearly in some patients with cardiovascular or pulmonary disease as work rate is increased, and [ O2 may thus be overestimated. 9] The measurements obtained with cardiopulmonary exercise testing are useful in understanding an individual patient's response to exercise and can be useful in the diagnostic evaluation of a patient with dyspnea.[9] [19] [20] EXERCISE PROTOCOLS The main types of exercise are isotonic or dynamic exercise, isometric or static exercise, and resistive (combined isometric and isotonic) exercise. Dynamic protocols most frequently are used to assess cardiovascular reserve, and those suitable for clinical testing should include a low-intensity warm-up phase. In general, 6 to 12 minutes of continuous progressive exercise during which the myocardial oxygen demand is elevated to the patient's maximal level is optimal for diagnostic and prognostic purposes.[1] [2] [3] The protocol should include a suitable recovery or cool-down period. If the protocol is too strenuous for an individual patient, early test termination results and will not allow an opportunity to observe clinically important responses. If the exercise protocol is too easy for an individual patient, the prolonged procedure tests endurance and not aerobic capacity. Thus, exercise protocols should be individualized to accommodate a patient's limitations. Protocols may be set up at a fixed duration of exercise for a certain intensity to meet minimal qualifications for certain industrial tasks or sports programs. STATIC EXERCISE.

This form of isometric exercise generates force with little muscle shortening and produces a greater blood pressure response than with dynamic exercise. Cardiac output does not increase as much as with dynamic exercise because increased resistance in active muscle groups limits blood flow. In a common form of static exercise, the patient's maximal force on a hand dynamometer is recorded. The patient then sustains 25 to 33 percent of maximal force for 3 to 5 minutes while ECG and blood pressures are recorded. The increase in myocardial O2 is often insufficient to initiate an ischemic response. ARM ERGOMETRY.

Arm crank ergometry protocols involve arm cranking at incremental workloads of 10 to 20 W for 2- or 3-minute stages. The heart rate and blood pressure responses to a given workload of arm exercise usually are greater than those for leg exercise. A bicycle ergometer with the axle placed at the level of the shoulders is used, and the subject sits or stands and cycles the peddles so that the arms are alternately fully extended. The most common frequency is 50 rpm. In normal individuals, maximal O2 and Efor arm cycling approximates 50 to 70 percent of leg cycling. Peak heart rate is approximately 70 percent of that during leg testing. Arm ergometry exercise protocols are useful for risk stratification of patients with suspected or documented CAD before

noncardiac surgery when leg exercise is not possible or insufficient to test cardiac reserve. BICYCLE ERGOMETRY.

Bicycle protocols involve incremental workloads calibrated in watts or kilopond/meters/minute (kpm). One watt is equivalent to approximately 6 kpm. Because exercise on a cycle ergometer is not weight bearing, kpm or watts can be converted to oxygen uptake in milliliters per minute. In mechanically braked bicycles, work is determined by force and distance and requires a constant pedaling rate of 60 to 80 rpm, according to the patient's preference. Electronically braked bicycles provide a constant workload despite changes in pedaling rate and are less dependent on a patient's cooperation. They are more costly than a mechanically braked bicycle but are preferred for diagnostic and prognostic assessment. Most protocols start with a power output of 10 or 25 W (150 kpm/min), usually followed by increases of 25 W every 2 or 3 minutes until endpoints are reached. Younger subjects may start at 50 W, with 50-W increments every 2 minutes. A ramp protocol differs from the staged protocols in that the patient starts at 3 minutes of unloaded pedaling at a cycle speed of 60 rpm. Work rate is increased by a uniform amount each minute, ranging from 5- to 30-W increments, depending on a patient's expected performance.[9] Exercise is terminated if the patient is unable to maintain a cycling frequency above 40 rpm. In the cardiac catheterization laboratory, hemodynamic measurements may be made during supine bicycle ergometry at rest and at one or two submaximal workloads. The bicycle ergometer is associated with a lower maximal O2 and anaerobic threshold than the treadmill; maximal heart rate, maximal E, and maximal lactate values are often similar. The bicycle ergometer has the advantage of requiring less space than a treadmill; it is quieter and permits sensitive precordial measurements without much motion artifact. However, in North America, treadmill protocols are more widely used in the assessment of patients with coronary disease. TREADMILL PROTOCOL.

The treadmill protocol should be consistent with the patient's physical capacity and the purpose of the test. In healthy individuals, the standard

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Bruce's protocol is popular, and a large diagnostic and prognostic data base has been published.[1] [2] [3] [4] Bruce's multistage maximal treadmill protocol has 3-minute periods to allow achievement of a steady state before workload is increased (Figs. 6-1 and 6-2) . In older individuals or those whose exercise capacity is limited by cardiac disease, Bruce's protocol can be modified by two 3-minute warm-up stages at 1.7 mph and 0 percent grade and 1.7 mph and 5 percent grade. A limitation of Bruce's protocol is the relatively large increase in

between stages and the additional energy cost of running as compared with walking at stages in excess of Bruce's stage III. The Naughton and Weber protocols use 1- to 2-minute stages with 1-MET increments between stages; these protocols may be more suitable for patients with limited exercise tolerance such as patients with congestive heart failure. The Asymptomatic Cardiac Ischemia Pilot trial (ACIP) and modified ACIP (mACIP) protocols use 2-minute stages with 1.5-MET increments between stages after two 1-minute warm-up stages with 1-MET increments. The ACIP protocols were developed to test patients with established CAD and result in a linear increase in heart rate and O2 , distributing the time to occurrence of ST segment depression over a wider range of heart rate and exercise time than protocols with more abrupt increments in workload between stages.[21] [22] The mACIP protocol produces a similar aerobic demand as the standard ACIP protocol for each minute of exercise and is well suited for short or elderly individuals who cannot keep up with a walking speed of 3 mph (see Fig. 6-2) . O2

Ramp protocols start the patient at relatively slow treadmill speed, which is gradually increased until the patient has a good stride. The ramp angle of incline is progressively increased at fixed intervals (e.g., 10 to 60 seconds), starting at zero grade with the increase in grade calculated on the basis of the patient's estimated functional capacity such that the protocol will be complete at between 6 and 12 minutes.[2] [3] [4] In this type of protocol, the rate of work increase is continuous and steady-state conditions are not reached. A limitation of ramp protocols is the requirement to estimate functional capacity from an activity scale; underestimation or overestimation of functional capacity occasionally results in an endurance test or premature cessation. One formula for estimating O2 from treadmill speed and grade is O2

(ml O2 ·kg-1 ·min-1 ) = (mph × 2.68) + (1.8 × 26.82 × mph × grade ÷ 100) + 3.5 [23]

The peak O2 is usually the same regardless of treadmill protocol used; the difference is the rate of time at which the peak O2 is achieved. It is important to encourage patients not to grasp the handrails of the treadmill during exercise. Functional capacity can be overestimated by as much as 20 percent in tests in which handrail support is permitted, and O2 is decreased. Because the degree of handrail support is difficult to quantify from one test to another, more consistent results can be obtained during serial testing when handrail support is not permitted. The 6-minute walk test can be used for patients who have marked left ventricular dysfunction or peripheral arterial occlusive disease and who cannot perform bicycle or treadmill exercise.[24] [25] Patients are instructed to walk down a 100-foot corridor at their own pace, attempting to cover as much ground as possible in 6 minutes. At the end of the 6-minute interval, the total distance walked is determined and the symptoms experienced by the patient are recorded. The 6-minute walk test as a clinical measure of

ambulatory function requires highly skilled personnel following a rigid protocol to elicit reproducible and reliable results. The coefficient of variation for distance walked during two 6-minute walk tests was 10 percent in one series of patients with peripheral arterial occlusive disease.[25]

Figure 6-2 Estimated oxygen cost of bicycle ergometer and selected treadmill protocols. The standard Bruce protocol starts at 1.7 mph and 10 percent grade (5 METs), with a larger increment between stages than protocols such as the Naughton, ACIP, and Weber protocols, which start at less than 2 METs at 2 mph and increase by 1- to 1.5-MET increments between stages. The Bruce protocol can be modified by two 3-minute warm-up stages at 1.7 mph and 0 percent grade and 1.7 mph and 5 percent grade.(Adapted from Fletcher GF, Balady G, Froelicher VF, et al: Exercise standards. A statement for healthcare professionals from the American Heart Association. Circulation 91:580, 1995. Copyright 1995 American Heart Association.)

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TECHNIQUES.

Patients should be instructed not to eat, drink caffeinated beverages, or smoke for 3 hours before testing and to wear comfortable shoes and loose-fitting clothes. Unusual physical exertion should be avoided before testing. A brief history and physical examination should be performed, and patients should be advised about the risks and benefits of the procedure. A written informed consent form is usually required.[7] [8] The indication for the test should be known. In many laboratories, the presence or absence of atherosclerotic risk factors is noted and cardioactive medication recorded. A 12-lead ECG should be obtained with the electrodes at the distal extremities. The timing of cardioactive medication ingestion before testing depends on the test indication. After the standard 12-lead ECG is recorded, a torso ECG should be obtained in the supine position and in the sitting or standing position. Postural changes can elicit labile ST-T wave abnormalities. Hyperventilation is not recommended before exercise. If a false-positive test result is suspected, hyperventilation should be performed after the test, and the hyperventilation tracing compared with the maximal ST segment abnormalities observed. The ECG and blood pressure should be recorded in both positions, and patients should be instructed on how to perform the test. Adequate skin preparation is essential for high-quality recordings, and the superficial layer of skin needs to be removed to augment signal-to-noise ratio. The areas of electrode application are rubbed with an alcohol-saturated pad to remove oil and rubbed with free sandpaper or a rough material to reduce skin resistance to 5000 ohms or less. Silver chloride electrodes with a fluid column to avoid direct metal-to-skin contact produce high-quality tracings; these electrodes have the lowest offset voltage. Cables connecting the electrodes and recorders should be light, flexible, and properly shielded. In a small minority of patients, a fishnet jersey may be required over the

electrodes and cables to reduce motion artifact. The electrode-skin interface can be verified by tapping on the electrode and examining the monitor or by measuring skin impedance. Excessive noise indicates that the electrode needs to be replaced; replacement before the test rather than during exercise can save time. The ECG signal can be digitized systematically at the patient's end of the cable by some systems, reducing power line artifact. Cables, adapters, and junction box have a finite life span and require periodic replacement to obtain the highest quality tracings. Exercise equipment should be calibrated regularly. Room temperature should be between 64 and 72°F (18 and 22°C) and humidity less than 60 percent. Treadmill walking should be demonstrated to the patient. The heart rate, blood pressure, and ECG should be recorded at the end of each stage of exercise, immediately before and immediately after stopping exercise, at the onset of an ischemic response, and for each minute for at least 5 to 10 minutes in the recovery phase. A minimum of three leads should be displayed continuously on the monitor during the test. There is some controversy about optimal patient position in the recovery phase. In the sitting position, less space is required for a stretcher, and patients are more comfortable immediately after exertion. The supine position increases end-diastolic volume and has the potential to augment ST segment changes.[26] ELECTROCARDIOGRAPHIC MEASUREMENTS LEAD SYSTEMS.

The Mason-Likar modification of the standard 12-lead ECG requires that the extremity electrodes be moved to the torso to reduce motion artifact. The arm electrodes should be located in the most lateral aspects of the infraclavicular fossae, and the leg electrodes in a stable position above the anterior iliac crest and below the rib cage. The Mason-Likar modification results in a right-axis shift and increased voltage in the inferior leads and may produce a loss of inferior Q waves and the development of new Q waves in lead aVL . Thus, the body torso limb lead positions cannot be used to interpret a diagnostic rest 12-lead ECG. The more cephalad the leg electrodes are placed, the greater is the degree of change and the greater is the augmentation of R wave amplitude, potentiating exercise-induced ST segment changes. Bipolar lead groups place the negative or reference electrode over the manubrium (CM5 ), right scapula (CB5 ), RV5 (CC5 ), or on the forehead (CH5 ), and the active electrode at V5 or proximate location to optimize R wave amplitude. In bipolar lead ML, which reflects inferior wall changes, the negative reference is at the manubrium and the active electrode in the left leg position. Bipolar lead groups may provide additional diagnostic information, and in some medical centers, lead CM5 is substituted for lead aVr in the Mason-Likar modified lead system (Fig. 6-3) . Bipolar leads are frequently used when only a limited ECG set is required (e.g., in cardiac rehabilitation programs). In one series of patients, the use of right precordial leads (V3-5 R) increased the sensitivity to detect exercise-induced ST segment shifts.[27] The use of more elaborate lead set systems is usually reserved for research purposes.

Types of ST Segment Displacement

In normal persons, the PR, QRS, and QT intervals shorten as heart rate increases. P amplitude increases, and the PR

Figure 6-3 J point depression of 2 to 3 mm in leads V4 to V6 with rapid upsloping ST segments depressed approximately 1 mm 80 msec after the J point. The ST segment slope in leads V 4 and V5 is 3.0 mV/sec. This response should not be considered abnormal.

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segment becomes progressively more downsloping in the inferior leads. J point, or junctional, depression is a normal finding during exercise (see Fig. 6-3) . In patients with myocardial ischemia, however, the ST segment usually becomes more horizontal (flattens) as the severity of the ischemic response worsens. With progressive exercise, the depth of ST segment depression may increase, involving more ECG leads, and the patient may develop angina. In the immediate postrecovery phase, the ST segment displacement may persist, with downsloping ST segments and T wave inversion, gradually returning to baseline after 5 to 10 minutes ( Figs. 6-4 and 6-5) . Ischemic ST segment displacement may be seen only during exercise, emphasizing the importance of adequate skin preparation and electrode placement to capture high-quality recordings during maximum exertion (see Fig. 6-6) . In about 10 percent of patients, the ischemic response may appear only in the recovery phase. The prevalence of recovery-onset ischemic ST segment changes is higher in asymptomatic populations compared with those with symptomatic CAD.[28] Patients should not leave the exercise laboratory area until the postexercise ECG has returned to baseline. Figure 6-7 illustrates eight different ECG patterns seen during exercise testing.[29] MEASUREMENT OF ST SEGMENT DISPLACEMENT.

For purposes of interpretation, the PQ junction is usually chosen as the isoelectric point. The TP segment represents a true isoelectric point but is an impractical choice for most routine clinical measurements. The development of 0.10 mV (1 mm) or greater of J point depression measured

Figure 6-4 Bruce protocol. In lead V4 , the exercise ECG result is abnormal early in the test, reaching 0.3 mV (3 mm) of horizontal ST segment depression at the end of exercise. The ischemic changes persist for at least 1 minute and 30 seconds into the recovery phase. The right panel provides a continuous plot of the J point, ST slope, and ST segment displacement at 80 msec after the J point (ST level) during exercise and in the recovery phase. Exercise ends at the vertical line at 4.5 min. The computer trends permit a more precise identification of initial onset and offset of ischemic ST segment depression. This

type of ECG pattern, with early onset of ischemic ST segment depression, reaching more than 3 mm of horizontal ST segment displacement and persisting several minutes into the recovery phase, is consistent with a severe ischemic response.

Figure 6-5 Bruce protocol. In this type of ischemic pattern, the J point at peak exertion is depressed 2.5 mm, the ST segment slope is 1.5 mV/sec, and the ST segment level at 80 msec after the J point is depressed 1.6 mm. This "slow upsloping" ST segment at peak exercise indicates an ischemic pattern in patients with a high coronary disease prevalence pretest. A typical ischemic pattern is seen at 3 minutes of the recovery phase when the ST segment is horizontal and 5 minutes after exertion when the ST segment is downsloping. Exercise is discontinued at the vertical line in the right panel at 7.5 minutes.

from the PQ junction, with a relatively flat ST segment slope (130 beats/min), the ST 60 measurement should be used. The ST segment at rest may occasionally be depressed. When this occurs, the J point and ST 60 or ST 80 measurements should be depressed an additional 0.10 mV or greater to be considered abnormal. When the degree of resting ST segment depression is 0.1 mV or greater, the exercise ECG becomes less specific, and myocardial imaging modalities should be considered.[5] [11] In patients with early repolarization and resting ST segment elevation, return to the PQ junction is normal. Therefore, the magnitude of exercise-induced ST segment depression in a patient with early repolarization should be determined from the PQ junction and not from the elevated position of the J point before exercise. Exercise-induced ST segment depression does not localize the site of myocardial ischemia, nor does it provide a clue about which coronary artery is involved. For example, it is not unusual for patients with isolated right CAD to exhibit exercise-induced ST segment depression only in leads V4 to V6 , nor is it unusual for patients with disease of the left anterior descending coronary artery to exhibit exercise-induced ST segment displacements in leads II, III, and aVf . Exercise-induced ST segment elevation is relatively specific for the territory of myocardial ischemia and the coronary artery involved. UPSLOPING ST SEGMENTS.

Junctional or J point depression is a normal finding during maximal exercise, and a

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Figure 6-6 Bruce protocol. The exercise ECG result is not yet abnormal at 8:50 minutes but becomes abnormal at 9:30 minutes (horizontal arrow right) of a 12-minute exercise test and resolves in the

immediate recovery phase. This ECG pattern in which the ST segment becomes abnormal only at high exercise workloads and returns to baseline in the immediate recovery phase may indicate a false-positive result in an asymptomatic individual without atherosclerotic risk factors. Exercise myocardial imaging would provide more diagnostic and prognostic information if this were an older person with several atherosclerotic risk factors.

rapid upsloping ST segment (>1 mV/sec) depressed less than 0.15 mV (1.5 mm) after the J point should be considered to be normal. Occasionally, however, the ST segment is depressed 0.15 mV (1.5 mm) or greater at 80 msec after the J point. This type of slow upsloping ST segment may be the only ECG finding in patients with well-defined obstructive CAD and may depend on the lead set used (see Fig. 6-5) . In patient subsets with a high CAD prevalence, a slow upsloping ST segment depressed 0.15 mV or greater at 80 msec after the J point should be considered to be abnormal. The importance of this finding in asymptomatic individuals or those with a low CAD prevalence is less certain. Increasing the degree of ST segment depression at 80 msec after the J point to 0.20 mV (2.0 mm) or greater in patients with a slow upsloping ST segment increases specificity but decreases sensitivity.[29] ST SEGMENT ELEVATION.

Exercise-induced ST segment elevation may occur in an infarct territory where Q waves are present or in a noninfarct territory. The development of 0.10 mV (1 mm) or greater of J point elevation, persistently elevated greater than 0.10 mV at 60 msec after the J point in three consecutive beats with a stable baseline, is considered an abnormal response (see Fig. 6-7) . This finding occurs in approximately 30 percent of patients with anterior myocardial infarctions and 15 percent of those with inferior ones tested early (within 2 weeks) after the index event and decreases in frequency by 6 weeks. As a group, postinfarct patients with exercise-induced ST segment elevation have a lower ejection fraction than those without, a greater severity of resting wall motion abnormalities, and a worse prognosis. Exercise-induced ST segment elevation in leads with abnormal Q waves is not a marker of more extensive CAD and rarely indicates myocardial ischemia. Exercise-induced ST-segment elevation may occasionally occur in a patient who has regenerated embryonic R waves after an acute myocardial infarction; the clinical significance of this finding is similar to that observed when Q waves are present. When ST segment elevation develops during exercise in a non-Q wave lead in a patient without a previous myocardial infarction, the finding should be considered as likely evidence of transmural myocardial ischemia caused by coronary vasospasm or a high-grade coronary narrowing (Fig. 6-9) . This finding is relatively uncommon, occurring in approximately 1 percent of patients with obstructive CAD. The ECG site of ST segment elevation is relatively specific for the coronary artery involved, and myocardial perfusion scintigraphy usually reveals a defect in the territory involved. T WAVE CHANGES.

The morphology of the T wave is influenced by body position, respiration, hyperventilation, drug therapy, and myocardial ischemia/necrosis. In patient populations

with a low CAD prevalence, pseudonormalization of T waves (inverted at rest and becoming upright with exercise) is a nondiagnostic finding (Fig. 6-10) . In rare instances, this finding may be a marker for myocardial ischemia in a patient with documented CAD, although it would need to be substantiated by an ancillary technique, such as the concomitant finding of a reversible myocardial perfusion defect.[30] OTHER ELECTROCARDIOGRAPHIC MARKERS.

Changes in R wave amplitude during exercise are relatively nonspecific and are related to the level of exercise performed. When the R wave amplitude meets voltage criteria for left ventricular hypertrophy, the ST segment response cannot be used reliably to diagnose CAD, even in the absence of a left ventricular strain pattern. Loss of R wave amplitude, commonly seen after myocardial infarction, reduces the sensitivity of the ST segment response in that lead to diagnose obstructive CAD. Adjustment of the extent of ST segment depression by R wave height in individual leads has not been consistently shown to improve the diagnostic value of the exercise ECG for CAD. U wave inversion may occasionally be seen in the precordial leads at heart rates of 120 beats/min. Although this finding is relatively specific for CAD, it is relatively insensitive.[31] COMPUTER-ASSISTED ANALYSIS

The use of computers has facilitated the routine analysis and measurements required from exercise ECG and can be performed on line as well as off line.[32] When the raw ECG data are high quality, the computer can filter and average or select median complexes from which the degree of J point displacement, ST segment slope, and ST displacement 60 to 80 msec after the J point (ST 60 to 80) can be measured. The selection of ST 60 or ST 80 depends on the heart rate response. At ventricular rates greater than 130 beats/min, the ST 80 measurement may fall on the upslope of the T wave, and the ST 60 measurement should be used instead. In some computerized systems, the PQ junction or isoelectric interval is detected by scanning before the R wave for the 10-msec interval with the least slope. J point, ST slope, and ST levels are determined (see Figs. 6-4 , 6-5 , and 6-6) ; the ST integral can be calculated from the area below the isoelectric line from the J point to ST 60 or ST 80.[29] Computerized treatment of ECG complexes permits reduction of motion and myographic artifacts. However, the averaged or median beats may occasionally be erroneous because of ECG signal distortion caused by noise, baseline wander, or changes in conduction, and identification of the PQ junction and ST segment onset may be imperfect. Therefore, it is crucial to ensure that the computer-determined averages or median complexes reflect the raw ECG data, and physicians should program the computer to print out raw data during exercise and inspect the raw data to be certain that the QRS template is accurately reproduced before accepting the automatic measurements. ST/HEART RATE SLOPE MEASUREMENTS.

Heart rate adjustment of ST segment depression appears to improve the sensitivity of the exercise test, particularly the prediction of multivessel CAD.[33] The ST/heart rate slope depends on the type of exercise performed, number and location of monitoring electrodes, method of measuring ST segment depression, and clinical characteristics of

the study population. Calculation of maximal ST/heart rate slope in mV/beats/min is performed by linear regression analysis relating the measured amount of ST segment depression in individual leads to the heart rate at the end of each stage of exercise, starting at the end of exercise. An ST/heart

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Figure 6-7 Illustration of eight typical exercise ECG patterns at rest and at peak exertion. The computer-processed incrementally averaged beat corresponds with the raw data taken at the same time point during exercise and is illustrated in the last column. The patterns represent worsening ECG responses during exercise. In the column of computer-averaged beats, ST 80 displacement (top number) indicates the magnitude of ST segment displacement 80 msec after the J point relative to the PQ junction or E point. ST segment slope measurement (bottom number) indicates the ST segment slope at a fixed time point after the J point to the ST 80 measurement. At least three noncomputer average complexes with a stable baseline should meet criteria for abnormality before the exercise ECG result can be considered abnormal (see Fig. 6-9) . The normal and rapid upsloping ST segment responses are normal responses to exercise. J point depression with rapid upsloping ST segments is a common response in an older, apparently healthy population. Minor ST depression can occur occasionally at submaximal workloads in patients with coronary disease; in this illustration, the ST segment is depressed 0.09 mV (0.9 mm) 80 msec after the J point. The slow upsloping ST segment pattern often demonstrates an ischemic response in patients with known coronary disease or those with a high pretest clinical risk of coronary disease. Criteria for slow upsloping ST segment depression include J point and ST 80 depression of 0.15 mV or more and ST segment slope of more than 1.0 mV/sec. Classic criteria for myocardial ischemia include horizontal ST segment depression observed when both the J point and ST 80 depression are 0.1 mV or more and ST segment slope is within the range of 1.0 mV/sec. Downsloping ST segment depression occurs when the J point and ST 80 depression are 0.1 mV and ST segment slope is -1.0 mV/sec. ST segment elevation in a non-Q wave noninfarct lead occurs when the J point and ST 60 are 1.0 mV or greater and represents a severe ischemic response. ST segment elevation in an infarct territory (Q wave lead) indicates a severe wall motion abnormality and in most cases is not considered an ischemic response.(From Chaitman BR: Exercise electrocardiographic stress testing. In Beller GA [ed]: Chronic Ischemic Heart Disease. In Braunwald E [series ed]: Atlas of Heart Diseases. Vol 5. Chronic Ischemic Heart Disease. Philadelphia, Current Medicine, 1995, pp 2.1-2.30.)

rate slope of 2.4 mV/beats/min is considered abnormal, and values that exceed 6 mV/beats/min are suggestive evidence of three-vessel CAD. The use of this measurement requires modification of the exercise protocol such that increments in heart rate are gradual, as in the Cornell protocol, as opposed to more abrupt increases in heart rate between stages, as in the Bruce's or Ellestad's protocols, which limit the ability to calculate statistically valid ST segment heart rate slopes. The measurement is not accurate in the early postinfarction phase. A modification of the ST segment/heart rate slope method is the ST segment/heart rate index calculation, which represents the average change of ST segment depression with heart rate throughout the course of the exercise test. The ST/heart rate index measurements are less than the ST/heart rate slope measurements, and a ST/heart rate index of 1.6 is defined as abnormal. A slight increase in the prognostic content of ST segment/heart rate slope measurements as compared with standard criteria was demonstrated in the Multiple Risk Factor Interventional Trial.[34] [35]

MECHANISM OF ST SEGMENT DISPLACEMENT

PATHOPHYSIOLOGY OF THE MYOCARDIAL ISCHEMIC RESPONSE.

Myocardial oxygen consumption (M 2 ) is determined by heart rate, systolic blood pressure, left ventricular end-diastolic volume, wall thickness, and contractility (see Chap. 34) .[2] [7] [12] The rate-pressure or double product (heart rate × systolic blood pressure) increases progressively with increasing work and can be used to estimate the myocardial perfusion requirement in normal persons and in many patients with coronary artery disease. The heart is an aerobic organ with little capacity to generate energy through anaerobic metabolism. Oxygen extraction in the coronary circulation is nearly maximal at rest. The only significant mechanism available to the heart to increase oxygen consumption is to increase perfusion, and there is a direct linear relationship between M 2 and coronary blood flow in normal individuals. The principal mechanism for increasing coronary blood flow during exercise is to decrease resistance at the coronary arteriolar level.[36] In

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Figure 6-8 Magnified ischemic exercise-induced ECG pattern. Three consecutive complexes with a relatively stable baseline are selected. The PQ junction (1) and J point (2) are determined; the ST 80 (3) is determined at 80 msec after the J point. In this example, average J point displacement is 0.2 mV (2 mm) and ST 80 is 0.24 mV (24 mm). The average slope measurement from the J point to ST 80 is -1.1 mV/sec.

patients with progressive atherosclerotic narrowing of the epicardial vessels, an ischemic threshold occurs, and exercise beyond this threshold can produce abnormalities in diastolic and systolic ventricular function, ECG changes, and chest pain. The subendocardium is more susceptible to myocardial ischemia than the subepicardium because of increased wall tension, causing a relative increase in myocardial oxygen demand in the subendocardium. Dynamic changes in coronary artery tone at the site of an atherosclerotic plaque may result in diminished coronary flow during static or dynamic exercise; i.e., perfusion pressure distal to the stenotic plaque actually falls as during exercise, resulting in reduced subendocardial blood flow.[37] Thus, regional left ventricular myocardial ischemia may result not only from an increase in myocardial oxygen demand during exercise but also from a limitation of coronary flow as a result of coronary vasoconstriction and inability of vessels to dilate near the site of an atherosclerotic plaque. In normal persons, the action potential duration of the endocardial region is longer than

that of the epicardial region, and ventricular repolarization is from epicardium to endocardium. The action potential duration is shortened in the presence of myocardial ischemia, and electrical gradients are created, resulting in ST segment depression or elevation, depending on the surface ECG leads.[38] Increased myocardial oxygen demand associated with a failure to increase or an actual decrease in regional coronary blood flow usually causes ST segment depression; ST segment elevation may occasionally occur in patients with more severe coronary flow reduction. NONELECTROCARDIOGRAPHIC OBSERVATIONS The ECG is only one part of the exercise response, and abnormal hemodynamics or functional capacity is just as important if not more so than ST segment displacement. BLOOD PRESSURE.

The normal exercise response is to increase systolic blood pressure progressively with increasing workloads to a peak response ranging from 160 to 200 mm Hg, with the higher range of the scale in older patients with less compliant vascular systems.[2] [7] As a group, African American patients--here and elsewhere--tend to have a higher systolic blood pressure response than do whites.[39] At high exercise workloads, it is sometimes difficult to obtain a precise determination of systolic blood pressure by auscultation.[40] In normal persons, the diastolic

Figure 6-9 A 48-year-old man with several atherosclerotic risk factors and a normal rest ECG result developed marked ST segment elevation (4 mm [arrows]) in leads V 2 and V3 with lesser degrees of ST segment elevation in leads V1 and V4 and J point depression with upsloping ST segments in lead II, associated with angina. This type of ECG pattern is usually associated with a full-thickness, reversible myocardial perfusion defect in the corresponding left ventricular myocardial segments and high-grade intraluminal narrowing at coronary angiography. Rarely, coronary vasospasm produces this result in the absence of significant intraluminal atherosclerotic narrowing.(From Chaitman BR: Exercise electrocardiographic stress testing. In Beller GA [ed]: Chronic Ischemic Heart Disease. In Braunwald E [series ed]: Atlas of Heart Diseases. Vol 5. Chronic Ischemic Heart Disease. Philadelphia, Current Medicine, 1995, pp 2.1-2.30.)

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Figure 6-10 Pseudonormalization of T waves in a 49-year-old man referred for exercise testing. The patient had previously been seen for typical angina. The rest electrocardiogram in this patient with coronary artery disease shows inferior and anterolateral T wave inversion, an adverse long-term prognosticator. The patient exercised to 8 METs, reaching a peak heart rate of 142 beats/min and a peak systolic blood pressure of 248 mm Hg. At that point, the test was stopped because of hypertension. During exercise, pseudonormalization of T waves occurs, and it returns to baseline (inverted T wave) in the postexercise phase. The patient denied chest discomfort, and no arrhythmia or ST segment displacement was noted. Transient conversion of a negative T wave at rest to a positive T wave during

exercise is a nonspecific finding in patients without prior myocardial infarction and does not enhance the diagnostic or prognostic content of the test; however, the ability to exercise to 8 METs without ischemic changes in the ST segment places this patient into a subset of lower risk. (From Chaitman BR: Exercise electrocardiographic stress testing. In Beller GA [ed]: Chronic Ischemic Heart Disease. In Braunwald E [series ed]: Atlas of Heart Diseases. Vol 5. Chronic Ischemic Heart Disease. Philadelphia, Current Medicine, 1995, pp 2.1-2.30.

blood pressure does not usually change significantly. Failure to increase systolic blood pressure beyond 120 mm Hg, or a sustained decrease greater than 10 mm Hg repeatable within 15 seconds, or a fall in systolic blood pressure below standing rest values is abnormal and reflects either inadequate elevation of cardiac output because of left ventricular systolic pump dysfunction or an excessive reduction in systemic vascular resistance.[41] An abnormal systolic blood pressure response in patients with a high prevalence of CAD is associated with more extensive CAD and more extensive myocardial perfusion defects; exertional hypotension ranges from 3 to 9 percent and is higher in patients with three-vessel or left main CAD. Conditions other than myocardial ischemia that have been associated with the failure to increase or an actual decrease in systolic blood pressure during progressive exercise are cardiomyopathy, cardiac arrhythmias, vasovagal reactions, left ventricular outflow tract obstruction, ingestion of antihypertensive drugs, hypovolemia, and prolonged vigorous exercise.[42] It is important to distinguish between a decline in blood pressure in the postexercise phase and a decrease or failure to increase systolic blood pressure during progressive exercise. The incidence of postexertional hypotension in asymptomatic subjects was 1.9 percent in 781 asymptomatic volunteers in the Baltimore Longitudinal Study on Aging, with a 3.1 percent incidence noted in subjects younger than 55 years and 0.3 percent incidence in patients older than 55 years.[43] In this series, most hypotensive episodes were symptomatic, and only two patients had hypotension associated with bradycardia and vagal symptoms. Although ST segment abnormalities suggestive of ischemia occurred in one-third of the patients with hypotension, none of the patients had a cardiac event during 4 years of follow-up. Rarely, in young patients, vasovagal syncope can occur in the immediate postexercise phase, progressing through sinus bradycardia to several seconds of asystole and hypotension before reverting to sinus rhythm. MAXIMAL WORK CAPACITY.

This variable is one of the most important prognostic measurements obtained from an exercise test.[44] [45] [46] [47] [48] Maximal work capacity in normal individuals is influenced by familiarization with the exercise test equipment, level of training, and environmental conditions at the time of testing. In patients with known or suspected CAD, a limited exercise capacity is associated with an increased risk of cardiac events, and in general, the more severe the limitation, the worse the CAD extent and prognosis. In estimating functional capacity, the amount of work performed (or exercise stage achieved) should be the parameter measured and not the number of minutes of exercise. Estimates of peak functional capacity for age and gender have been well established for most of the exercise protocols in common use, subject to the limitations described in the section on cardiopulmonary testing. Comparison of an individual's performance against normal standards provides an estimate of the degree of exercise impairment. There is a rough correlation between observed peak functional capacity during exercise treadmill testing

and estimates derived from clinical data and specific activity questionnaires.[49] Serial comparison of functional capacity in individual patients to assess significant interval change requires a careful examination of the exercise protocol used during both tests, of drug therapy and time of ingestion, of systemic blood pressure, and of other conditions that might influence test performance. All these variables need to be considered before attributing changes in functional capacity to progression of CAD or worsening of left ventricular function. Major reductions in exercise capacity usually indicate significant worsening of cardiovascular status; modest changes may not. SUBMAXIMAL EXERCISE.

The interpretation of exercise test results for diagnostic and prognostic purposes requires

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consideration of maximal work capacity. When a patient is unable to complete moderate levels of exercise or reach at least 85 to 90 percent of age-predicted maximum, the level of exercise performed may be inadequate to test cardiac reserve. Thus, ischemic ECG, scintigraphic, or ventriculographic abnormalities may not be evoked and the test may be nondiagnostic. Nondiagnostic test results are more common in patients with peripheral vascular disease, orthopedic limitation, or neurological impairment and in patients with poor motivation. Pharmacologic stress imaging studies should be considered in this setting.[5] [6] [11] HEART RATE RESPONSE.

The sinus rate increases progressively with exercise, mediated in part through sympathetic and parasympathetic innervation of the sinoatrial node and circulating catecholamines. In some patients who may be anxious about the exercise test, there may be an initial overreaction of heart rate and systolic blood pressure at the beginning of exercise, with stabilization after approximately 30 to 60 seconds. An inappropriate increase in heart rate at low exercise workloads may occur in patients who are in atrial fibrillation, physically deconditioned, hypovolemic, or anemic or who have marginal left ventricular function; this increase may persist for several minutes in the recovery phase. The term chronotropic incompetence refers to a heart rate increment per stage of exercise that is less than normal or a peak heart rate below predicted at maximal workloads.[50] [51] This finding may indicate sinus node disease, may be present with drug therapy such as beta blockers or in patients with compensated congestive heart failure, or may indicate a myocardial ischemic response. In a series of 2953 low-risk subjects who were referred for treadmill exercise myocardial perfusion imaging and who were not taking beta-adrenergic blocking drugs, failure to achieve 85 percent of age-predicted maximal heart rate, or a low chronotropic index (3%) might require more frequent follow-up testing on an annual basis in the absence of a change of symptoms.[53] DIAGNOSTIC USE OF EXERCISE TESTING Appreciation of the noninvasive test literature to diagnose CAD requires an understanding of standard terminology such as sensitivity, specificity, and test accuracy[1] [2] [3] [4] [5] [6] (Tables 6-1 and 6-G-2) . The sensitivity of the exercise ECG in patients with CAD is approximately 68 percent, and specificity is 77 percent.[2] In patients with single-vessel disease, the sensitivity ranges from 25 to 71 percent, with exercise-induced ST displacement most frequent in patients with left anterior descending CAD, followed by those with right CAD and those with isolated left circumflex CAD. In patients with multivessel CAD, sensitivity is approximately 81 percent and specificity is 66 percent.[2] The sensitivity and specificity for left main or three-vessel CAD are approximately

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TABLE 6-1 -- TERMS USEFUL IN EVALUATION OF TEST RESULTS True positive (TP)=abnormal test results in individual with disease False positive (FP)=abnormal test results in individual without disease True negative (TN)=normal test result in individual without disease False negative (FN)=normal test result in individual with disease Sensitivity: percentage of patients with CAD who have an abnormal result=TP/(TP+FN) Specificity: percentage of patients without CAD who have a normal result=TN/(TN+FP) Predictive value: percentage of patients with abnormal result who have CAD=TN/(TN+FN) Test accuracy: percentage of true test results=(TP+TN)/total number tests performed Likelihood ratio: odds of a test result being true: of an abnormal test: sensitivity/(1-specificity); of a normal test: specificity/(1-sensitivity)

CAD=coronary artery disease. 86 percent and 53 percent. The exercise ECG tends to be less sensitive in patients with extensive anterior wall myocardial infarction and when a limited exercise ECG lead set is used. Approximately 75 to 80 percent of the diagnostic information on exercise-induced ST segment depression in patients with a normal rest ECG is contained in leads V4 to V6 . Exercise ECG is less specific when patients in whom false-positive results are more common are included--i.e., those with valvular heart disease, left ventricular hypertrophy, marked resting ST segment depression, or digitalis therapy.[5] Table 6-2 lists the more common causes of noncoronary exercise-induced ST segment depression. The traditional reference standard against which the exercise ECG has been measured is a qualitative assessment of the coronary angiogram using 50 to 70 percent obstruction of the luminal diameter as the angiographic cutpoint. Limitations are inherent in angiographic classification of patients into one-, two-, and three-vessel CAD, and the length of the coronary artery narrowing and the impact of serial lesions are not accounted for in correlative studies comparing diagnostic exercise testing with coronary angiographic findings. Other approaches, including intracoronary Doppler flow studies and quantitative coronary angiography, have been proposed to assess coronary vascular reserve; these may be more accurate than qualitative assessment of the angiogram.[54] [55] [56] [57] [58] In patients with ischemic-appearing ST segment depression during exercise and normal findings on coronary angiography (syndrome X), coronary endothelial dysfunction as measured by coronary vasomotor responsiveness to acetylcholine does not account for the ischemic ST segment response.[59] TABLE 6-2 -- NONCORONARY CAUSES OF ST SEGMENT DEPRESSION Severe aortic stenosis Glucose load Severe hypertension

Left ventricular hypertrophy

Cardiomyopathy

Hyperventilation

Anemia

Mitral valve prolapse

Hypokalemia

Intraventricular conduction disturbance

Severe hypoxia

Preexcitation syndrome

Digitalis use

Severe volume overload (aortic, mitral regurgitation)

Sudden excessive exercise

Supraventricular tachyarrhythmias

Selective referral of patients with a positive test result for further study both decreases the rate of detection of true negative test results and increases the rate of detection of false-positive results, thus increasing sensitivity and decreasing specificity.[1] [2] [3] [4] Froelicher and colleagues, in a study of 814 consecutive patients who presented with

angina pectoris and agreed to undergo both exercise testing and coronary angiography, reported an exercise ECG sensitivity and specificity of 45 percent and 85 percent, respectively for obstructive CAD using visual analysis in this population with reduced work-up bias.[60] Computerized ST segment measurements were similar to visual ST segment measurements in this study. A false-positive result is more common when only the inferior lead group (leads 2, 3, aVf ) is abnormal at high exercise workloads. BAYESIAN THEORY.

The depth of exercise-induced ST-segment depression and the extent of the myocardial ischemic response can be thought of as continuous variables. Cutpoints such as 1 mm of horizontal or downsloping ST segment depression as compared with baseline cannot completely discriminate patients with disease from those without disease, and the requirement of more severe degrees of ST segment depression to improve specificity will decrease sensitivity. Sensitivity and specificity are inversely related, and false-negative and false-positive results are to be expected when ECG or angiographic cutpoints are selected to optimize the diagnostic accuracy of the test.[1] [2] [3] [4] [5] [6] [61] The use of Bayesian theory incorporates the pretest risk of disease and the sensitivity and specificity of the test (likelihood ratio) to calculate the posttest probability of coronary disease. The results of a patient's clinical information and exercise test results are used to make a final estimate of the probability of CAD. Atypical or probable angina in a 50-year-old man or a 60-year-old woman is associated with approximately 50 percent probability for CAD before exercise testing is performed. The diagnostic power of the exercise test is maximal when the pretest probability of CAD is intermediate (30 to 70 percent). MULTIVARIATE ANALYSIS.

Multivariate analysis of noninvasive exercise tests to estimate posttest risk also can provide important diagnostic information. Multivariate analysis offers the potential advantage that it does not require that the tests be independent of each other or that sensitivity and specificity remain constant over a wide range of disease prevalence rates. However, the multivariate technique depends critically on how patients are selected to establish the reference data base. Both Bayesian and multivariate approaches are commonly used to provide diagnostic and prognostic estimates of patients with CAD. SEVERITY OF ELECTROCARDIOGRAPHIC ISCHEMIC RESPONSE.

The exercise ECG result is more likely to be abnormal in patients with more severe coronary arterial obstruction, with more extensive CAD, and after more strenuous levels of exercise. Early onset of angina, ischemic ST segment depression, and fall in blood pressure at low exercise workloads are the most important exercise parameters associated with an adverse prognosis and multivessel CAD.[62] Additional adverse markers include profound ST segment displacement, ischemic changes in five or more ECG leads, and persistence of the changes late in the recovery phase of exercise

(Table 6-3) . EXERCISE TESTING IN DETERMINING PROGNOSIS Exercise testing provides not only diagnostic information but also more importantly prognostic data. The value of exercise testing to estimate prognosis must be considered in light of what is already known about a patient's risk status. Left ventricular dysfunction, CAD extent, electrical instability,

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TABLE 6-3 -- EXERCISE PARAMETERS ASSOCIATED WITH AN ADVERSE PROGNOSIS AND MULTIVESSEL CORONARY ARTERY DISEASE Duration of symptom-limiting exercise 10 METs) usually have an excellent prognosis regardless of the anatomical extent of CAD. The test provides an estimate of the functional significance of angiographically documented coronary artery stenoses. The impact of exercise testing in patients with proven or suspected CAD was studied by Weiner and colleagues in 4083 medically treated patients in the CASS study.[69] A high-risk patient subset was identified (12

percent of the population), with an annual mortality of 5 percent a year when exercise workload was less than Bruce's stage I ( 50 percent was similar to the survival rates of patients with a peak O2

14 ml O2 ·kg -1 ·min-1 and significantly greater than the 61 ± 5 percent of the 110 patients with a peak O2

50 percent. The data indicate that a low peak and percent predicted O2 identify high-risk patients with congestive heart failure whose survival may be improved by cardiac transplantation.(From Osada N, Chaitman BR, Miller LW, et al: Cardiopulmonary exercise testing identifies low risk patients with heart failure and severely impaired exercise capacity considered for heart transplantation. J Am Coll Cardiol 31:577, 1998.) O2

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time for the ventricular rate to return to baseline during recovery. The transplanted heart relies heavily on the Frank-Starling mechanism to increase cardiac output during mild to moderate exercise. Systemic vascular resistance may be increased because of cyclosporine therapy. The exercise ECG is relatively insensitive in detecting coronary artery vasculopathy after cardiac transplantation.[160] [162] However, the new development of an abnormal exercise ECG result several years after cardiac transplantation may indicate focal intraluminal narrowing. SAFETY AND RISKS OF EXERCISE TESTING Exercise testing has an excellent safety record. The risk is determined by the clinical characteristics of the patient referred for the procedure. In nonselected patient populations, the mortality is less than 0.01 percent and morbidity less than 0.05 percent.[164] The risk is greater when the test is performed soon after an acute ischemic event. In a survey of 151,941 tests conducted within 4 weeks of an acute myocardial infarction, mortality was 0.03 percent, and 0.09 percent of patients either had a nonfatal reinfarction or were resuscitated from cardiac arrest. [165] The relative risk of a major complication is about twice as great when a symptom-limited protocol is used as compared with a low-level protocol. Nevertheless, in the early postinfarction phase, the risk of a fatal complication during symptom-limited testing is only 0.03 percent. The risk is less for low-risk patients who are seen in the emergency department and who undergo exercise testing for risk stratification.[93] Exercise testing can be safely performed in patients with compensated congestive heart failure, with no major complications reported in 1286 tests in which a bicycle ergometer was used.[166] The risk of exercise testing in patients referred for life-threatening ventricular arrhythmias was examined by Young and colleagues[167] in a series of 263 patients who underwent 1377 tests; 2.2 percent developed sustained ventricular tachyarrhythmias that required cardioversion, cardiopulmonary resuscitation, or antiarrhythmic drugs to restore sinus rhythm. The ventricular arrhythmias were more frequent in tests performed on antiarrhythmic drug therapy as compared with the baseline drug-free state. In contrast to the high risk in the aforementioned patient subsets, the risk of complications in asymptomatic subjects is extremely low, with no fatalities reported in several series. [1] [2] [3] [4] [5] [6]

The risk of incurring a major complication during exercise testing can be reduced by performing a careful history and physical examination before the test and observing patients closely during exercise with monitoring of the ECG, arterial pressure, and symptoms. The standard 12-lead ECG should be verified before the test for any acute or recent change. The contraindications to exercise testing are well defined (Table 6-4) . Patients with critical obstruction to left ventricular outflow are at increased risk of cardiac events during exercise. In selected patients, low-level exercise can be useful in determining the severity of the left ventricular outflow tract gradient. The cool-down period should be prolonged to at least 2 minutes in patients with TABLE 6-4 -- CONTRAINDICATIONS TO EXERCISE TESTING

Acute myocardial infarction (10 mm Hg from baseline blood pressure despite an increase in workload, when accompanied by other evidence of ischemia Moderate to severe angina (grade ¾ ) Increasing nervous system symptoms (e.g., ataxia, dizziness, or near-syncope) Signs of poor perfusion (cyanosis or pallor) Technical difficulties in monitoring ECG or systolic blood pressure Subject's desire to stop Sustained ventricular tachycardia ST elevation ( 1.0 mm) in noninfarct leads without diagnostic Q waves (other than V1 or aVr ) RELATIVE INDICATIONS Drop in systolic blood pressure of 10 mm Hg from baseline blood pressure despite an increase in workload, in the absence of other evidence of ischemia ST or QRS changes such as excessive ST depression (>3 mm of horizontal or downsloping ST segment depression) or marked axis shift Arrhythmias other than sustained ventricular tachycardia, including multifocal PVCs, triplets of PVCs, supraventricular tachycardia, heart block, or bradyarrhythmias Fatigue, shortness of breath, wheezing, leg cramps, or claudication Development of bundle branch block of intraventricular conduction delay that cannot be distinguished from ventricular tachyardia Increasing chest pain Hypertensive response

ECG=electrocardiogram; PVCs=premature ventricular contractions. Modified from Fletcher GF: Exercise standards: A standard for healthcare professionals from the American Heart Association Writing Group. Circulation 91:580, 1995. stenotic valves to avoid sudden pressure-volume shifts that occur in the immediate postexercise phase. Uncontrolled systemic hypertension is a contraindication to exercise testing. Patients should continue antihypertensive drug therapy on the day of testing. Patients who present with systemic arterial pressure readings of 220/120mm Hg or greater should rest for 15 to 20 minutes, and their blood pressure should be remeasured. If blood pressure remains at these levels, the test should be postponed until the hypertension is better controlled. A resuscitator cart and defibrillator should be available in the room where the test procedure is carried out, as should appropriate cardioactive medication available to treat cardiac arrhythmias, AV block, hypotension, and persistent chest pain. An intravenous line should be started in high-risk patients such as those being tested for adequacy of control of life-threatening ventricular arrhythmias. The equipment and supplies in the cart should be checked on a regular basis. A previously specified routine for cardiac emergencies needs to be determined; this includes patient transfer and admission to a coronary care unit if necessary. Clinical judgment is required to determine which patients can be safely tested in an office as opposed to a hospital-based setting. High-risk patients, such as those with evident left ventricular dysfunction, severe angina pectoris, a history of cardiac syncope, and significant ambient ventricular ectopy on the pretest examination, should be tested in the hospital. Low-risk patients, such as asymptomatic individuals and those with a low pretest risk of disease, may be tested by specially trained nurses or physician assistants who have received advanced cardiac life support certification, with a physician in close proximity. TERMINATION OF EXERCISE.

The use of standard test indications to terminate an exercise test reduces risk (Table 6-5) .

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TABLE 6-6 -- EXERCISE TEST REPORT INFORMATION Demographic data: name, patient identifier, date of birth/age, gender, weight, height, test date Indication(s) for test

Patient descriptors: atherosclerotic risk profile, drug usage, resting ECG findings Exercise test results Protocol used Reason(s) for stopping exercise Hemodynamic data: rest and peak heart rate, rest and peak blood pressure, percent maximum achieved heart rate, maximum rate of perceived exertion (Borg's scale), peak workload, peak METs, total exercise duration in minutes Evidence for myocardial ischemia: time to onset and offset of ischemic ST segment deviation or angina, maximum depth of ST segment deviation, number of abnormal exercise ECG leads, abnormal systemic blood pressure responses General comments ECG=electrocardiogram. Termination of exercise should be determined in part by the patient's recent activity level. The rate of perceived patient exertion can be estimated by the Borg's scale. The scale is linear, with values of 9, very light; 11, fairly light; 13, somewhat hard; 15, hard; 17, very hard; and 19, very, very hard. Borg's readings of 14 to 16 approximate anaerobic threshold, and readings of 18 or greater approximate a patient's maximum exercise capacity. It is helpful to grade exercise-induced chest discomfort on a 1 to 4 scale, with 1 indicating the initial onset of chest discomfort and 4 the most severe chest pain the patient has ever experienced. The exercise technician should note the onset of grade 1 chest discomfort on the work sheet, and the test should be stopped when the patient reports grade 3 chest pain. In the absence of symptoms, it is prudent to stop exercise when a patient demonstrates 0.3 mV (3 mm) or greater of ischemic ST segment depression or 0.1 mV (1 mm) or greater of ST segment elevation in a noninfarct lead without an abnormal Q wave. Significant worsening of ambient ventricular ectopy during exercise or the unsuspected appearance of ventricular tachycardia is an indication to terminate exercise. A progressive, reproducible decrease in systolic blood pressure of 10 mm Hg or more may indicate transient left ventricular dysfunction or an inappropriate decrease in systemic vascular resistance and is an indication to terminate exercise. The test should be stopped if the arterial blood pressure is 250 to 270/120 to 130 mm Hg or greater. Ataxia may indicate cerebral hypoxia. The exercise test report should contain basic demographic data, the indication for testing, a brief description of the patient's profile, and exercise test results (Table 6-6) .

REFERENCES 1.

Ellestad MH: Stress Testing: Principles and Practice. 4th ed. Philadelphia, FA Davis, 1995.

2.

Froelicher VF, Myers J: Exercise and the Heart. 3rd ed. Philadelphia, W.B. Saunders, 1999.

3.

Jones NL: Clinical Exercise Testing. 4th ed. Philadelphia, WB Saunders, 1997.

Fletcher GF, Flipse TR, Kligfield P, et al: Current status of ECG stress testing. Curr Probl Cardiol 23:353, 1998. 4.

Gibbons RJ, Balady GJ, Beasley JW, et al: ACC/AHA guidelines for exercise testing. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on exercise testing). J Am Coll Cardiol 30:260, 1997. 5.

ESC Working Group on Exercise Physiology, Physiopathology and Electrocardiography: Guidelines for cardiac exercise testing. Eur Heart J 14:969, 1993. 6.

Fletcher GF, Balady GJ, Froelicher VF, et al: Exercise standards. A statement for healthcare professionals from the American Heart Association. Writing Group. Circulation 91:580, 1995. 7.

Pina IL, Balady GJ, Hanson P, et al: Guidelines for clinical exercise testing laboratories. A statement for healthcare professionals from the Committee on Exercise Cardiac Rehabilitation, American Heart Association. Circulation 91:912, 1995. 8.

Wasserman K, Hansen JE, Sue DY, et al: Principles of Exercise Testing and Interpretation. 3rd ed. Philadelphia, Lippincott, Williams & Wilkins, 1999. 9.

Hachamovitch R, Berman DS, Shaw LJ, et al: Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: Differential stratification for risk of cardiac death and myocardial infarction. Circulation 97:535, 1998. 10.

Marwick TH: Cardiac Stress Testing & Imaging: A Clinician's Guide. New York, Churchill Livingstone, 1996. 11.

EXERCISE PHYSIOLOGY 12.

Gauton AC: Textbook of Medical Physiology. 9th ed. Philadelphia, WB Saunders, 1995.

Fleg JL, Schulman S, O'Connor F, et al: Effects of acute beta-adrenergic receptor blockade on age-associated changes in cardiovascular performance during dynamic exercise. Circulation 90:2333, 1994. 13.

Schulman SP, Fleg JL, Goldberg AP, et al: Continuum of cardiovascular performance across a broad range of fitness levels in healthy older men. Circulation 94:359, 1996. 14.

Fleg JL, O'Connor FC, Gerstenblith GH, et al: Impact of age on the cardiovascular response to dynamic upright exercise in healthy men and women. J Appl Physiol 78:890, 1995. 15.

Imai K, Sato H, Hori M, et al: Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure. J Am Coll Cardiol 24:1529, 1994. 16.

Weber KT, Janicki JS, McElroy PA, et al: Concepts and applications of cardiopulmonary exercise testing. Chest 93:843, 1988. 17.

Norton LH, Squires B, Craig NP, et al: Accuracy of pulse oximetry during exercise stress testing. Int J Sports Med 13:523, 1992. 18.

Wasserman K, Beaver WL, Whipp BJ: Gas exchange theory and the lactic acidosis (anaerobic) threshold. Circulation 81:II-14, 1990. 19.

Eliasson AH, Phillips YY, Rajagopal KR, Howard RS: Sensitivity and specificity of bronchial provocation testing: An evaluation of four techniques in exercise-induced bronchospasm. Chest 102:347, 1992. 20.

Tamesis B, Stelken A, Byers S, et al: Comparison of the Asymptomatic Cardiac Ischemia Pilot and modified Asymptomatic Cardiac Ischemia Pilot versus Bruce and Cornell exercise protocols. Am J Cardiol 72:715, 1993. 21.

Chaitman BR, Stone PH, Knatterud GL, et al: Asymptomatic Cardiac Ischemia Pilot (ACIP) study: Impact of anti-ischemia therapy on 12-week rest ECG and exercise test outcomes. J Am Coll Cardiol 26:585, 1995. 22.

Blair SN, Gibbons LW, Painter P, et al: Guidelines for exercise testing and prescription. 3rd ed. Philadelphia, Lea & Febiger, 1988. 23.

Bittner V, Weiner DH, Yusuf S, et al: Prediction of mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. JAMA 270:1702, 1993. 24.

Montgomery PS, Gardner AW: The clinical utility of a six-minute walk test in peripheral arterial occlusive disease patients. J Am Geriatr Soc 46:706, 1998. 25.

Badruddin SM, Ahmad A, Mickelson J, et al: Supine bicycle versus post-treadmill exercise echocardiography in the detection of myocardial ischemia: A randomized single-blind crossover trial. J Am Coll Cardiol 33:1485, 1999. 26.

DIAGNOSTIC TESTING Michaelides AP, Psomadaki ZD, Dilaveris PE, et al: Improved detection of coronary artery disease by exercise electrocardiography with the use of right precordial leads. N Engl J Med 340:340, 1999. 27.

Rywik TM, Zink RC, Gittings NS, et al: Independent prognostic significance of ischemic ST segment response limited to recovery from treadmill exercise in asymptomatic subjects. Circulation 97:2117, 1998. 28.

Chaitman BR: Exercise electrocardiographic stress testing. In Beller GA (ed): Chronic Ischemic Heart Disease. In Braunwald E (series ed): Atlas of Heart Diseases. Vol V. Chronic Ischemic Heart Disease. Philadelphia, Current Medicine, 1995, pp 2.1-2.30. 29.

Mobilia G, Zanco P, Desideri A, et al: T wave normalization in infarct-related electrocardiographic leads during exercise testing for detection of residual viability: Comparison with positron emission tomography. J Am Coll Cardiol 32:75, 1998. 30.

Chikamori T, Yamada M, Takata J, et al. Exercise-induced prominent U waves as a marker of significant narrowing of the left circumflex or right coronary artery. Am J Cardiol 74:495, 1994. 31.

Caralis DG, Shaw L, Bilgere B, et al: Application of computerized exercise ECG digitization: Interpretation in large clinical trials. J Electrocardiol 25:101, 1992. 32.

Okin PM, Kligfield R: Gender specific criteria and performance of the exercise electrocardiogram. Circulation 92(5):1209, 1995. 33.

Okin PM, Prineas RJ, Grandits G, et al: Heart rate adjustment of exercise induced ST segment depression identifies men who benefit from a risk factor reduction program. Circulation 96:2899, 1997. 34.

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Okin PM, Grandits G, Rautaharju PM, et al: Prognostic value of heart rate adjustment of exercise induced ST segment depression in the Multiple Risk Factor Interventional Trial. J Am Coll Cardiol 27:1437, 1996. 35.

Berdeaux A, Ghaleh B, Dubois-Rande JL, et al: Role of vascular endothelium in exercise-induced dilation of large epicardial coronary arteries in conscious dogs. Circulation 89:2799, 1994. 36.

Julius BK, Vassalli G, Mandinov L, Hess OM: Alpha-adrenoreceptor blockade prevents exercise-induced vasoconstriction of stenotic coronary arteries. J Am Coll Cardiol 33:1499, 1999. 37.

Kubota I, Yamaki M, Shibata T, et al: Role of ATP sensitivie K+ channel on ECG ST segment elevation during a bout of myocardial ischemia: A study on epicardial mapping in dogs. Circulation 88:1854, 1993. 38.

Ekelund LG, Suchindran CM, Karon JM, et al: Black-white differences in exercise blood pressure. Circulation 31:1568, 1990. 39.

White WB, Lund-Johansen P, Omvik P: Assessment of four ambulatory blood pressure monitors and measurements by clinicians versus intraarterial blood pressure at rest and during exercise. Am J Cardiol 65:60, 1990. 40.

Reman A, Zelos G, Andrews NP, et al: Blood pressure changes during transient myocardial ischemia: Insights into mechanisms. J Am Coll Cardiol 30:1249, 1997. 41.

Lele SS, Scalia G, Thomson H, et al: Mechanism of exercise hypotension in patients with ischemic heart disease: Role of neurocardiogenically mediated vasodilation. Circulation 90:2701, 1994. 42.

EXERCISE TESTING DETERMINING PROGNOSIS Fleg JL, Lakatta EG: Prevalence and significance of postexercise hypotension in apparently healthy subjects. Am J Cardiol 57:1380, 1986. 43.

Chaitman BR, McMahon RP, Terrin M, et al: Impact of treatment strategy on predischarge exercise test in the Thrombolysis in Myocardial Infarction (TIMI) II trial. Am J Cardiol 71:131, 1993. 44.

Morris CK, Ueshima K, Kawaguchi T, et al: The prognostic value of exercise capacity: A review of the literature. Am Heart J 122:1423, 1991. 45.

Stevenson LW, Steimle AE, Fonarow G, et al: Improvement in exercise capacity of candidates awaiting heart transplantation. J Am Coll Cardiol 25:163, 1995. 46.

Vanhees L, Fagard R, Thijs L, et al: Prognostic significance of peak exercise capacity in patients with coronary artery disease. J Am Coll Cardiol 23:358, 1994. 47.

48.

Younis LT, Chaitman BR: The prognostic value of exercise testing. Cardiol Clin 11:229, 1993.

Myers J, Do D, Herbert W, et al: A nomogram to predict exercise capacity from a specific activity questionnaire and clinical data. Am J Cardiol 73:591, 1994. 49.

Lauer MS, Francis GS, Okin PM, et al: Impaired chronotropic response to exercise stress testing as a predictor of mortality. JAMA 281:524,1999. 50.

Lauer M, Mehta R, Pashkow FJ, et al: Association of chronotropic incompetence with echocardiographic ischemia and prognosis. J Am Coll Cardiol 32:1280 1998. 51.

McCance AJ, Forfar JC: Selective enhancement of the cardiac sympathetic response to exercise by anginal chest pain in humans. Circulation 80:1642, 1989. 52.

Gibbons RJ, Chatterjee K, Daley J, et al: ACC/AHA/ACP guidelines for the management of chronic stable angina. A report of the American College of Cardiology/American Heart Association, American College of Physicians Task Force on practice guidelines (Committee on management of patients with chronic stable angina). Circulation 99:2829, 1999. 53.

Kern MJ, Donohue TJ, Aguirre FA, et al: Clinical outcome of deferring angioplasty in patients with normal translesional pressure flow velocity measurements. J Am Coll Cardiol 25:178, 1995. 54.

Reis SE, Holubkov R, Lee JS, et al: Coronary flow velocity response to adenosine characterizes coronary microvascular function in women with chest pain and no obstructive coronary disease. J Am Coll Cardiol 33:1469, 1999. 55.

Nico HJ, Pijls NH, DeBruyne B, et al: Measurement of fractional flow reserve to assess the functional severity of coronary artery stenosis. N Engl J Med 334:1703, 1996. 56.

Danzi GB, Pirelli S, Mauri L, et al: Which variable of stenosis severity best describes the significance of an isolated left anterior descending artery lesion? Correlation between quantitative coronary angiography, intracoronary Doppler measurements and high dose dipyridamole echocardiography. J Am Coll Cardiol 31:526, 1998. 57.

Schulman SP, Lasorda D, Farah T, et al: Correlations between coronary flow reserve measured with a Doppler guide wire and treadmill exercise testing. Am Heart J 134:99, 1997. 58.

Cannon RO, Curiel RV, Prasad A, et al: Comparison of coronary endothelial dynamics with electrocardiographic and left ventricular contractile responses to stress in the absence of coronary artery disease. Am J Cardiol 82:710, 1998. 59.

Froelicher VF, Lehmann KG, Thomas R: Veterans Affairs Cooperative Study in Health Services #016 (QUEXTA) Study Group. The electrocardiographic exercise test in a population with reduced workup bias: Diagnostic performance, computerized interpretation and multivariable prediction. Ann Intern Med 128:965, 1998. 60.

Wennberg DE, Kellet MA, Dickens DJ, et al: The association between local diagnostic testing intensity and invasive cardiac procedures. JAMA 275(15):1161, 1996. 61.

Bogaty P, Guimond J, Robitaille NM, et al: A reappraisal of exercise electrocardiographic indexes of the severity of ischemic heart disease: Angiographic and scintigraphic correlates. J Am Coll Cardiol 313:582, 1998. 62.

Ekelund LG, Suchindran CM, McMahonr R, et al: Coronary heart disease morbidity and mortality in hypercholesterolemic men predicted from an exercise test: The Lipid Research Clinics Coronary Primary Prevention Trial. J Am Coll Cardiol 14:556, 1989. 63.

Rautaharju PM, Prineas RJ, Eiffier WJ, et al: Prognostic value of exercise electrocardiograms in men at high risk of future coronary heart disease: Multiple Risk Factor Intervention Trial experience. J Am Coll Cardiol 8:1, 1986. 64.

Bruce RA, Fischer LD: Exercise-enhanced assessment of risk factors for coronary heart disease in healthy men. J Electrocardiol 20:162, 1987. 65.

Fleg JL, Gertenblith G, Zonerman AB, et al: Prevalence and prognostic significance of exercise induced silent myocardial ischemia detected by thallium scintigraphy and electrocardiography in asymptomatic volunteers. Circulation 81:428, 1990. 66.

Fagan LF, Shaw L, Kong BA, et al: Prognostic value of exercise thallium scintigraphy in patients with good exercise tolerance and a normal or abnormal exercise electrocardiogram and suspected or confirmed coronary artery disease. Am J Cardiol 69:607, 1992. 67.

Josephson RA, Shefrin E, Lakatta EG, et al: Can serial exercise testing improve the prediction of coronary events in asymptomatic individuals? Circulation 8:20, 1990. 68.

Weiner DH, Ryan T, McCabe CH, et al: Prognostic importance of a clinical profile and exercise test in medically treated patients with coronary artery disease. J Am Coll Cardiol 3:772, 1984. 69.

Mark DB, Hlatky MA, Harrell FE, et al: Exercise treadmill score for predicting prognosis in coronary heart disease. Ann Intern Med 106:793, 1987. 70.

Mark DB, Shaw L, Harrell FE Jr, et al: Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease. N Engl J Med 325:849, 1991. 71.

Froelicher V, Morrow K, Brown M, et al: Prediction of atherscolerotic cardiovascular death in men using a prognostic score. Am J Cardiol 73:133, 1994. 72.

Morise AP, Haddad WJ, Beckner D: Development and validation of a clinical score to estimate the probability of coronary artery disease in men and women presenting with suspected coronary disease. Am J Cardiol 102(4):350, 1997. 73.

Miller TD, Christian TF, Taliercio CP, et al: Severe exercise-induced ischemia does not identify high risk patients with normal left ventricular function and one- or two-vessel coronary artery disease. J Am Coll Cardiol 23:219, 1994. 74.

Quyyumi AA, Panza JA, Diodati JG, et al: Prognostic implications of myocardial ischemia during daily life in low risk patients with coronary artery disease. J Am Coll Cardiol 21:700, 1993. 75.

Benhorin J, Pinsker G, Moriel M, et al: Ischemic threshold during two exercise testing protocols and during ambulatory electrocardiographic monitoring. J Am Coll Cardiol 22:671, 1993. 76.

Klein J, Chao SY, Berman DS, Rozanski A: Is "silent" myocardial ischemia really as severe as symptomatic ischemia? The analytical effect of patient selection biases. Circulation 89:1958, 1994. 77.

78.

Narins CR, Zareba W, Moss AJ, et al: Clinical implications of silent versus symptomatic exercise

induced myocardial ischemia in patients with stable coronary disease. J Am Coll Cardiol 29:756, 1997. Rogers WJ, Bourassa MG, Andrews TC, et al: Asymptomatic Cardiac Ischemia Pilot (ACIP) study: Outcome at one year for patients with asymptomatic cardiac ischemia randomized to medical therapy or revascularization. The ACIP investigators. J Am Coll Cardiol 26(3):594, 1995. 79.

Stone PH, Chaitman BR, Forman S, et al: Prognostic significance of myocardial ischemia detected by ambulatory electrocardiogram, exercise treadmill testing, and resting electrocardiogram to predict cardiac events by 1 year (The Asymptomatic Cardiac Ischemia Pilot [ACIP] Study). Am J Cardiol 80:1395, 1997. 80.

Safstrom K, Nielsen NE, Bjorkholm A, et al: Unstable coronary artery disease in post-menopausal women. Identifying patients with significant coronary artery disease by basic clinical parameters and exercise test. Eur Heart J 19:899, 1998. 81.

U.S. Department of Health and Human Services, Public Health Service Agency for Health Care Policy and Research, National Heart, Lung and Blood Institute: Clinical Practice Guideline. Unstable Angina: Diagnosis and Management. AHCPR Publication No. 94-0602, Number 10, March 1994. 82.

Lindahl B, Andren B, Ohlsson J, et al: Noninvasive risk stratification in unstable coronary artery disease: Exercise test and biochemical markers. Am J Cardiol 80:40E, 1997. 83.

Juneau M, Colles P, Theroux P, et al: Symptom-limited versus low level exercise testing before hospital discharge after myocardial infarction. J Am Coll Cardiol 20:927, 1992. 84.

Khoury Z, Keren A, Stern S: Correlation of exercise-induced ST depression in precordial electrocardiographic leads after inferior wall acute myocardial infarction with thallium-201 stress scintigraphy, coronary angiography and two-dimensional echocardiography. Am J Cardiol 73:868, 1994. 85.

Morgan CD, Gent M, Daly PA, et al: Graded exercise testing following thrombolytic therapy for acute myocardial infarction: The importance of timing and infarct location. Can J Cardiol 10:897, 1994. 86.

154

Moss AJ, Goldstein RE, Hall J, et al: Detection and significance of myocardial ischemia in stable patients after recovery from an acute coronary event. JAMA 269:2379, 1993. 87.

Stevenson R, Umachandran V, Ranjadayalan K, et al: Reassessment of treadmill stress testing for risk stratification in patients with acute myocardial infarction treated by thrombolysis. Br Heart J 70:415, 1993. 88.

Arnold AER, Simoons ML, Detry JMR, et al: Prediction of mortality following hospital discharge after thrombolysis for acute myocardial infarction: Is there a need for coronary angiography? Eur Heart J 14:306, 1993. 89.

Peterson ED, Shaw L, Califf RM, et al: Risk stratification after myocardial infarction. Ann Intern Med 126:561, 1997. 90.

Senaratne MP, Irwin ME, Shaben S: Feasibility of direct discharge from the coronary/intermediate care unit after acute myocardial infarction. J Am Coll Cardiol 33:1040, 1999. 91.

Nakano A, Lee JD, Shimizu H, et al: Reciprocal ST segment depression associated with exercise induced ST-segment elevation indicates residual viability after myocardial infarction. J Am Coll Cardiol 33:620, 1999. 92.

Stein RA, Chaitman BR, Balady GJ, et al: Safety and utility of exercise testing in emergency room chest pain centers. An advisory from the Committee on Exercise, Rehabilitation, and Prevention, Council on Clinical Cardiology. Circulation (in press). 93.

Kirk JD, Turnipseed S, Lewis WR, et al: Evaluation of chest pain in low-risk patients presenting to the emergency department--the role of immediate exercise testing. Ann Emerg Med 32:1, 1998. 94.

Farkouh ME, Smars PA, Reeder GS, et al: A clinical trial comparing a chest pain observation unit with routine admission in patients with unstable angina. N Engl J Med 339:1882, 1999. 95.

Chaitman BR, Miller DD: Perioperative cardiac evaluation for noncardiac surgery noninvasive cardiac testing. Prog Cardiovasc Dis 40:405, 1998. 96.

Eagle KA, Brundage BH, Chaitman BR, et al: Guidelines for perioperative cardiovascular evaluation for noncardiac surgery. Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. (Committee on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Circulation 93:1278, 1996. 97.

Best PJ, Tajik AJ, Gibbons RJ, et al: The safety of treadmill exercise stress testing in patients with abdominal aortic aneurysms. Ann Intern Med 129(8):628, 1998. 98.

Marburger DT, Brubaker PH, Pollock WE, et al: Reproducibility of cardiopulmonary exercise testing in elderly patients with congestive heart failure. Am J Cardiol 82(7):905, 1998. 99.

Jaski BE, Kim J, Maly RS, et al: Effects of exercise during long-term support with a left ventricular assist device. Results of the experience with left ventricular assist device with exercise (EVADE) pilot trial. Circulation 95(1):2401, 1997. 100.

Hambrecht R, Adams V, Gielen S, et al: Exercise intolerance in patients with chronic heart failure and increased expression of inducible nitric oxide synthase in the skeletal muscle. J Am Coll Cardiol 33(1):174, 1999. 101.

Stelken A, Younis L, Jennison SH, et al: Prognostic value of cardiopulmonary exercise testing using percent achieved of predicted oxygen uptake for patients with ischemic and dilated cardiomyopathy. J Am Coll Cardiol 27(2):345, 1996. 102.

Wasserman K, Zhang YY, Gitt A, et al: Lung function and exercise gas exchange in chronic heart failure. Circulation 96(7):2221, 1997. 103.

Osada N, Chaitman BR, Miller LW, et al: Cardiopulmonary exercise testing identifies low risk patients with heart failure and severely impaired exercise capacity considered for heart transplantation. J Am Coll Cardiol 31:582, 1998. 104.

LeJemtel TH, Liang C, Stewart DK, et al: Reduced peak aerobic capacity in asymptomatic left ventricular systolic dysfunction: A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 90:2757, 1994. 105.

Waagstein F, Bristow MR, Swedberg K, et al: Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy: Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Lancet 342:1441, 1993. 106.

Vescovo G, Libera LD, Serafini F, et al: Improved exercise tolerance after losartan and enalapril in heart failure. Circulation 98:1742, 1998. 107.

Myers J, Gullestad L, Vagelos R, et al: Clinical, hemodynamic, and cardiopulmonary exercise test determinants of survival in patients referred for evaluation of heart failure. Ann Intern Med 129:293, 1998. 108.

Belardinelli R, Georgiou D, Cianci G, et al: Randomized, controlled trial of long-term moderate exercise training in chronic heart failure. Effects on functional capacity, quality of life, and clinical outcome. Circulation 99:1173, 1999. 109.

Metra M, Faggiano P, D'Aloia A, et al: Use of cardiopulmonary exercise testing with hemodynamic monitoring in the prognostic assessment of ambulatory patients with chronic heart failure. J Am Coll Cardiol 33:943, 1999. 110.

Myers J, Gullestad L: The role of exercise testing and gas-exchange measurement in the prognostic assessment of patients with heart failure. Curr Opin Cardiol 13:145, 1998. 111.

Lang CC, Rayos GH, Chomsky DB, et al: Effect of sympathoinhibition on exercise performance in patients with heart failure. Circulation 96:238, 1997. 112.

Chomsky DB, Lang CC, Rayos GH, et al: Hemodynamic exercise testing. A valuable tool in the selection of cardiac transplantation candidates. Circulation 94:3176, 1996. 113.

Opasich C, Pinna GD, Bobbio M, et al: Peak exercise oxygen consumption in chronic heart failure: Toward efficient use in the individual patient. J Am Coll Cardiol 314:775, 1998 114.

Harrington DA, Anker SD, Chua TP, et al: Skeletal muscle function and its relation to exercise tolerance in chronic heart failure. J Am Coll Cardiol 30:1758, 1997. 115.

Chua TP, Ponikowski PP, Harrington DA, et al: Clinical correlates and prognostic significance of the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol 29:1585, 1997. 116.

Mancini DM, LaManca J, Donchez L, et al: The sensation of dypsnea during exercise is not determined by the work of breathing in patients with heart failure. J Am Coll Cardol 28:391, 1996. 117.

Mancini DM, Eisen H, Kussmaul W, et al: Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 83:778, 1991. 118.

Kadish AH, Weisman HF, Veltri EP, et al: Paradoxical effects of exercise on the QT interval in patients with polymorphic ventricular tachycardia receiving type 1a antiarrhythmic agents. Circulation 81:14, 1990. 119.

Cascio WE, Woefel A, Knisley SB, et al: Use dependence of amiodarone during the sinus tachycardia of exercise in coronary artery disease. Am J Cardiol 61:1042, 1988. 120.

Maurer MS, Shefrin EA, Fleg JL: Prevalence and prognostic significance of exercise-induced supraventricular tachycardia in apparently healthy volunteers. Am J Cardiol 75:788, 1995. 121.

Grady TA, Chiu AC, Snader CE, et al: Prognostic significance of exercise-induced left bundle branch block. JAMA 279:153, 1998. 122.

Heinsimer JA, Irwin JM, Basnight LL: Influence of underlying coronary artery disease on the national history and prognosis of exercise-induced left bundle branch block. Am J Cardiol 60:1065, 1987. 123.

Yen RS, Miranda C, Froelicher VF: Diagnostic and prognostic accuracy of the exercise electrocardiogram in patients with preexisting right bundle branch block. Am Heart J 127:1521, 1994. 124.

Yamabe H, Okumura K, Yasue H: Comparison of the effects of exercise and isoproterenol on the antegrade refractory period of the accessory pathway in patients with Wolff-Parkinson-White syndrome. Jpn Circ J 58:22, 1994. 125.

Janosik DL: Effect of exercise on pacing hemodynamics. In Ellenbogen KA, Neal Kay G, Wilkoff BL (eds): Clinical Cardiac Pacing. 2nd ed. Philadelphia, WB Saunders, 1999. 126.

Haennel RG, Logan T, Dunne C, et al: Effects of sensor selection on exercise stroke volume in pacemaker dependent patients. Pacing Clin Electrophysiol 21:1700, 1998. 127.

CLINICAL APPLICATIONS Elborn JS, Stanford CF, Nicholls DP: Reproducibility of cardiopulmonary parameters during exercise in patients with chronic cardiac failure. The need for a preliminary test. Eur Heart J 11:75, 1990. 128.

Bogaty P, Kingma JG Jr, Robitaille NM, et al: Attenuation of myocardial ischemia with repeated exercise in subjects with chronic stable angina. Relation to myocardial contractility, intensity of exercise and the adenosine triphosphate-sensitive potassium channel. J Am Coll Cardiol 32:1665, 1998. 129.

Franklin BA, Hogan P, Bonzheim K, et al: Cardiac demands of heavy snow shoveling. JAMA 273:880, 1995. 130.

Melandri G, Semprini F, Cervi V, et al: Benefit of adding low molecular weight heparin to the conventional treatment of stable angina pectoris: A double-blind, randomized, placebo-controlled trial. Circulation 88:2517, 1993. 131.

Roger VL, Jacobsen SJ, Pellika PA, et al: Gender differences in use of stress testing and coronary heart disease mortality: A population based study in Olmsted County, Minnesota. J Am Coll Cardiol 32:345, 1998. 132.

Alexander KP, Shaw LJ, Delong ER, et al: Value of exercise treadmill testing in women. J Am Coll Cardiol 32:1657, 1998. 133.

Weiner DA, Ryan TJ, Parsons L, et al: Long-term prognostic value of exercise testing in men and women from the Coronary Artery Surgery Study (CASS) registry. Am J Cardiol 75(14):865, 1995. 134.

Weiner DA, Ryan TJ, Parsons L, et al: Significance of silent myocardial ischemia during exercise testing in women: Report from the Coronary Artery Surgery Study. Am Heart J 129(3):465, 1995. 135.

Singh JP, Larson MG, Manolio TA, et al: Blood pressure response during treadmill testing as a risk factor for new-onset hypertension. The Framingham Study. Circulation 99:1831, 1999. 136.

Allison TG, Corderio MA, Miller TD, et al: Prognostic significance of exercise-induced systemic hypertension in healthy subjects. Am J Cardiol 83:371, 1999. 137.

Otterstad JE, Davies M, Ball SG, et al: Left ventricular hypertrophy and myocardial ischaemia in hypertension: The THAMES study. Eur Heart J 14:622, 1993. 138.

Lim PO, MacFayden RJ, Clarkson PB, et al: Impaired exercise tolerance in hypertensive patients. Ann Intern Med 124(1):41, 1996. 139.

Hilton TC, Shaw LJ, Chaitman BR, et al: Prognostic significance of exercise thallium-201 testing in patients aged greater than or equal to 70 years with known or suspected coronary artery disease. Am J Cardiol 69:45, 1992. 140.

Ciaroni S, Delonca J, Righetti A: Early exercise testing after acute myocardial infarction in the elderly: Clinical evaluation and prognostic significance. Am Heart J 126:304, 1993. 141.

155

Caracciolo EA, Chaitman BR, Forman SA, et al: Diabetics with coronary disease have a prevalence of asymptomatic ischemia during exercise treadmill testing and ambulatory ischemia monitoring similar to that of nondiabetic patients. An ACIP database study. Circulation 93(12):2097, 1996. 142.

Valensi P, Sachs RN, Lormeau B, et al: Silent myocardial ischemia and left ventricle hypertrophy in diabetic patients. Diabetes Metab 23:409, 1997. 143.

Bonow RO, Carabello B, deLeon AC Jr, et al: ACC/AHA guidelines for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease). J Am Coll Cardiol 32:1486, 1998. 144.

Borer JS, Hockreiter C, Herrold EM, et al: Prediction of indications for valve replacement among asymptomatic or minimally symptomatic patients with chronic aortic regurgitation and normal left ventricular performance. Circulation 97:518, 1998. 145.

Otto CM, Burwash IG, Legget ME, et al: Prospective study of asymptomatic valvular aortic stenosis. Clinical, echocardiographic, and exercise predictors of outcome. Circulation 95:2262, 1997. 146.

Elhendy A, van Domburg RT, Bax JJ, et al: Safety, hemodynamic profile, and feasibility of dobutamine stress technetium myocardial perfusion single-photon emission CT imaging for evaluation of coronary artery disease in the elderly. Chest 117(3):649, 2000. 146A.

Zouridakis EG, Cox ID, Garcia-Moll X, et al: Negative stress echocardiographic responses in normotensive and hypertensive patients with angina pectoris, positive exercise stress testing, and normal coronary arteriograms. Heart 83(2):141, 2000. 146B.

Lele SS, Thomson HL, Belenkie I, et al: Exercise capacity in hypertrophic cardiomyopathy. Role of stroke volume limitation, heart rate, and diastolic filling characteristics. Circulation 92:2886, 1995. 147.

Jones S, Elliott PM, McKenna WJ, et al: Cardiopulmonary responses to exercise in patients with hypertrophic cardiomyopathy. Heart 80:60, 1998. 148.

Kim JJ, Lee CW, Park SW, et al: Improvement in exercise capacity and exercise blood pressure response after transcoronary alcohol ablation therapy of septal hypertrophy in hypertrophic 149.

cardiomyopathy. Am J Cardiol 83:1220, 1999. Bourassa MG, Pepine CJ, Forman SA, et al: Asymptomatic Cardiac Ischemia Pilot (ACIP) study: Effects of coronary angioplasty and coronary artery bypass graft surgery on recurrent angina and ischemia. The ACIP investigators. J Am Coll Cardiol 26:606, 1995. 150.

Weiner DA, Ryan TJ, Parsons L, et al: Prevalence and prognostic significance of silent and symptomatic ischemia after coronary bypass surgery: A report from the Coronary Artery Surgery Study (CASS) randomization population. J Am Coll Cardiol 18:343, 1991. 151.

Parisi AF, Folland ED, Hartigan P: A comparison of angioplasty with medical therapy in the treatment of single-vessel coronary artery disease: Veterans Affairs ACME Investigators. N Engl J Med 326:10, 1992. 152.

Yli-Mayry S, Huikuri HV, Airaksinen KE, et al: Usefulness of a postoperative exercise test for predicting cardiac events after coronary artery bypass grafting. Am J Cardiol 70:56, 1992. 153.

Bourassa MG, Knatterud GL, Pepine CJ, et al: Asymptomatic Cardiac Ischemia Pilot (ACIP) study. Improvement of cardiac ischemia at one year after PTCA and CABG. Circulation 92:II1-7, 1995. 154.

Marwick TH, Zuchowski C, Lauer MS, et al: Functional status and quality of life in patients with heart failure undergoing coronary bypass surgery after assessment of myocardial viability. J Am Coll Cardiol 33:750, 1999. 155.

Ferrari M, Schnell B, Werner GS, et al: Safety of deferring angioplasty in patients with normal coronary flow velocity reserve. J Am Coll Cardiol 33:82, 1999. 156.

Dagianti A, Rosanio S, Penco M, et al: Clinical and prognostic usefulness of supine bicycle exercise echocardiography in the functional evaluation of patients undergoing elective percutaneous transluminal coronary angioplasty. Circulation 95:1176, 1997. 157.

Diegeler A, Schneider J, Lauer B, et al: Transmyocardial laser revascularization using the holium-yag laser for treatment of end stage coronary artery disease. Eur J Cardiothorac Surg 13(4):392, 1998. 158.

Osada N, Chaitman BR, Donohue TJ, et al: Long-term cardiopulmonary exercise performance after heart transplantation. Am J Cardiol 79(4):451, 1997. 159.

Lampert E, Mettauer B, Hoppeler H, et al: Skeletal muscle response to short endurance training in heart transplant recipients. J Am Coll Cardiol 32:420, 1998. 160.

Kao AC, Trigt PV, Shaeffer-McCall GS, et al: Central and peripheral limitations to upright exercise in untrained cardiac transplant recipients. Circulation 89:2605, 1994. 161.

Verhoeven PP, Lee FA, Ramahi TM, et al: Prognostic value of noninvasive testing one year after orthotopic cardiac transplantation. J Am Coll Cardiol 28(1):183, 1996. 162.

Ehrman J, Keteyian S, Fedel F, et al: Cardiovascular responses of heart transplant recipients to graded exercise testing. J Appl Physiol 73:260, 1992. 163.

164.

Stuart RJ, Ellestad MH: National survey of exercise stress testing facilities. Chest 77:94, 1980.

165.

Hamm LF, Crow RS, Stull GA, Hannan P: Safety and characteristics of exercise testing early after

acute myocardial infarction. Am J Cardiol 63:1193:1989. Tristani FE, Hughes CV, Archibald DG, et al: Safety of graded symptom-limited exercise testing in patients with congestive heart failure. Circulation 76:VI-54, 1987. 166.

Young DZ, Lampert S, Graboys TB, Lown B: Safety of maximal exercise testing in patients at high risk for ventricular arrhythmia. Circulation 70:184, 1984. 167.




GUIDELINES USE OF EXERCISE TOLERANCE TESTING Thomas H. Lee Guidelines for the use of exercise testing were published by an American College of Cardiology/American Heart Association (ACC/AHA) task force in1997.[1] These guidelines consider the usefulness of exercise testing for (1) diagnosis (2) risk stratification in patients with chronic coronary artery disease or after acute myocardial infarction, and (3) several specific populations. This document updated prior guidelines from the ACC/AHA from 1986[2] and drew on other guidelines and position statements on topics related to exercise testing from the ACC/AHA and drew on other guidelines and position statements on topics related to exercise testing from the ACC/AHA and other organizations.

PERFORMANCE OF THE TEST. The ACC/AHA guidelines agreed with prior recommendations that exercise testing should be supervised by an appropriately trained physician.[3] The test itself can be performed by properly trained nonphysician personnel, but these personnel should be working under the supervision of a physician who should be in the immediate vicinity and available for emergencies. The guidelines note that exercise tests do not always require the involvement of a cardiologist. Absolute and relative contraindications to exercise testing were adapted from a prior statement from the AHA[4] (Table 6-G-1) . The guidelines note that for some patients with relative contraindications, the benefits of exercise testing outweigh the risks; in

such patients, testing may be appropriate. Absolute and relative indications for terminating exercise are summarized in Table 6-5 , p. 151.

DIAGNOSIS OF OBSTRUCTIVE CORONARY ARTERY DISEASE. Exercise testing is considered clearly appropriate for the purpose of diagnosis of coronary artery disease in most adults with an intermediate probability of coronary artery disease (Table 6-G-2) . The focus on the use of this test in patients with an intermediate probability of coronary disease recognizes that testing is unlikely to change the diagnosis for patients with either a low or a high probability of coronary disease based on age and other clinical data. The guidelines provided a framework for qualitative assessment of the probability of coronary disease on the basis of such information (Table 6-G-3) . The ACC/AHA guidelines specifically note that exercise testing is appropriate in patients with a complete right bundle branch block or less than 1 mm of resting ST depression. They also conclude that cessation of therapy with digoxin or beta blockers is not necessary before exercise testing, even though the effects of these agents can sometimes complicate interpretation of test results.

RISK STRATIFICATION IN PATIENTS WITH PROBABLE CORONARY DISEASE. Even if the evidence for coronary disease is so clear for a patient that an exercise test cannot influence the diagnosis, testing may improve management through risk stratification. Exercise testing is especially likely to be valuable as part of the initial evaluation of patients with suspected or known coronary disease (see Table 6-G-2) since the results may help identify high-risk subsets of patients who are likely to have their survival improved with coronary artery bypass graft surgery or coronary angioplasty. Exercise testing is also appropriate in patients who have had a significant change in clinical status because the test may clarify whether the new symptoms are due to coronary artery

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TABLE 6-6-G-1 -- CONTRAINDICATIONS TO EXERCISE TESTING (ACC/AHA GUIDELINES) Absolute Relative*

Acute myocardial infarction (within 2d) Unstable angina not previously stabilized by medical therapy Uncontrolled cardiac arrhythmias causing symptoms or hemodynamic compromise Symptomatic severe aortic stenosis Uncontrolled symptomatic heart failure Acute pulmonary embolus or pulmonary infarction Acute myocarditis or pericarditis Acute aortic dissection

Left main coronary stenosis Moderate stenotic valvular heart disease Electrolyte abnormalities Severe arterial hypertension Tachyarrhythmias or bradyarrhythmias Hypertrophic cardiomyopathy and other forms of outflow tract obstruction Mental or physical impairment leading to an inability to exercise adequately High-degree atrioventricular block

From Gibbons RJ, Balady GJ, Beasley FW, et al: ACC/AHA guidelines for exercise testing: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing). J Am Coll Cardiol 30:260-315, 1997; modified from Fletcher GF, Balady G, Froelicher VF, et al: Exercise standards: A statement for healthcare professionals from the American Heart Association Writing Group. Special Report. Circulation 91: 580-615, 1995. *Relative contraindications can be superseded if the benefits of exercise outweigh the risks. The appropriate timing of testing depends on the level of risk of unstable angina. In the absence of definitive evidence, the committee suggests systolic blood pressure greater than 200 mm Hg and/or diastolic blood pressure greater than 110 mm Hg.

TABLE 6-6-G-2 -- APPROPRIATENESS OF EXERCISE TESTING FOR SPECIFIC PATIENT SUBSE AND INDICATIONS Indication Class I: Class IIa: Class IIb: Class III: Appropriate Probably Probably Not Inappropriate Appropriate Appropriate

Exercise testing Adult patients Patients with in diagnosis of (including those vasospastic obstructive CAD with complete angina right bundle branch block or less than 1 mm of resting ST depression) with an intermediate pretest probability of CAD (see Table 6-G-3 ) based on gender, age, and symptoms (specific exceptions are noted in Classes II and III)

Patients with a high Patients with the pretest probability of following baseline EC CAD by age, abnormalities: symptoms, and gender Preexcitation (Wolff-Parkinson-Wh syndrome Electronically pac ventricular rhythm Greater than 1 m of resting ST depression Complete left bundle branch block Patients with a low pretest probability of CAD by age, symptoms, and gender Patients with less than 1 mm of baseline ST depression and taking digoxin Patients with ECG criteria for left ventricular hypertrophy and less than 1 mm of baseline ST depression

Risk assessment and prognosis in patients with symptoms or a prior history of CAD

Patients None undergoing initial evaluation with suspected or known CAD. Specific exceptions are noted below in Class IIb

Patients with the following ECG abnormalities: Preexcitation (Wolff-Parkinson-White) syndrome Electronically paced ventricular rhythm Greater than 1 mm of resting ST depression Complete left bundle branch block

Patients with suspected or known CAD previously evaluated with significant change in clinical status

Patients with a stable clinical course who undergo periodic monitoring to guide treatment

Patients with a documented myocard infarction or prior coronary angiograph demonstrating significant disease ha an established diagnosis of CAD; however, ischemia a risk can be determine by testing

Patients with severe comorbidity likely to limit life expectancy and/or candidacy for revascularization

After myocardial Before discharge infarction for prognostic assessment, activity prescription, and evaluation of medical therapy (submaximal at about 4 to 7 d) Early after discharge for prognostic assessment, activity prescription, evaluation of medical therapy, and cardiac rehabilitation if the predischarge exercise test was not done (symptom limited/about 14-21 d) Late after discharge for prognostic assessment, activity prescription, evaluation of medical therapy, and cardiac rehabilitation if the early exercise test was submaximal (symptom limited/about 3-6 wk)

After discharge for activity counseling and/or exercise training as part of cardiac rehabilitation in patients who have undergone coronary revascularization

Before discharge in patients who have undergone cardiac catheterization to identify ischemia in the distribution of a coronary lesion of borderline severity Patients with the following ECG abnormalities: Complete left bundle branch block Preexcitation syndrome Left ventricular hypertrophy Digoxin therapy Greater than 1 mm of resting ST segment depression Electronically paced ventricular rhythm Periodic monitoring in patients who continue to participate in exercise training or cardiac rehabilitation

Severe comorbidity likely to limit life expectancy and/or candidacy for revascularization

Exercise testing Evaluation of using ventilatory exercise gas analysis capacity and response to therapy in patients with heart failure who are being considered for heart transplantation

Evaluation of exercise capacity when indicated for medical reasons in patients whom subjective assessment of maximal exercise in unreliable

Assistance in the differentiation of cardiac vs. pulmonary limitations as a cause of exercise-induced dyspnea or impaired exercise capacity when the cause is uncertain Exercise testing None in asymptomatic persons without known CAD

Evaluation of the Routine use to evalua patient's response to exercise capacity specific therapeutic interventions in which improvement in exercise tolerance is an important goal or endpoint

Determination of the intensity of exercise training as part of comprehensive cardiac rehabilitation

None

Evaluation of persons Routine screening of with multiple risk factors asymptomatic men o (see the text) women Evaluation of asymptomatic men older than 40 yr and women older than 50 yr Who plan to start vigorous exercise (especially if sedentary) or Who are involved in occupations in which impairment might have an impact on public safety or Who are at high risk for CAD because of other diseases (e.g., chronic renal failure)

Valvular heart disease

None

None

Exercise testing Demonstration of After discharge before and after ischemia before for activity revascularization revascularization counseling and/or exercise training as part of cardiac Evaluation of rehabilitation in patients with patients who recurrent have undergone symptoms coronary suggesting revascularization ischemia after

Evaluation of exercise Diagnosis of CAD is capacity of patients with patients with valvular valvular heart disease heart disease

Detection of restenosis Localization of ischem in selected, high-risk for determining the s asymptomatic patients of intervention within the first months after angioplasty Periodic monitoring of selected, high-risk asymptomatic patients for restenosis, graft occlusion, or disease progression

revascularization

Investigation of heart rhythm disorders

Identification of appropriate settings in patients with rate-adaptive pacemakers

Evaluation of patients with known or suspected exercise-induced arrhythmias

Routine, periodic monitoring of asymptomatic patien after percutaneous transluminal coronary angioplasty or corona artery bypass graft surgery without spec indications

Investigation of isolated Investigation of isolat ventricular ectopic ectopic beats in youn beats in middle-aged patients patients without other evidence of CAD

Evaluation of medical, surgical, or ablative therapy in patients with exercise-induced arrhythmias (including atrial fibrillation) CAD = coronary artery disease; ECG = electrocardiogram.

disease. Exercise testing for patients with unstable angina is recommended as soon as the patient has stabilized clinically. In contrast, the ACC/AHA guidelines do not offer strong support for routine exercise testing of patients with a stable clinical course (see Table 6-G-3) . The ACC/AHA guidelines explicitly state that the exercise test should be the standard initial mode of stress testing for risk stratification of patients with a normal electrocardiogram who are not taking digoxin. The guidelines assert that "There is no compelling evidence in patients who are classified as low risk based on clinical and exercise testing information that an imaging modality adds significant new prognostic information to a standard exercise test." In intermediate-risk patients, the text

acknowledges that myocardial perfusion imaging appears to add value for risk stratification.

AFTER MYOCARDIAL INFARCTION. The ACC/AHA guidelines are strongly supportive of one to two exercise tests for risk stratification after acute myocardial infarction (see Table 6-G-3) . Submaximal tests are appropriate prior to discharge from the hospital. If predischarge testing is not performed, symptom-limited tests about 14 to 21 days after the myocardial infarction are appropriate. If predischarge testing was performed, a full symptom-limited test 3 to 6 weeks after infarction is appropriate. These guidelines indicated that cardiac rehabilitation should be "considered standard care that should be integrated into the treatment plan of patients with" coronary artery disease, and they supported exercise testing for this purpose. However, the guidelines indicated that the appropriateness of some uses of exercise testing as part of cardiac rehabilitation was not established. Use of exercise testing after patients have undergone coronary revascularization was considered uncertain, but supported by most evidence (Class IIa). However, periodic monitoring with exercise testing in patients who are participating in cardiac rehabilitation programs was considered to have less support from research data.

USE OF VENTILATORY GAS ANALYSIS. The ACC/AHA guidelines were explicitly supportive of the use of ventilatory gas analysis for certain specific indications in patients with cardiovascular and pulmonary disease. The most clearly appropriate indications were when cardiac transplantation was being considered or when differentiation between cardiac and pulmonary limitations in functional status was uncertain because of other clinical data. Some evidence exists to support the appropriateness of such testing when patients' subjective assessment of maximal exercise is unreliable (Class IIa). Routine use of ventilatory gas analysis to assess exercise capacity was considered inappropriate.

EXERCISE TESTING IN WOMEN. The guidelines recommend that strategies for exercise testing in women be the same as those used in men. The text acknowledged problems with false-positive results but indicated that the data were insufficient to support routine stress imaging as the initial test for coronary disease in women.

ASYMPTOMATIC PATIENTS WITHOUT KNOWN CORONARY ARTERY DISEASE. The ACC/AHA guidelines were generally not supportive of the use of exercise testing to

screen for coronary artery disease in asymptomatic patients. The guideline authors acknowledged that this assessment was discordant with widespread practice patterns but concluded that existing data indicate that such screening leads to a high rate of false-positive results. This lack of support for screening asymptomatic patients with exercise testing is consistent with guidelines from the U.S. Preventive Services Task Force[5] and the American College of Physicians.[6] The ACC/AHA guidelines identified some indications of uncertain appropriateness for which the weight of evidence was not strong. One such "Class IIb" indication was evaluation of patients with multiple risk factors, which was defined as hypercholesterolemia (>240 mg/dl), hypertension (systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg), smoking, diabetes, and a family history of heart attack or sudden cardiac death in a first-degree relative younger than 60 years. An alternative approach is to select patients with a Framingham risk score consistent with at least a moderate risk of serious cardiac events within 5 years. Exercise testing was also considered to be of marginal (Class IIb) appropriateness for men older than 40 years or women older than 50 who (1) were starting a vigorous exercise program, (2) might endanger the safety of others if they had a sudden cardiac event, or (3) had a high risk for coronary disease because of other diseases. A minority of the ACC/AHA committee favored a Class III recommendation for exercise testing in patients with multiple risk factors or people starting TABLE 6-6-G-3 -- PROBABILITY OF CORONARY ARTERY DISEASE BY AGE, GENDER, AND SYMPTOMS (FROM ACC/AHA GUIDELINES) * Age Gender Typical/Definite Atypical/Probable Nonanginal Asymptomatic (yr) Angina Angina Pectoris Chest Pain Pectoris 30-39

Men Intermediate Women Intermediate

Intermediate Very low

Low Very low

Very low Very low

40-49

Men High Women Intermediate

Intermediate Low

Intermediate Low Very low Very low

50-59

Men High Women Intermediate

Intermediate Intermediate

Intermediate Low Low Very low

60-69

Men High Women High

Intermediate Intermediate

Intermediate Low Intermediate Low

*No data exist for patients younger than 30 or older than 69 years, but it can be assumed that prevalence of coronary artery disease increases with age. In a few cases, patients with ages at the extremes of the decades listed may have probabilities slightly outside the high or low range. High indicates 90 percent; intermediate, 10 to 90 percent; low, less than 10 percent; and very low, less than 5 percent.

159

exercise programs. Support for these positions is provided by guidelines from the American College of Sports Medicine, which recommends exercise electrocardiography for men older than 40 years, women older than 50, and other asymptomatic persons with multiple cardiac risk factors prior to beginning a vigorous exercise program.[7]

VALVULAR HEART DISEASE. The ACC/AHA guidelines supported only limited use of exercise testing as part of the routine care of patients with valvular heart disease. The primary value of exercise testing in such patients is to assess atypical symptoms, exercise capacity, and the extent of disability (Class IIb). However, use of the exercise test to screen for coronary artery disease was considered inappropriate. The guidelines noted that exercise testing may sometimes be useful and appropriate in patients with aortic stenosis. Although severe symptomatic aortic stenosis is considered a contraindication to exercise testing, this evaluation can be safely performed under close observation by an experienced physician.

BEFORE AND AFTER REVASCULARIZATION. The ACC/AHA guidelines were supportive of the use of exercise testing to demonstrate ischemia before revascularization or to evaluate the significance of recurrent symptoms afterward. However, routine periodic testing of asymptomatic patients was considered inappropriate (Class III). The appropriateness of testing was considered equivocal in patients who were undergoing cardiac rehabilitation after revascularization or in asymptomatic patients who were considered to be at high risk for restenosis, graft occlusion, or disease progression.

INVESTIGATION OF HEART RHYTHM DISORDERS. Exercise testing was considered to have narrow appropriate indications for use in the evaluation of rhythm disorders, including the assessment of settings for rate-adaptive pacemakers. Patients with known or suspected exercise-induced arrhythmias were considered reasonably appropriate (Class IIa) candidates for exercise testing. Exercise testing was also considered reasonably appropriate for assessment of therapy in patients who had been shown to have exercise-induced arrhythmias. Use of exercise testing for assessment of isolated ectopic beats was discouraged.

REFERENCES

Gibbons RJ, Balady GJ, Beasley JW, et al: ACC/AHA guidelines for exercise testing: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing). J Am Coll Cardiol 30:260-315, 1997. 1.

Schlant RC, Blomqvist CG, Brandenburg RO, et al: Guidelines for exercise testing. A report of the American College of Cardiology/American Heart Association Task Force on Assessment of Cardiovascular Procedures (Subcommittee on Exercise Testing). J Am Coll Cardiol 8:725-738, 1986. 2.

Schlant RC, Friesinger GC II, Leonard JJ: Clinical competence in exercise testing: A statement for physicians from the ACP/ACC/AHA Task Force on Clinical Privileges in Cardiology. J Am Coll Cardiol 16:1061-1065, 1990. 3.

Fletcher GF, Balady G, Froelicher VF, et al: Exercise standards: A statement for healthcare professionals from the American Heart Association Writing Group. Special Report. Circulation 91:580-615, 1995. 4.

Guide to Clinical Preventive Services. Report of the U.S. Preventive Services Task Force. 2nd ed. Washington, DC, US Department of Health and Human Services, 1995, pp 3-14. 5.

American College of Physicians: Efficacy of exercise thallium-201 scintigraphy in the diagnosis and prognosis of coronary artery disease. Ann Intern Med 113:703-704, 1990. 6.

American College of Sports Medicine: Guidelines for Exercise Testing and Prescription. 4th ed. Philadelphia, Lea & Febiger, 1991. 7.




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Chapter 7 - Echocardiography WILLIAM F. ARMSTRONG HARVEY FEIGENBAUM

Echocardiography is a group of interrelated applications of ultrasound including two-dimensional anatomical imaging, M-mode echocardiography, Doppler techniques, and contrast echocardiography. Echocardiography uses sound in the frequency range of 1 to 10 MHz. Typically when imaging adult patients, frequencies range from 2 to 5 MHz. For pediatric and some specialized adult applications higher frequencies of 7.5 and 10 MHz may also be used. PRINCIPLES OF CARDIAC ULTRASONOGRAPHY IMAGE GENERATION

The underlying premise of cardiac ultrasonography is that the speed of sound through tissue is equal to that in water (1450 m/sec). Ultrasound scanners emit a series of ultrasound bursts at a given frequency. The number of bursts or pulses per second is the "pulse repetition frequency." The ultrasound energy is then reflected from cardiac and other structures and returned to the transducer. By determining the time required for round trip transit, the distance of a reflective object from the transducer can be

calculated. The returning strength of the ultrasound signal is directly proportional to the reflective intensity of the object and likewise is integrated into the displayed image. The resolution with which structures can be defined is dependent on the transducer frequency, with higher resolution provided by high-frequency transducers but at the cost of reduced depth of penetration. The nature of the image that is acquired and displayed is determined by the number of ultrasound interrogation lines and the manner in which they are processed. M-mode echocardiography was the earliest form of cardiac ultrasonography used clinically. M-mode echocardiography relies on interrogation along a single line of ultrasound either emitted from an independent transducer or along a cursor within a two-dimensional image. The M-mode echocardiogram only provides information with respect to the distance of each object from the transducer and provides no information in the lateral dimension (Fig. 7-1) . M-mode echocardiography was once the mainstay of echocardiography, but in modern laboratories it is relegated to a secondary role. It may still have some incremental value for highly precise measurements, and its temporal resolution far exceeds that of two-dimensional scanning. A two-dimensional echocardiogram is created when a fan-shaped array, consisting of multiple interrogation lines, is emitted typically over a 90-degree sector from the transducer and analyzed. There are two methods by which the fan-shaped sector of ultrasound beams can be created. Most widely used is a phased-array system in which a linear array of ultrasound crystals is electronically steered through an imaging arc. The second method relies on high-speed mechanical rotation of one or usually more ultrasound crystals to mechanically steer the ultrasound beam through the predefined arc. Doppler ultrasonography relies on analysis of a shift in the frequency of the ultrasound beam due to interaction with moving targets. The Doppler shift data can be displayed as a velocity profile or a color flow image. In the following sections we first discuss the methods by which anatomical images are recorded and then discuss Doppler methodology. The actual clinical echocardiographic examination consists of simultaneous and integrated two-dimensional and Doppler evaluation, supplemented by other specific and goal-oriented imaging modalities.

Figure 7-1 Normal M-mode echocardiogram in which the M-mode beam is swept from the aortic valve through the mitral valve and to the level of the papillary muscles. Note the normal boxlike opening of the aortic valve and the biphasic, "M"-shaped opening pattern of the mitral valve. There is posterior motion of the ventricular septum synchronous with anterior motion of the posterior wall. AV = aortic valve; DAo = descending aorta; LA = left atrium; LV = left ventricle; MV = mitral valve; RV = right ventricle.

161

Figure 7-2 Schematic of the transducer orientation used for acquiring parasternal views. The scanning plane of the ultrasound beam is superimposed on a schematic of the heart. Plane 1 represents a parasternal long-axis view in which the right ventricular outflow tract, proximal portion of the aorta and aortic valve, anterior ventricular septum, cavity of the left ventricle containing the mitral valve, and inferoposterior wall of the left ventricle can be visualized. Scanning plane 1 results in an ultrasound image as noted in Figure 7-1 . Scanning plane 2 is obtained by rotating the transducer 90 degrees and can be used to obtain a family of short-axis views of the heart. (From Feigenbaum H: Echocardiography, 4th ed. Malvern, PA, Lea & Febiger, 1986.) THE ANATOMICAL ECHOCARDIOGRAPHIC EXAMINATION (SeeChap. 3.)

The mainstay of the echocardiographic examination is transthoracic two-dimensional echocardiography (TTE). The fan-shaped scan plane is directed into the chest to provide tomographic imaging planes (Figs. 7-2 , 7-3 , 7-4 , 7-5 , 7-6 , and 7-7 ). Each returning ultrasound signal is then registered and converted to a two-dimensional image of the interrogated plane. This process is repeated 20 to 120 times per second, resulting in a frame rate of 20 to 120 Hz. The sequence of imaged frames results in a real-time moving image of the heart. The frame rate for two-dimensional imaging is dependent on line density and scanning depth. Smaller areas can be imaged at substantially higher (100-120 Hz) frame rates than can be larger sectors, which typically are imaged at 30 Hz. For the transthoracic examination, patients are typically placed in a left lateral position and scanned from several different left intercostal spaces. The standard transthoracic views (Table 7-1) are recorded from parasternal and apical transducer positions. Subcostal and suprasternal transducer positions can also be used. From any transducer position, the Doppler modalities, including pulsed, continuous-wave, and color flow imaging, can be recorded. Other imaging windows, such as the right sternal border, can be used for specific examinations. Traditionally, two-dimensional echocardiograms and Doppler echocardiograms have been recorded on videotape for subsequent analysis and activities. In modern ultrasound equipment the image is acquired in a digital format and stored as such (Fig. 7-8) . Digital images can be displayed side by side or as a quad screen containing multiple views for visualization simultaneously. Digital images are free from degradation seen when the source image is transferred to analog videotape and can be transmitted to remote sites for review. [1] [2]

Figure 7-3 Parasternal long-axis view of the left ventricle in diastole (top) and systole (bottom). Chambers and cardiac structures are as noted. This view corresponds to plane 1 of Figure 7-1 . AO = aorta; LA = left atrium; LV = left ventricle; RV = right ventricular outflow tract; MV = mitral valve.

Figure 7-4 Schematic showing the relationship of the parasternal long- and short-axis views of the heart. The central figure is a schematized parasternal long-axis view. Images 1 through 4 can be obtained by rotating the probe 90 degrees from the long axis and then angling the probe through the positions noted as 1 through 4 on the central schematic. Echocardiograms recorded from these different planes are

presented in Figure 7-5 . (From Feigenbaum H: Echocardiography. 4th ed. Malvern, PA, Lea & Febiger, 1986.)

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Figure 7-5 Short-axis two-dimensional echocardiograms recorded in planes depicted in Figure 7-4 . The two left panels are recorded at the level of the papillary muscles in diastole (top) and systole (bottom). Note the symmetrical thickening of the myocardium and inward motion of the endocardium representing normal ventricular function in systole. The top right panel is recorded at the level of the aortic valve, and the bottom right panel is recorded at the level of the mitral valve in diastole. Abbreviations are as per other figures; TV = tricuspid valve; RA = right atrium; PA = pulmonary artery; IVC = inferior vena cava.

Figure 7-6 Schematic of the ultrasound scanning planes for apical four- and two-chamber views. With the scanning plane directed as in plane 1, all four chambers are intersected. Scanning plane 1 results in an image as presented in the left panel of Figure 7-7 . By rotating the probe approximately 90 degrees, scanning plane 2 intersects only the left ventricle and left atrium, as is noted in the right panel of Figure 7-7 . (From Feigenbaum H: Echocardiography. 5th ed. Malvern, PA, Lea & Febiger, 1994.) Examination and Appearance of the Normal Heart PARASTERNAL LONG-AXIS VIEW.

In this view (see Fig. 7-3) , both the inferoposterior wall and interventricular septum are visualized, each of which is mildly concave toward the other. The normal ascending aorta is visualized, including its annulus, sinus of Valsalva, and proximal portion of the ascending aorta. The anterior and posterior leaflets of the mitral valve can be visualized in the parasternal long-axis position, with the anterior leaflet appearing more elongated. Typically, the posterolateral papillary muscle is also visualized from this transducer position. Anterior to the aorta, a portion of the right ventricular outflow tract is visualized. By medially angulating the transducer the right ventricular inflow tract can be visualized in which the inferior vena cava, right atrium, tricuspid valve, and right ventricle are visualized (Fig. 7-9) . From the parasternal transducer position a short-axis view of the heart can be obtained by rotating the transducer 90 degrees (see Figs. 7-4 and 7-5) . At the base of the heart, the circular aorta and the aortic valve with three equally sized leaflets are visualized, as well as the right ventricular outflow tract, which is seen as an inverted "U" overlying the aorta. By angling the transducer toward the apex, a short-axis view of the mitral valve can be visualized from which the actual orifice can be seen and quantified. With further angulation, the circular cavity of the left ventricle is visualized, including both of the papillary muscles. The normal short-axis geometry of the left ventricle is circular, whether it is visualized at the level of the mitral valve, papillary muscle, or apex. In the

163

Figure 7-7 Apical four- and two-chamber views of the left ventricle corresponding to the schematic presented in Figure 7-6 . Note the normal "bullet shape" geometry of the left ventricle and the more triangular right ventricle. Note also the more apical insertion of the tricuspid valve compared with the mitral valve. Abbreviations are as per other figures.

short-axis projections at the level of the mitral valve and below, the right ventricle appears as a more trabeculated crescent-shaped structure. FOUR-CHAMBER VIEW.

From this view, the left ventricle has a normal bullet-shaped geometry. The anterior and posterior mitral valve leaflets can be visualized. The left atrium and pulmonary veins are visualized in high-quality studies as well (see Fig. 7-7) . In the four-chamber view, the right ventricle appears as a triangular structure. The TABLE 7-1 -- TWO-DIMENSIONAL ECHOCARDIOGRAPHIC EXAMINATION PARASTERNAL APPROACH Long-axis plane Root of aorta-aortic valve, left atrium, left ventricular outflow tract Body of left ventricle-mitral valve Left ventricular apex Right ventricular inflow tract-tricuspid valve Short-axis plane Root of the aorta-aortic valve, pulmonary valve, tricuspid valve, right ventricular outflow tract, left atrium, pulmonary artery, coronary arteries Left ventricle-mitral valve Left ventricle-papillary muscles Left ventricle-apex APICAL APPROACH Four-chamber plane Four chamber Four chamber with aorta Long-axis plane Two chamber-left ventricle, left atrium Two chamber with aorta

SUBCOSTAL APPROACH Four-chamber plane--all four chambers and both septa Short-axis plane Left ventricle Right ventricle Inferior vena cava SUPRASTERNAL APPROACH Four-chamber plane Arch of aorta-descending aorta Long-axis plane Arch of aorta-pulmonary artery, left atrium tricuspid valve inserts into the annulus of the right ventricle at a position slightly more apical than the mitral valve. This results in a small portion of the ventricular septum (the atrioventricular septum) falling between the septal leaflets of the tricuspid and mitral valves. By rotating the transducer 90 degrees from the four-chamber view, a two-chamber view of the left ventricle and atrium can be obtained (see Fig. 7-7) . SUBCOSTAL AND SUPRASTERNAL VIEWS.

In addition to parasternal and apical transducer positions, subcostal and suprasternal positions also provide imaging windows in adult patients. The subcostal transducer position can be very effective in patients with chronic lung disease in whom parasternal and apical views are obscured by intervening lung tissue. Typically, patients are imaged in the supine position with the knees bent and the transducer placed in the subxiphoid position. Imaging during held inspiration often is effective at bringing the heart into optimal position. Views similar to a four-chamber view as well as a series of short-axis views can be obtained from this transducer position. The subcostal views also provide excellent visualization of the atrial septum and the connection between the inferior vena cava (IVC) and right atrium (Fig. 7-10) . SUPRASTERNAL VIEWS.

These views are obtained by placing the transducer in the suprasternal notch. This transducer position may be somewhat uncomfortable for many patients. It provides a view of the arch of the aorta and includes the great vessels in the majority of patients and portions of the main pulmonary artery (Fig. 7-11) . Anatomical Variants

Several well-recognized anatomical and developmental variants can be seen with echocardiography. It is important to recognize these as normal variants to avoid

confusion with pathological processes.[3] [4] MUSCLE TRABECULATIONS.

The right ventricle is more heavily trabeculated than the left, and, similarly, the right atrium is more trabeculated than the left atrium. High-resolution scanning virtually always detects multiple muscle trabeculations in the right ventricle, the most prominent of which is the moderator band, which is a muscular structure traversing from the lateral wall to the septum of the right ventricle near the apex (Fig. 7-12) . On occasion, secondary

164

Figure 7-8 Demonstration of quad screen format for displaying of digitized echocardiograms. This format allows simultaneous display in real time (here depicted as still images) of four different images of the heart for immediate evaluation and comparison.

muscle bundles are likewise noted. In any situation in which right ventricular hypertrophy occurs the trabeculations become more prominent. It is important to recognize this phenomenon to avoid confusing a heavily trabeculated right ventricle with tumor, vegetation, thrombus, or other mass. The left ventricle is typically less trabeculated than the right, and other than the papillary muscles it is infrequent to note muscle trabeculations in the left ventricle. Occasionally, a trabeculated left ventricular apex is encountered, the degree of which rarely approaches that seen in the right ventricle. Not infrequently, pseudochordae are seen in the left ventricular apex. Anatomically, these are structures similar to mitral valve chordae but take an aberrant course,

Figure 7-9 Two-dimensional echocardiogram of the right ventricular inflow tract, recorded from the parasternal transducer position. Abbreviations are as per other figures.

typically across the apex of the left ventricle. They are less often seen in the left ventricular outflow tract. They are more easily visualized in patients with cardiomyopathy and dilated hearts than in normal hearts, where they may lie against the endocardium and therefore not be visible. RIGHT AND LEFT ATRIAL STRUCTURES.

Several developmental remnants can be noted in the right atrium. These include the eustachian valve (Fig. 7-13) and Chiari network. In the embryo, a continuous membrane courses from the IVC to the coronary sinus to direct oxygenated blood from the IVC

directly across the foramen ovale. During cardiac development this membrane reabsorbs. In the majority of patients a small remnant known as the eustachian valve can be seen at the margin of the right atrial-IVC junction. A second remnant is occasionally seen attached to the coronary sinus. This is known as a Chiari network and consists of a fine filamentous membrane, with multiple perforations attached to the coronary sinus. On rare occasions, the complete eustachian valve is seen as a linear echo coursing from the IVC to the coronary sinus. In this instance it has multiple perforations and rarely, if ever, is truly obstructive. Either the eustachian valve or a Chiari network can result in redirection of blood flow within the atrium and unusual patterns of blood flow noted with contrast echocardiography. The right atrial appendage is typically visualized only with transesophageal echocardiography (TEE). It is a more trabeculated structure than the left atrial appendage, and, on occasion, trabeculae in the right atrial appendage have been confused for thrombi. Recognizing the full range of appearance of the right atrial appendage is essential to avoid this error. The left atrium has a smoother wall than the right atrium. The left atrial appendage is occasionally visualized from TTE, either in the apical two-chamber view or in a parasternal short-axis view. It is optimally visualized with TEE, where it has the appearance of a "dog's ear" (Fig. 7-14) . A substantial percentage of individuals have a multilobed

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Figure 7-10 Two-dimensional echocardiograms recorded from the subcostal transducer position. The upper panel is a subcostal four-chamber view in which all four cardiac chambers are visualized as well as the plane of the mitral and tricuspid valves. The interatrial septum is visualized in its entire length in this view. The lower panel is recorded in a short-axis view at the level of the aortic valve from the subcostal position. The right atrium, tricuspid valve, right ventricle, and pulmonary artery are visualized as well as the circular aorta. The interatrial septum and inferior vena cava are both visualized in this view as well. Abbreviations are as per other figures; IVC = inferior vena cava; IAS = interatrial septum.

left atrial appendage, which can result in a confusing appearance because the septation between the two lobes may be confused for thrombus.[4] ATRIAL SEPTUM.

The normal interatrial septum is visualized both in its primum and more superior portions, connected by thin tissue of the foramen ovale. There is substantial variation in the thickness and prominence of the more muscular primum and superior portions of the atrial septum. A commonly encountered anomaly of the atrial septum is lipomatous atrial hypertrophy in which there is benign infiltration by lipomatous tissue of the primum and superior atrial septum (Fig. 7-15) . The valve of the foramen ovale is spared, resulting in a "dumbbell" configuration of the atrial septum. The amount of infiltration is highly

variable and can range from less than 1.0 cm to 5 cm or more. The tissue is homogeneous and somewhat brighter than the normal atrial septum. It should not be confused with intracardiac tumor or thrombus.

Figure 7-11 Two-dimensional echocardiogram recorded from a suprasternal transducer position. The arch of the aorta as well as a portion of the ascending and descending aorta can be visualized. Note also the great vessels arising from the arch (arrows). DA = descending aorta; LCA = left carotid artery; LSA = left subclavian artery. Quantification of Ventricular Performance

Echocardiography provides an excellent method for quantification of ventricular function. Linear measurements such as wall thickness, internal chamber dimension, and the derived parameters such as fractional shortening traditionally have been obtained from M-mode echocardiography. Normal values for adults and children are well established (Table 7-2) .[5] [6] [7] [53A] [55A] [55B] [65A] Global ventricular function and cardiac volumes can be measured with a variety of algorithms using two-dimensional echocardiography.[7A] The most commonly

Figure 7-12 Apical four-chamber view of the heart revealing a prominent moderator band. The moderator band (arrow) appears as a muscle density structure traversing the apex of the right ventricle (arrow). This is a normal anatomical structure that should not be confused with a pathological process.

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Figure 7-13 Transthoracic parasternal echocardiograms recorded in a patient with a prominent eustachian valve (EV). This is a normal anatomical variant that should not be confused for a mass, vegetation, or other pathological structure. The top panel is a right ventricular inflow tract view recorded from the left sternal border. Both the right atrium and right ventricle can be seen, and the tricuspid valve is closed. Note the linear echo arising from the junction of the right atrium and inferior vena cava coursing into the body of the right atrium. In real time this linear echo has highly mobile motion, mimicking valvular motion. The bottom panel is recorded in a parasternal short-axis view at the base of the heart. The same linear echo is noted in the bottom of the right atrium (arrow).

employed method for quantitation of ventricular volume is Simpson's rule (Fig. 7-16) . Once the chamber volumes have been determined, ejection fraction can be calculated. Calculation of ejection fraction represents only a small aspect of quantification of ventricular performance. Determination of left ventricular volume requires manual tracings of the endocardial border in diastole and systole. Instrumentation exists that can automatically determine the endocardial border and calculate volumes and ejection fraction (Fig. 7-17)[8] Application of this technology requires high-quality images with a favorable signal-to-noise ratio. These automatically determined ventricular volumes can

be combined with arterial pressure measurements to create pressure-volume loops for more sophisticated evaluation of ventricular performance.[9] [10]

Figure 7-14 Transesophageal echocardiogram recorded at a 30-degree angle demonstrating the appearance of normal left atrial appendage. The body of the left atrium is at the apex of the scan and the normal "ear-shaped" left atrial appendage can be seen communicating with the body of the left atrium (arrow).

Figure 7-17 Apical four-chamber image in which an algorithm for automatic border detection has been used to determine instantaneous left ventricular volume. The white line outlining the endocardial border has been automatically drawn by the ultrasound machine. A graphic output of instantaneous ventricular volume and calculated ejection fraction is presented below the echocardiographic image.

Left ventricular mass can be measured by several different methods. One of the earliest was the "cube" method, which used M-mode septal, posterior wall, and left ventricular internal dimensions and assumed normal ventricular geometry.[7] [11] [11A] More recently, several two-dimensional

Figure 7-15 Transesophageal echocardiogram recorded in a patient with lipomatous atrial septum. From the transthoracic view, marked homogeneous thickening of the atrial septum is noted. In the transesophageal echocardiogram this can be appreciated as disproportionate infiltration and thickening of the basal and primum portions of the atrial septum with relative sparing of the area of the foramen ovale.

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TABLE 7-2 -- NORMAL VALUES OF M-MODE ECHOCARDIOGRAPHIC MEASUREMENTS IN ADULTS RANGE (cm) MEAN NO. OF (cm) SUBJECTS Age (years)

13 to 54

26

134

Body surface area (M2 )

1.45 to 2.22

1.8

130

RVD--flat

0.7 to 2.3

1.5

84

RVD--left lateral

0.9 to 2.6

1.7

83

LVID--flat

3.7 to 5.6

4.7

82

LVID--left lateral

3.5 to 5.7

4.7

81

Posterior LV wall thickness

0.6 to 1.1

0.9

137

Posterior LV wall amplitude

0.9 to 1.4

1.2

48

IVS wall thickness

0.6 to 1.1

0.9

137

Mid IVS amplitude

0.3 to 0.8

0.5

10

Apical IVS amplitude

0.5 to 1.2

0.7

38

Left atrial dimension

1.9 to 4.0

2.9

133

Aortic root dimension

2.0 to 3.7

2.7

121

Aortic cusps' separation

1.5 to 2.6

2.9

93

Percentage of fractional shortening- 34% to 44% Mean rate of circumferential shortening (Vcf) or mean normalized shortening velocity

1.02 to 1.94 circ/sec

36% 1.3 circ/sec

20% 38

RVD = right ventricular dimension; LVID = left ventricular internal dimension; d = end diastole; s = end systole; LV = left ventricle; IVS = interventricular septum. methods have been shown to provide enhanced accuracy, especially in abnormally shaped ventricles.[12] Normal wall motion consists of simultaneous myocardial thickening and inward motion of the endocardium toward the center of the chamber. [13] The most common cause of a regional wall motion abnormality is myocardial ischemia or infarction. The extent of a wall motion abnormality can be measured in several different ways. Echocardiography is a tomographic technique that visualizes all of the cardiac walls. Traditionally for quantitative purposes the left ventricle is divided into 16 segments.[14] Each segment can be attributed to one of the three major epicardial coronary arteries (Fig. 7-18) . There is substantial overlap in the posterior segments and inferior and lateral apical segments. For each of these 16 segments a wall motion score can be assigned (Fig. 7-19) . This is a unitless hierarchical number in which 1 represents normal motion; 2, hypokinesis; 3, akinesis;

Figure 7-16 Apical four-chamber view from which left ventricular volume has been calculated using Simpson's rule. The endocardium has been traced and automatically subdivided into a series of discs. The volume of each of the discs is then calculated as disc area (pir 2 ) multiplied by the height of each disc. The volume of each separate disc is then summed to provide the volume of the ventricle (116 ml).

and 4, dyskinesis. Each wall is then assigned a score, and the average score for the 16 segments is then calculated. This number is directly proportional to the extent and severity of wall motion abnormalities. There are several variations on a wall motion score, including addition of scores for aneurysm, mild hypokinesis, and hyperkinesis.

The wall motion score can be calculated for all 16 segments of the left ventricle or separately for anterior and posterior segments, representing the left anterior descending and right plus circumflex coronary artery territories, respectively. An M-mode interrogation line can be used to quantify endocardial excursion and myocardial thickening in any targeted segment (Fig. 7-20) . There are several more complex methods for quantification of left ventricular function. Most rely on tracing the endocardial border in diastole and systole in either a short-axis or apical view. Radians are then constructed from the center of mass, and either changes in radian length or changes in area subtended by an arc are then quantified. [15] ABNORMALITIES OF SEPTAL MOTION.

The interventricular septum is a shared wall between the right and left ventricles, and thus its motion can be affected by processes in either ventricle. Myocardial ischemia and infarction cause a fairly characteristic absence of systolic thickening and dyskinesis of the septum. There are multiple nonischemic causes for septal wall motion abnormalities as well. Conduction Disturbances.

Both left bundle branch block and Wolff-Parkinson-White syndrome,[16] with a septal pathway, can result in abnormalities of septal motion. Left bundle branch block characteristically causes an early systolic downward motion followed by relaxation of the ventricular septum and a secondary downward contraction. This is best appreciated with M-mode echocardiography. This phenomenon is most common in the proximal anterior septum and is less prominent in the distal septum. A similar pattern is seen in patients with ventricular pacing; however, the maximum location of abnormal motion is highly variable, depending on the location of the pacemaker lead. Wolff-Parkinson-White syndrome results in ventricular preexcitation in a localized area of the left or right ventricle. The preexcited area contracts slightly earlier than the remainder of the heart and can be seen in the ventricular septal posterior or lateral walls. The abnormality associated with Wolff-Parkinson-White syndrome is less dramatic than that seen with left bundle branch block. Although newer

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Figure 7-18 Schematic representation of a 16-segment division of the left ventricle and the associated coronary artery distributions.

two-dimensional scanning instruments have temporal resolution sufficient to detect an abnormality of wall motion due to a conduction disturbance, the high temporal resolution of M-mode echocardiography may be necessary for precise identification of the wall

motion abnormalities. CONSTRICTIVE PERICARDITIS (see Chap. 50) .

Constrictive pericarditis interferes with the normal sequence of right and left ventricular filling and results in subtle septal wall motion abnormalities.[17] This typically causes early downward motion of the septum, followed by paradoxical motion. Multiple patterns of septal motion abnormalities have been noted in constrictive pericarditis. As with electrical conduction disturbances, these may be best identified with M-mode echocardiography. VENTRICULAR OVERLOAD.

Either a volume or pressure overload of the right ventricle results in a ventricular septal motion abnormality.[18] In each instance the right ventricle is dilated. In a pure volume overload there is diastolic flattening of the ventricular septum so that the left ventricular geometry in diastole assumes a "D" shape rather than circular geometry. Because this is a low pressure phenomenon the left ventricle becomes circular in early systole before onset of ventricular ejection (Fig. 7-21) . A right ventricular pressure overload results in flattening of the septum not only in diastole but also in systole. The degree of flattening is directly proportional to the elevation in right ventricular systolic pressure. Frank reversal of septal curvature is seen in individuals with systemic level right-sided heart pressures. A final septal motion abnormality that is commonly encountered is the "postoperative septum." This abnormality is characterized by paradoxical anterior motion of the septum in systole, with preserved myocardial thickening. Often posterior wall excursion appears exaggerated.[19] This phenomenon may be seen in any form of cardiac surgery in which the pericardium has been opened. It often resolves 3 to 5 years after surgery. Doppler Principles and Equations

The Doppler principle states that the frequency of ultrasound reflected from a stationary object is identical to the transmitted frequency. If an object is moving toward the transducer, the reflected frequency will be higher than the transmitted frequency; and conversely if an object is moving away from the transducer, the reflected frequency will be lower. The difference between the transmitted and received frequencies is the Doppler shift (Fig. 7-22) . The magnitude of the Doppler shift is determined by the velocity and direction of the moving object and can be calculated by the Doppler equation. The Doppler equation relates the angle of interrogation, the Doppler shift, or change in frequency between the transmitted and reflected frequency, and a constant that is equal to the speed of sound in water, to the velocity and direction of the moving object (Fig. 7-23) . A major contributor to this equation is the angle theta, with which the interrogating beam intercepts flow. For

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Figure 7-19 Typical wall motion score presentation. For each of the 16 segments a score of 1 to 4 has been assigned, representing normal or abnormal wall motion. The scores are then summed and averaged to calculate an overall wall motion score that is directly proportionate to the size and severity of the wall motion abnormality.

maximum accuracy, interrogation should be directly in the line of flow, that is, theta = 0 degrees. Because the cosine of 0 degrees = 1.0, solving the Doppler equation is a fairly straightforward process. With increasing angle theta the cosine becomes progressively less than 1.0 and when incorporated into the equation results in a systematic and increasingly severe underestimation of the true velocity. For practical purposes an angle of interrogation less than 20 degrees is essential to ensure clinically accurate information. Most modern instrumentation contains algorithms for correcting theta when it is not equal to 0 degrees. Unfortunately, the true direction of the laminar flow is often not known, and attempts at correction are likely to result in creation of additional error. For the purposes of cardiac imaging, Doppler echocardiography is most commonly employed for determining the direction and velocity of red blood cells moving

Figure 7-20 M-mode echocardiogram recorded in a patient with severe left ventricular systolic dysfunction. Note the dilated left ventricle and a decreased excursion of the septum and posterior wall compared with the normal example seen in Figure 7-1 . There is additional evidence of left ventricular systolic dysfunction in that the mitral valve E point septal separation is increased (double-headed arrow). Evidence of elevated end-diastolic pressure is noted in the "B bump" (arrowhead), which delays final closure of the mitral valve.

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Figure 7-21 Short-axis two-dimensional echocardiogram depicting a right ventricular volume overload pattern. Compare the normal geometry of the left ventricle in a short-axis view (see Fig. 7-5) to that noted here. In the right ventricular volume overload pattern there is dilation of the right ventricle and flattening of the ventricular septum (downward pointing arrows) so that in diastole the ventricle takes on a "D"-shaped configuration rather than circular geometry. With systole there is restitution of normal circular geometry (upward arrows).

within the cardiovascular system. By convention, motion toward the transducer is recorded as a signal above the zero velocity line and motion away from the transducer as a signal below this line (Fig. 7-24) .

CALCULATION OF PRESSURE GRADIENTS.

Once the velocity of the target has been determined, this information can be used to determine pressure gradients across a restrictive orifice using the Bernoulli equation.[20] The Bernoulli equation contains multiple elements, including convective acceleration and viscous friction (Fig. 7-25) . Of note, convective acceleration and viscous friction are relatively weak contributors in most biological systems and can

Figure 7-22 Demonstration of the Doppler effect. In each instance the transmitted ultrasound beam is denoted emanating from the upper transducer and the returning beam off of the reflecting object (dark circle) coming to the lower transducer. The upper panel depicts a stationary target in which the transmit frequency (ft ) is equal to the returning frequency (fr ) and there is no Doppler shift. The middle panel depicts an object moving toward the transducer in which the returning frequency (f r ) is greater than the transmit frequency (ft ). In the lower schematic the object is moving away from the transducer and the returning frequency (fr ) is less than the transmit frequency (f t ). The Doppler shift (f d ) equals the difference between these two frequencies. (From Feigenbaum H: Echocardiography. 4th ed. Malvern, PA, Lea & Febiger, 1986.)

be effectively ignored. The Bernoulli equation in its simplest form states that DeltaP (the pressure gradient across a restrictive orifice) = 4V 2 , where V = the peak instantaneous velocity of flow through the restrictive orifice. In reality, the equation incorporates not only the peak instantaneous velocity at the restrictive orifice but also the velocity noted

Figure 7-23 Demonstration of the Doppler equation for determining the velocity of a moving object. The Doppler shift (fd ) is calculated as the difference between the returning (f r ) and transmit (ft ) frequencies. The Doppler equation relates the Doppler shift (f d ) to the transmit frequency, the angle of interrogation (theta), the velocity of the moving object (V), and the speed of sound (C). The equation can be rearranged to solve for velocity as is noted in the third equation above. (From Feigenbaum H: Echocardiography. 4th ed. Malvern, PA, Lea & Febiger, 1986.)

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Figure 7-24 Combination of aortic stenosis and aortic insufficiency demonstrating the directional nature of spectral Doppler. The continuous-wave Doppler is recorded from the apex of the left ventricle along a line oriented through the aortic valve. Aortic stenosis is present with a peak velocity of 4 m/sec (400 cm/sec) that is directed away from the transducer and hence recorded below the zero crossing line. Aortic insufficiency is also present and is noted as a diastolic signal recorded above the zero crossing line. AI = aortic insufficiency; AS = aortic stenosis.

in the acceleration zone, V2. For most clinically relevant conditions such as severe

aortic stenosis, V1 is substantially greater than V2 and hence V2 can effectively be ignored. There are several instances in which the V2 velocity must be included. These include the obvious case of a serial obstruction, as well as other situations in which V2 is relatively large compared with V1, such as in milder degrees of aortic stenosis and aortic stenosis combined with aortic insufficiency. THE BASIC DOPPLER EXAMINATION: NORMAL FLOW PATTERNS.

All four cardiac valves can be interrogated using either pulsed or continuous-wave Doppler and substantial physiological data derived from the recorded signals.[20] Figure 7-26 is a representation of normal Doppler flow patterns across the aortic and mitral valves. Highly sensitive Doppler instrumentation frequently picks up mild amounts of physiological regurgitation, which is more common for the tricuspid and pulmonic than the aortic and

Figure 7-25 The Bernoulli equation can be used to calculate a pressure gradient across any restrictive orifice. The components of the Bernoulli equation are convective acceleration, flow acceleration, and viscous friction. The full equation can be modified to P1 - P2 = V2 2 - V 1 2 ×4 and further simplified in the absence of a significant V1 velocity to DeltaP = 4V 2 . P2 = pressure diastole to an obstruction; V2 = Doppler velocity diastole to an obstruction; V 1 = velocity proximal to an obstruction; P1 = pressure proximal to an obstruction. (From Feigenbaum H: Echocardiography. 4th ed. Malvern, PA, Lea & Febiger, 1986.)

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Figure 7-26 Pulsed Doppler spectral recordings of normal mitral and aortic valve flows. The top panel is recorded from the left ventricular apex and shows normal mitral valve inflow with a relatively higher E than A velocity. The bottom panel is also recorded from the left ventricular apex and shows flow moving away from the transducer in the left ventricular outflow tract with a peak velocity of approximately 1 m/sec.

mitral valves. In the normal heart under physiological circumstances, the maximum velocity typically encountered is approximately 1.6 m/sec. Pulmonary vein and hepatic vein flows can also be recorded in the majority of patients (Fig. 7-27) . PULSED VERSUS CONTINUOUS-WAVE DOPPLER.

Doppler ultrasonography is used in two basic methods. The first is pulsed Doppler, which can be considered a "steerable stethoscope" in which a sample volume of variable size can be superimposed on the two-dimensional echocardiographic image. Range gating is used to ensure that only Doppler shifts from one discrete site are interpreted for velocity calculations. Thus, pulsed Doppler allows determination of direction and flow velocity at a precise point within the cardiac system. It is limited,

however, in its maximum velocity by the Nyquist limit. The Nyquist limit is defined as the pulse repetition frequency divided by 2. For typical imaging systems the maximum recordable velocity with a pulsed rate system is 1.5 to 2 m/sec. Many stenotic and regurgitant velocities exceed this limit, at which point the spectral display is paradoxically recorded as a velocity in the opposite direction of the moving target. This phenomenon is known as "aliasing" (Fig. 7-28) . [21] Continuous-wave Doppler imaging continuously interrogates the returning ultrasound beam for Doppler shifts. The line of interrogation is identifiable; however, the precise location of the maximum velocity must be deduced by integrating the interrogation line direction with known cardiac anatomy. Whereas continuous-wave Doppler imaging provides less precise localization of gradients, it is not limited by velocity limits and hence can record velocities exceeding those anticipated in a biological system. MULTIGATE DOPPLER.

In an effort to increase the maximum velocity detectable with pulsed Doppler, a technique of multigating can be employed in which multiple pulsed gates are simultaneously employed, thus increasing the effective Nyquist limit.[22] Multigate Doppler allows detection of velocities as high as 3.5 to 5 m/sec with the ability to identify one of the gates as the site of origin. In large part, multigate Doppler has been fully supplanted by steerable continuous-wave Doppler methodology. COLOR FLOW DOPPLER.

Color flow Doppler imaging represents a variation on multigate pulsed Doppler imaging and thus is subject to its velocity limitations. In color flow Doppler, instead of only a single site being interrogated for a Doppler shift, a variable-sized matrix of sampling points can be created and used to simultaneously interrogate velocity

Figure 7-27 Normal pulmonary (upper panel) and hepatic (lower panel) vein flows. Nearly continuous, multiphasic flow is seen in the normal pulmonary and hepatic veins. Note that there is higher velocity of pulmonary vein inflow during ventricular systole then during diastole.

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Figure 7-28 Pulsed (top) and continuous-wave (bottom) Doppler recording of mitral regurgitation. The lower panel recorded with continuous-wave Doppler is free of the aliasing phenomenon, and the true peak velocity of the mitral regurgitation jet (5.5 m/sec) is fully displayed. The top panel was recorded in pulsed Doppler, which results in "aliasing." Once the velocity has exceeded the Nyquist limit (in this case 1.6 m/sec) the signal is paradoxically displayed above the zero crossing line.

over a large area of the heart. Because this represents multiple pulsed sample volumes, each of which must be independently interrogated, frame rates are relatively low in Doppler flow imaging. Color flow imaging is the display solution for managing the data that are derived from thousands of sample sites simultaneously. The typical color flow display algorithm involves displaying velocities toward the transducer in varying shades of red and those heading away from the transducer in varying shades of blue with either the intensity or hue paralleling the actual velocity.[23] [24] If multiple velocity shifts are present at an interrogation point, this is defined as "variance" and may be colored in a yellow or green confetti-like image. Normal color flow Doppler findings include the ability to track mitral and tricuspid inflow patterns and left and right ventricular outflow. Normal mitral inflow appears as a red encoded signal moving from the mitral orifice along the lateral wall to the left ventricular apex, where it reverses course and appears as a blue encoded signal along the septum. The flow profile accelerates with atrial systole. With systole the organized flow in the left ventricular outflow tract appears as a series of color shifts as the accelerating flow exceeds the relatively low Nyquist limit of color Doppler imaging. Pathological flow will be detected either as turbulence due to a restricted orifice, as pathological flow through an abnormal communication (e.g., an atrial septal defect), or as a regurgitant flow signal in a downstream chamber. The above represents traditional color flow imaging algorithms. In reality, multiple different color schemes and variance maps can be employed. It should be emphasized that the visualized jet area is heavily dependent on Doppler gain settings. At higher heart rates, the relatively low frame rate of color flow imaging also compromises accuracy. Substantial experience and attention to technical detail is essential to provide accurate clinical information from color flow Doppler imaging. DOPPLER CALCULATION OF RIGHT VENTRICULAR SYSTOLIC PRESSURE.

Obviously, application of the Bernoulli equation allows calculation of gradients across stenotic valves, but likewise it can be used to calculate a gradient between any high-pressure and low-pressure chamber. A commonly used application of the Bernoulli equation is the determination of the right ventricular systolic pressure.[25] Tricuspid regurgitation is very common in many disease states. By determining the peak velocity of a tricuspid regurgitation jet one can then calculate the right ventricular to right atrial pressure gradient (Fig. 7-29) . A key component of this is estimation of right atrial pressure. Approaches to this determination include assigning an empirical constant, assigning a floating constant of 5, 10, or 15 mm Hg (depending on the size of the right atrium, severity of regurgitation, and appearance of the inferior vena cava), or assigning a floating constant of 10 percent of the peak gradient. Each of these methodologies appears to result in satisfactory estimation of intercardiac pressure. CALCULATION OF FLOW.

Because the Doppler spectral profile provides a highly accurate measure of the velocity of the moving blood, this value when combined with a measured or calculated area can provide data regarding actual volumetric flow (Fig. 7-30) . Multiplying the cross-sectional area of the flow times the velocity time integral yields the actual volume of flow during that pulse interval. If the left ventricular outflow tract is interrogated, this value then represents the stroke volume of the left ventricle.[26] [27] This, in turn, can be used to

calculate cardiac output. The greatest source of error in this calculation is often determination of the cross-sectional area of the left ventricular outflow tract, which may not assume circular geometry. Additionally, because of the formula for determining area from diameter (A = pir 2 ), any error in measuring the diameter of the flow channel is squared. Thus, determination of stroke volume and cardiac output may have greater clinical value in following serial trends than in precise

Figure 7-29 Measurement of right ventricular systolic pressure using the tricuspid regurgitation jet. The gradient between the right ventricle and right atrium (P 1 - P 2 ) can be calculated from the velocity of the tricuspid regurgitation jet using the modified Bernoulli equation (DeltaP = 4V 2 ). Actual right ventricular systolic pressure is then calculated as the sum of the pressure gradient between the two chambers and an assumed right atrial pressure (P ra ). Right atrial pressure can be estimated from examination of the jugular veins, by evaluation of the inferior vena cava for collapse during inspiration, or by using an empirical or floating constant (see text for further details). (From Feigenbaum H: Echocardiography. 5th ed. Malvern, PA, Lea & Febiger, 1994.)

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Figure 7-30 Principle of Doppler determination of volumetric flow. Flow through the tubular object can be calculated as area (A) times mean velocity (V). This phasic flow times the heart rate (HR) equals cardiac output (CO) in a biological system. The velocity is determined from the pulsed Doppler signal. The instantaneous stroke volume can be determined on a beat-by-beat basis; in addition, stroke volume multiplied times heart rate yields cardiac output. The cross section or area can be either directly measured or calculated from the diameter of the circular structure. (From Feigenbaum H: Echocardiography. 4th ed. Philadelphia, Lea & Febiger, 1986.)

determination of volumetric flow. For clinical purposes, however, this remains a valuable technique. Similar calculations of flow volume can be performed for the pulmonic and mitral valves as well.[28] An expansion of volume flow calculation involves the "continuity equation" (Fig. 7-31) . The underlying principle of the continuity equation is that the volume of flow entering a channel must equal the volume of flow exiting that channel.[29] If the cross-sectional area is equal at the entrance and exit points, then flow velocity will likewise be equal at those two points. If, however, the cross-sectional area decreases at the downstream site, then, of necessity, velocity must increase to maintain the same volumetric flow. The continuity equation can be applied for determination of aortic valve area in aortic stenosis and less often for mitral valve area or other conditions. The relatively low Nyquist limit of color Doppler flow imaging can be used to determine volumetric flow as well. Flow converging on a relatively restrictive area will accelerate as it nears the downstream exit. Because of the relatively low Nyquist limit of color flow Doppler imaging, this results in a series of aliasing lines where the color flow signal will alternately change from blue to red. By purposely utilizing relatively low Nyquist limits

and expanded views, the echocardiographer can determine the distance from the actual flow exit point to one of the aliasing lines. Because the velocity at which flow aliases is known, the velocity of flow at that point is likewise known. If one assumes that flow converges at equal velocities symmetrically toward an orifice, then by applying the geometric formula for a hemisphere one can determine the surface area of flow in motion at any of the aliasing points that represents identifiable velocities ( Fig. 7-32 ). From this, one can then calculate the actual volume of flow from this proximal isovelocity surface area as velocity times surface area.[30] [31] In general terms, for any given Nyquist limit the larger the proximal isovelocity surface area, the greater the amount of flow involved. Therefore, quantitation of proximal isovelocity surface area allows an additional clue as to the volume of regurgitant flow. Proximal isovelocity surface area calculations can be performed for any flow that accelerates toward a relatively restrictive orifice, including mitral regurgitation, aortic insufficiency, and shunt lesions. The major limitation of the use of proximal isovelocity surface area is the assumption that flow moves in a hemispherical manner. This assumption is true only for flow converging on a relatively flat surface. If flow is channeled through a funnel, corrections must be made for a surface area less than a full hemisphere.

Figure 7-32 Demonstration of the proximal isovelocity surface area method for determining flow. The figure on the right is a color flow image of the acceleration of flow toward a regurgitant orifice in a patient with mitral regurgitation. Note the sequential shift in color from blue to red and back to blue. The boundary between blue and red represents an aliasing line at which velocity has exceeded the Nyquist limits, which are displayed on the color bar. The schematic on the left outlines the calculations necessary to determine flow. For any given aliasing line a hemisphere of flow is assumed. The surface area of a hemisphere is calculated as 2 pir 2 . Flow is equal to the product of the surface area times the velocity, which is determined from the Nyquist limit.

Close inspection of a regurgitant jet between either ventricle and its corresponding atrium can also provide clues to ventricular performance. It should be recognized that in early systole ventricular pressure exceeds atrial pressure by a wide margin and thus ejection of blood into the downstream atrium is at low resistance, resulting in a high dP/dt that corresponds to the forcefulness of ventricular contraction. [32] [33] If myocardial failure occurs, the ability of the ventricle to eject forcefully is compromised and dP/dt decreases. This is also noted in spectral Doppler echocardiography of continuous-wave ejection parameters by a decrease in the ejection velocity slope ( Fig. 7-33 ). Actual dP/dt can be calculated by determining the time in milliseconds between a regurgitant velocity of 1 and 3 m/sec. This corresponds to a pressure difference of 32 mm Hg. If the time over which this pressure difference is obtained is measured, a noninvasive dP/dt can be calculated.

Figure 7-31 Principle of using Doppler calculations for the continuity equation to determine the area of the stenotic orifice. The continuity equation stipulates that the volume of flow entering a tubular chamber must equal that exiting it. Because flow equals volume times area at each end of the flow stream, the calculation for flow at each end can be solved for the unknown restricted orifice area (A 2 ). A1 = area proximal to the stenosis; A2 = area of stenosis; V1 = velocity proximal to the stenosis; V2 = velocity

through the stenosis.

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Figure 7-33 Use of the mitral regurgitation spectral display to determine positive and negative dP/dt of left ventricular contraction. The spectral mitral regurgitation jet is displayed at high sweep speed to maximize temporal resolution. The time in milliseconds required for velocity to increase from 1 to 3 m/sec is then measured. This time is then divided into 32 mm Hg (the pressure difference between 1 and 3 m/sec) to determine dP/dt noninvasively.

The continuous-wave spectral profile can also provide clues as to the nature of obstruction in many disease states. It should be emphasized that the spectral profile provides high temporal resolution for determining the timing of pressure gradients. Thus, the contour of the spectral profile provides clues as to whether an obstruction is fixed or develops over time, in which case the peak gradient will occur late rather than early.[34] The latter is classic for dynamic obstruction in hypertrophic cardiomyopathy. Close examination of a regurgitant profile can also reveal evidence that atrial pressure has acutely elevated toward the end of ejection when velocities taper off rapidly in the latter half of systole. Much attention has been paid to mitral valve inflow patterns as they relate to diastolic function of the left ventricle.[35] [36] [37] [37A] This assessment must be done in patients who are in sinus rhythm, during which there are discrete E and A wave velocities of the mitral valve inflow. In normal individuals, early velocities exceed later velocities and the E to A ratio is typically greater than 1.2. With impaired relaxation of the left ventricle this ratio declines and the rate of decay of the E wave velocity likewise decreases. Figure 7-34 schematizes several mitral valve Doppler inflow patterns. There are a number of other influences on the E to A ratio, including age and heart rate. With a pathological increase in left ventricular stiffness accompanied by excess volume, there is an augmentation of the normal E to A ratio. This increased E to A ratio is classic for a restrictive cardiomyopathy and constrictive pericarditis but is also typically seen in patients with end-stage heart disease of virtually any type who have markedly elevated diastolic pressures. It is imperative to incorporate the anatomical and other Doppler information into an assessment of mitral valve inflow patterns in an effort to provide clinically relevant information. Evaluation of mitral valve closure patterns with M-mode echocardiography can provide additional information on intracardiac hemodynamics.[38] Doppler can be used to evaluate the inflow patterns of the hepatic and pulmonary veins as well.[39] [40] Both hepatic and pulmonary vein inflow are biphasic with predominant flow in ventricular systole (see Fig. 7-27) . Examination of the flow patterns can provide valuable clues in a variety of disease states, including mitral regurgitation, restrictive and constrictive processes, and other diseases that elevate left ventricular diastolic pressure.

Figure 7-34 Schematic depiction of mitral valve and pulmonary vein inflow patterns. A, A normal mitral valve inflow pattern with both early (E) and atrial contraction related (A) flow velocities. Note that the E velocity exceeds the A velocity in the normal situation. The isovolumetric relaxation time (IVRT) is as noted. The deceleration time (DT) is defined as the milliseconds from peak E-wave velocity to zero velocity. B, The same, normal mitral valve inflow pattern on which normal pulmonary vein flow velocities have been superimposed. Note that systolic pulmonary vein flow (PVs) exceeds the velocity of diastolic pulmonary vein flow (PVd) and that there is a normal amount of retrograde pulmonary vein flow (PVa) related to atrial contraction. C, The mitral valve inflow and pulmonary vein flow pattern in a noncompliant stiff ventricle with poor relaxation. There is a characteristic decrease in the E to A ratio of the mitral valve inflow pattern associated with a decrease in the diastolic component of pulmonary vein flow. D, The example of "restrictive physiology" with decreased left ventricular compliance and high left atrial pressures. Note the exaggerated E to A ratio and the short deceleration time of mitral valve E-wave flow. The diastolic component of pulmonary vein flow is accentuated and the systolic component decreased, and the pulmonary vein retrograde flow during atrial contraction is also accentuated. E, The situation of "pseudo-normalization" in which the mitral valve inflow pattern falls between that seen in C and D and thus mimics the normal mitral valve inflow seen in A. Pulmonary vein flow, however, remains abnormal, with a relative predominance of diastolic pulmonary vein flow compared with the systolic flow. There is also accentuation of pulmonary vein retrograde flow during atrial systole.

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SPECIFIC IMAGING FORMATS AND TECHNIQUES TRANSESOPHAGEAL ECHOCARDIOGRAPHY.

For this technique the ultrasound transducer has been miniaturized and mounted on the tip of a flexible gastroscope-like instrument. The mechanics of the instrument allow both flexion and lateral motion of the tip to optimize views. Early TEE probes provided only a single plane of interrogation, with subsequent probes providing two perpendicularly oriented planes that could be viewed in alternate fashion. Modern TEE probes contain an array of ultrasound crystals at the tip of the probe that allow rotation of the ultrasound scanning plane through 360 degrees. There are specific indications and contraindications to TEE as well as well-recognized inherent risks. TEE is indicated in patients in whom TTE is either unlikely to provide diagnostic information or has been nondiagnostic. Specific examples in which TEE is of proven incremental yield include detection of aortic dissection, evaluation of the mechanism of mitral regurgitation, and evaluation of patients for source of cardiac emboli. TEE is relatively contraindicated in individuals with significant esophageal pathology. TEE is typically performed under intravenous conscious sedation after local anesthesia of the oropharynx. The exact choice of intravenous agents is institutionally dependent but frequently consists of a combination of narcotics and a benzodiazepine agent. Complications associated with TEE include those associated with the agents used for conscious sedation as well as complications related to the mechanical aspects of probe insertion. The latter can involve trauma to any aspect of the teeth, gums, oropharynx, or esophagus. Esophageal complications are most likely to arise in individuals with

preexisting esophageal disorders; and trauma to the oropharynx, teeth, and gums is more likely in patients who are uncooperative. There are a family of fairly standardized views that are obtained during the TEE examination.[41] Most echocardiographers begin by examining the heart from behind the left atrium because this view provides a fairly rapid means for

Figure 7-39 Routine gray scale and color B-mode scans demonstrating the enhanced visual sensitivity for faint signals. The upper panels are two views of a left atrial appendage recorded in a patient with atrial fibrillation; the left panel is recorded in routine gray scale. There are very vague ;qosmokelike;qc echoes swirling within the body of the left atrial appendage consistent with stagnant blood. The right-hand panel was recorded in the same patient at the same gain and dynamic range settings but using color encoded imaging. Note the greater ease with which the low intensity echoes are visually depicted. The two bottom panels represent spectral Doppler of aortic insufficiency recorded in gray scale (bottom left) and in B-color (bottom right), again demonstrating the greater ease of visual detection with the color encoded signal.

orienting the operator. Figures 7-35 and 7-36 outline views in the horizontal and longitudinal planes that correspond to 0- and 90-degree scanning planes using a multidirectional rotating transducer. Figures 7-37 and 7-38 are transesophageal echocardiograms recorded from several of the transducer positions schematized in Figures 7-35 and 7-36 . COLOR B-MODE SCANNING.

In an effort to enhance visual detection of anatomical boundaries and spectral Doppler signals, the fundamental gray scale image can be colorized.[42] This has shown promise for detection and tracking of endocardial boundaries and for visualization of faint spectral Doppler signals ( Fig. 7-39 ). HARMONIC IMAGING.

A recent adaptation of cardiac ultrasonography relies on the generation of harmonic frequencies during transmission of the ultrasound beam.[43] [44] [45] [45A] [45B] Traditionally, transducers have had narrow bandwidth ultrasound elements that transmit and receive at narrowly defined frequencies. Modern transducers have a wide bandwidth that allows transmission and receipt of ultrasound over a broad range of frequencies. The traditional view of harmonics is that an object once insonated with ultrasound may resonate and hence reflect back ultrasound not only at the fundamental, transmitted frequency but also at harmonics of that frequency. In the traditional view of harmonics an object can be imaged at 2 MHz but reflect ultrasound back at 2 MHz and at 4- and 8-MHz harmonics. Recently, it has been recognized that the transmission of ultrasound through tissue actually creates harmonic frequencies during propagation. Because the transmitted frequency is not a narrow discrete frequency but rather a broad range of frequencies, the full range of reflected frequencies and the resultant harmonics are likewise substantially broader than originally conceived. This is the premise for what has

been termed tissue harmonic imaging. Harmonic frequencies increase in strength with depth of penetration but represent

Figure 7-35 Schematic demonstrating the transesophageal echocardiographic images that can be obtained in a horizontal plane. Figures 2A and 2B are obtained from the transgastric location, 3A and 3B from the midesophageal position, and 1A and 1B from the upper esophageal position. (Images can be displayed with the apex of the sector either up [A figures] or the apex down [B figures].) Echocardiographic images corresponding to figures 1A, 2A, and 3A are presented in Figure 7-37 . RPA = right pulmonary artery; SVC = superior vena cava; LPA = left pulmonary artery; IVC = inferior vena cava; S = stomach; FO = fossa ovalis; other abbreviations are as per previous figures. (From Feigenbaum H: Echocardiography. 5th ed. Malvern, PA, Lea & Febiger, 1994.)

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Figure 7-36 Transesophageal echocardiographic views obtained in the longitudinal transducer position. The A series of figures are recorded with the apex down and the B series with the apex up. 3A and 3B are recorded in the gastric position, 2A and 2B from the midesophagus, and 1A and 1B from the upper esophagus. LUPV = left upper pulmonary vein; LAA = left atrial appendage; other abbreviations are as per previous figures. (From Feigenbaum H: Echocardiography, 5th ed. Malvern, PA, Lea & Febiger, 1994.)

only a small portion of the total reflected ultrasound energy. The advantage of the reflected harmonic frequencies is that they are free of near-field reverberation and shadowing effect. This results in an increased signal-to-noise ratio of the harmonic signal (Fig. 7-40) . This type of imaging shows tremendous promise for improved visualization of the myocardium but at the cost of a minor reduction in resolution. Additionally, tissue signature is brighter than usual and there is loss of detail for evaluation of fine valvular structures. COLOR M-MODE.

Color M-mode echocardiography combines routine M-mode scanning with superimposed color Doppler information. As with M-mode echocardiography, the x axis represents time and the y axis represents distance from the transducer. The M-mode component is identical to that previously discussed for routine M-mode echocardiography. Along the single line of interrogation, Doppler information is then color encoded and superimposed on the M-mode display ( Fig. 7-41 ). This technique provides high temporal resolution for timing cardiac events and can have particular value in determining the timing of a regurgitant valvular lesion and in determining the rate of inflow into the left ventricle. [45C] [45D] It is limited in that it provides information regarding velocity of flow in only one dimension. CONTRAST ECHOCARDIOGRAPHY.

Ultrasound reflects off all structures but increasingly off structures with different acoustic properties.[46] Thus, a tissue fluid interface is a more potent reflector of ultrasound than the interior of a solid structure. An even more potent reflector of ultrasound is a gas/fluid interface, such as can be created by microcavitations or bubbles. Contrast echocardiography is a complex field currently in evolution. The simplest contrast agent is agitated saline, created by forcefully injecting saline mixed with a small quantity of air between two syringes. This creates a solution of microbubbles that are 30 to 200 mum in diameter. The resultant microbubbles are intrinsically unstable and subject to coalescence, and their effect is relatively transient. Their large size precludes passage through the pulmonary bed. Agitated saline contrast is the standard technique for detection of intracardiac shunts.[47] Because

Figure 7-41 Color M-mode echocardiography. With this methodology color flow imaging is superimposed on an M-mode echocardiogram. This provides excellent temporal resolution for timing intracardiac events. The left panel was recorded in a normal, disease-free individual from the apex of the left ventricle. Notice that both early and late (E and A) mitral inflow can be detected. The systolic interval (white arrowheads) is devoid of flow. The right panel was recorded in a patient with mitral valve prolapse and late systolic mitral regurgitation. Note the prominent early flow velocity through the mitral valve and a late systolic regurgitant flow (white arrowheads).

saline microbubbles are too large to pass through the pulmonary capillary bed,[48] their appearance in the left side of the heart is indirect evidence of a pathological intracardiac shunt.[49] Attempts at creating a more stable population of microbubbles have been undertaken for a number of years and have included stabilizing agitated saline with indocyanine green dye and creation of manufactured microbubbles. The available manufactured microbubbles have been based on albumin[50] or other protein spheres, and more recently the air has been substituted with a perfluorocarbon.[51] [52] Perfluorocarbon agents have low diffusibility and intense echo-reflective properties. These agents provide full and complete opacification of the left ventricular cavity after intravenous injection (Fig. 7-42) .[45A] [45B] [51] [52] [53] [53A] These agents can also be used to enhance spectral Doppler signals of both right- and left-sided valves.[54] [55] A role in detection of left ventricular and atrial appendage thrombus has recently been suggested.[55A] [55B] They have also shown tremendous promise for evaluation of myocardial perfusion. Myocardial perfusion echocardiography should be considered a developmental tool of immense promise rather than a routine clinical tool at this time. Specialized imaging techniques are necessary to optimize contrast detection. Compared with fundamental imaging, harmonic imaging is substantially more sensitive for detection of contrast medium in the ventricular cavity and myocardium. It has recently been recognized that contrast microbubbles are destroyed by interaction with the ultrasound beam, especially at high-energy levels.[56] Intermittently triggering the imaging beam avoids this destruction and results in more effective detection of ultrasound contrast.[57] [58] Use of a low mechanical index also results in less bubble

destruction. THREE-DIMENSIONAL ECHOCARDIOGRAPHY.

There are two basic approaches to three-dimensional echocardiography. The first is to compile a series of sequential two-dimensional scans using either an external frame of reference or internal transducer locator to then create a three-dimensional matrix of the cardiac image.[59] [60] [61] This can then be surface rendered to create an actual three-dimensional image of the cardiac structures (Fig. 7-43) , or the three-dimensional data set can be "resliced" to provide a secondary two-dimensional image along any imaging plane. The second approach to three-dimensional imaging has

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Figure 7-37 Transesophageal echocardiograms recorded in a horizontal plane. The upper and lower panels were recorded in a true 0-degree plane at a high level behind the left atrium and at a midesophageal level, respectively. In the left atrial view a typical four-chamber view of the heart is obtained in which all four cardiac chambers as well as the mitral and tricuspid valves are clearly visualized. The lower panel was recorded at 0 degrees with the probe inserted deeper in the esophagus. A typical short-axis view of the left ventricle is obtained in which a circular left ventricle and crescent-shaped right ventricle are seen. This view is analogous to a parasternal short-axis view; however, the orientation is inverted such that the inferior wall is at the top of the image and the anterior wall at the bottom. The bottom panel was recorded at 35 degrees and with pull back of the transducer slightly from the position needed for the upper panel. This provides a short-axis view at the base of the heart at which the circular aorta with an open aortic valve is clearly visualized.

been real-time three-dimensional imaging in which a transducer creates an actual three-dimensional volume of interrogation.[62] [63] [64] This three-dimensional data set can then be rendered into a three-dimensional image, or secondarily two-dimensional imaging planes can be derived. Three-dimensional imaging has advantages with respect to quantitative precision in unusually shaped ventricles and in accurate anatomical description of complex anatomy such as complex congenital heart disease.[60] [61] [65] [65A] It is still limited by relatively low frame rates and/or the time required for processing the three-dimensional image. INTRAVASCULAR ULTRASONOGRAPHY.

Intracardiac ultrasonography is a discipline largely employed by the invasive

Figure 7-38 Transesophageal echocardiographic images recorded in view orthogonal to the horizontal images seen in Figure 7-37 . The top panel is recorded at the same level in the esophagus as the top panel in Figure 7-37 at a 95-degree angle. In this view the left atrium and left ventricle as well as left atrial appendage (LAA) are clearly visualized. Distinct scallops of the closed mitral valve are also well seen. The middle panel is likewise recorded at the same level in the esophagus with rotation of the probe

clockwise. In this view the left atrium and right atrium as well as inferior vena cava (IVC) and superior vena cava (SVC) are clearly visualized. The bottom panel was recorded at 135 degrees. This view provides excellent visualization of the left ventricular outflow tract and proximal aorta.

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Figure 7-40 Parasternal long-axis view recorded in both fundamental (top) and second harmonic imaging (bottom). The orientation of this image is identical to that in Figure 7-3 . Note the marked increase in echogenicity of the septum and posterior wall, as well as increased echo density of the aortic and mitral valves. In this example, tissue harmonic imaging has provided an obvious distinction between the blood pool and myocardium, compared with fundamental imaging. Abbreviations are as per previous figures.

cardiologist in the catheterization laboratory. This ultrasound technique relies on ultraminiaturization of ultrasound transducers that are then incorporated into the tip of intracardiac catheters. The catheters can be as small as 5 French for intracoronary work or as large as 10 or 12 French, which can be used inside cardiac chambers.[66] [67] Typically, either a phased array of crystals is placed circumferentially around the catheter tip or a single crystal, often reflected by a mirror, is mechanically rotated at the tip of a catheter. In either instance, high frequencies of 10 to 40 MHz are used. The smaller catheters can be placed, through a guiding catheter, into epicardial coronary arteries. They provide a high-resolution view of intracardiac anatomy (Fig. 7-44) and have provided previously unavailable visualization of morphology within the coronary artery and characterization of the intracoronary tissue.[68] [69] [70] Calcification and atherosclerosis can be identified and the eccentric or concentric nature of plaque likewise determined. Intracoronary ultrasonography has been instrumental in determining the success of interventions such as stent deployment in coronary artery disease.[71] [71A] [71B] Figure 7-45 (Figure Not Available) depicts intracoronary ultrasound studies demonstrating increasing degrees of severity of atherosclerosis. A closely related technology is the use of miniaturized Doppler wires for monitoring intracoronary flow velocity.[72] [73] Intravascular ultrasonography has also been used in the evaluation of patients with known or suspected aortic dissection, in which case it provides a high-resolution intraluminal view of dissection pathology and yields incremental information with respect to the origin of branch vessels. It has been instrumental in refining the techniques of emergent fenestration in stenting for acute type III dissections. TISSUE CHARACTERIZATION.

Tissue characterization refers to the detailed evaluation of the entire reflected ultrasound signal in an effort to extract information regarding actual tissue character. Typically, this has relied on evaluation of data in the radiofrequency signal component before processing into a diagnostic, visual image. One of the more promising applications has been in evaluating the cyclic variation in returning ultrasound signal intensity (cyclic variation in backscatter) as a marker of myocardial ischemia.[74]

DOPPLER TISSUE INTERROGATION.

With specific alteration in Doppler filters, the myocardium can be targeted for Doppler interrogation. The resulting Doppler signals can be color encoded and incorporated into the two-dimensional image, thus displaying directional information. Additionally, quantitative data regarding velocity of motion in diastole and systole can be extracted.[75] [76] [76A] [76B] [76C]

Advantages and Limitations of Echocardiography

As with any diagnostic technique, echocardiography has distinct advantages and disadvantages. Cardiac ultrasonography itself carries no risk to the patient, operator, bystanders, pregnant women, or fetus. Specialized examinations such as contrast echocardiography, TEE, and stress echocardiography carry the minimal risk associated with the procedural modifications necessary for their undertaking. Modern ultrasound instruments are capable of visualizing all four cardiac chambers, all four cardiac valves, and the great vessels. They provide high-resolution tomographic views in unlimited planes, which facilitates the ability to diagnose virtually all forms of anatomical cardiovascular disease. The addition of Doppler interrogation allows determination of physiological parameters as they relate to blood flow and myocardial velocities. Echocardiography does have specific limitations. Because ultrasound does not transmit well through calcified structures or bone, an appropriate acoustic window is necessary for optimal visualization. In neonates and infants, ultrasound can pass through noncalcified cartridge and the windows available exceed those in adults. In the adult population a noncalcified window must be obtained that typically is in the intercostal spaces or from the subxiphoid positions. In patients with narrow intercostal spaces, imaging can be problematic. A greater limitation is the degree to which the air-filled structures reflect ultrasound. Intervening lung tissue in patients with obstructive lung disease can result in suboptimal or even inadequate imaging. Another area of concern for echocardiography is its potential for overuse. Because it is low cost and carries no risk, the tendency for its overuse or inappropriate use is substantial. The American College of Cardiology, American Heart Association, and American Society of Echocardiography have outlined recommendations for appropriate training in echocardiography[77] and likewise recommendations on its appropriate clinical use.[78]

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Figure 7-42 Demonstration of left ventricular contrast medium enhancement after intravenous injection of a perfluorocarbon-based agent. The panels on the left are recorded before administration of contrast agent, and those on the right after opacification of the left ventricular cavity. Note the enhanced ability to

identify the left ventricular cavity and distinguish it from the endocardial border after opacification.

ACQUIRED VALVULAR HEART DISEASE (see Chap. 46) Mitral Valve Disease

Virtually all types of mitral valve disease can be characterized anatomically using echocardiography. Doppler techniques provide accurate physiological information that complements the anatomical assessment. Figure 7-46 outlines the motion pattern of the normal mitral valve and the valve in multiple disease states, each of which are discussed. Mitral Stenosis

Mitral stenosis was the first valvular lesion to be comprehensively evaluated with echocardiography. Two-dimensional echocardiography and Doppler ultrasonography remain the mainstay of diagnosis and characterization of this lesion. In the vast majority of adult patients, mitral stenosis is the result of rheumatic heart disease, with rarer cases of congenital mitral stenosis being encountered in adult patients. Rarely, heavy calcification of the mitral annulus results in functional restriction of the left ventricular inflow and can result in a left atrial to left ventricular gradient mimicking valvular mitral stenosis.

Figure 7-43 Surface-rendered three-dimensional echocardiogram showing a normal aortic valve. The panel on the left shows the valve in the open position, and a roughly triangular orifice is seen. The image has been captured at mid opening. At the right the valve is seen in the closed position and the right, left, and noncoronary cusps are clearly visualized.

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Figure 7-44 Intracardiac ultrasound image recorded from within the cavity of the right atrium. Note the fairly thick tissue at the primum and more superior aspect of the atrial septum and the very thin valve of the foramen ovale.

The hallmark of mitral stenosis on two-dimensional echocardiography is thickening and restriction of motion of both mitral valve leaflets, with the predominant pathological process being at the tips of the leaflets and proximal chordae (Fig. 7-47) . In more advanced cases, the body of the leaflet itself may become involved; and in even more advanced cases substantial calcification occurs within the leaflet itself and on the subvalvular apparatus, including the chordae and papillary muscle tips (Fig. 7-48) . The earliest effect of rheumatic disease on the mitral valve is the result of inflammation and thickening of leaflet tips that restricts the motion of the tips while allowing free motion of

the body of the leaflets. This results in a characteristic "doming" diastolic motion of the mitral valve. The motion Figure 7-45 (Figure Not Available) Intracoronary ultrasonic images demonstrating the different severity of coronary atherosclerosis. A, Small rim of thickened endothelium (arrow). B, Larger amount of eccentric endothelial thickening (arrows). C, Massive atherosclerotic plaque that is wider (arrows) than the residual lumen. D, Calcification in the plaque (CA) produces shadowing (S). (From Feigenbaum H: Echocardiography. 5th ed. Malvern, PA, Lea & Febiger, 1994.)

Figure 7-46 Schematic outlining both normal and abnormal mitral valve closure patterns. See text for details.

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Figure 7-47 Parasternal long-axis view of a patient with mitral stenosis and a pliable noncalcified mitral valve leaflet. Note the "doming" motion of the mitral valve leaflets (arrowheads). Valves with these morphologic features are excellent candidates for percutaneous balloon valvotomy.

of the anterior leaflet has also been described as a "hockey stick" configuration. Restriction of the tips effectively results in a funnel-like mitral valve apparatus with the restrictive orifice being at the tips of the leaflets. This appearance is easily recognized from TTE in both the parasternal long-axis and apical four-chamber views. With careful attention to detail, the actual restrictive orifice of the mitral valve can be visualized and planimetered from a parasternal short-axis view (Fig. 7-49) . This planimetered area correlates well with the area determined in the catheterization laboratory. M-mode echocardiography was the initial diagnostic tool for evaluation of mitral stenosis. By using this technique, the thickened leaflets could be identified as well as the restricted motion. The restricted motion pattern resulted in a flattening of the E-F slope of the mitral valve (Fig. 7-50) . The E-F slope can be quantified and tracked as a measure of stenosis severity but provides no truly quantitative value by today's standards. ASSESSMENT OF SEVERITY.

In addition to determining the anatomical extent and severity of the stenotic lesion, assessment of physiological significance is made using Doppler echocardiography.[79] [79A] Color flow imaging is instrumental in determining the degree of concurrent mitral regurgitation. Both continuous-wave and pulsed Doppler echocardiography can be obtained at rest and with exercise and provide accurate quantification of the transvalvular gradient (Fig. 7-51) . [80] Determination of the transvalvular gradient should be performed in patients both at rest and with modest degrees of exercise. A population of symptomatic patients exists who have relatively unimpressive gradients at rest that increase dramatically with mild exercise.

A second Doppler method for determining the severity of mitral stenosis involves calculating the pressure half time (P½ t), which is the time in milliseconds required for the peak pressure gradient to decline to one half of its original value. The pressure half time can be related to an anatomical valve area by the formula: mitral valve area =P ½ t ÷ 220 milliseconds. This relationship is probably valid only for isolated mitral stenosis and is not accurate for quantitation of the mitral valve orifice if concurrent mitral regurgitation[81] or significant aortic insufficiency is present.[82] The relationship also has diminished accuracy in instances in which left ventricular diastolic compliance is markedly abnormal, such as in patients with severe hypertension or aortic stenosis[83] and immediately after mitral balloon valvotomy.[84] Other more detailed methods for determining the mitral valve area involve determination of quantitative mitral valve flow. This can be performed using the continuity equation in a manner analogous to that for aortic stenosis.[85] Either flow and dimensions at the level of the mitral valve annulus or forward going flow in the left ventricular outflow tract can be used in this equation. Obviously this approach has limitations in patients with concurrent regurgitation or multivalve disease.

Figure 7-48 Parasternal long-axis view in diastole (top) and systole (bottom) in a patient with rheumatic heart disease and mitral stenosis. In the top panel note the diffuse thickening of the mitral valve. The reduced orifice can be seen in this end-diastolic frame (arrow). The bottom panel was recorded in systole and provides a view of the chordal apparatus, which can be seen to be diffusely thickened and fibrotic. Valves with this appearance are less ideal candidates for percutaneous intervention than the valve presented in Figure 7-47 .

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Figure 7-49 Parasternal short-axis view at the level of the mitral valve orifice recorded in a patient with mitral stenosis. The frame was recorded in end diastole, and the actual orifice of the stenotic mitral valve can be visualized and in this instance has been planimetered. The measured mitral valve area is approximately 1.1 cm2 .

In addition to determining the presence and severity of mitral stenosis, it is important to evaluate the heart for secondary effects. Secondary effects of mitral stenosis include left atrial dilation with subsequent stasis and thrombus formation and secondary pulmonary hypertension. Evaluation of the left atrium for blood stasis and thrombus requires TEE (Fig. 7-52) . The aortic, tricuspid, and pulmonic valves can likewise be directly interrogated for evidence of rheumatic involvement. The most common significant sequelae of mitral stenosis is development of secondary pulmonary hypertension with subsequent right-sided heart dysfunction and tricuspid regurgitation. As with other diseases in which the right side of the heart is evaluated, the tricuspid regurgitation jet can be interrogated for determination of right ventricular systolic and, presumably,

pulmonary artery systolic pressures. It is important to fully evaluate the anatomical features of mitral stenosis in patients in whom a mitral balloon valvotomy is contemplated. Four features of mitral valve anatomy have been identified that correlate with success of this procedure. These include valve pliability, thickening, calcification, and subvalvular involvement. Each of these can be quantified on a score of 0 to 4 and a total score tabulated. Scores above 14 represent valves unlikely to be successfully treated with a percutaneous approach.[86] [87] There is a disproportionate impact of calcification and subvalvular involvement on the likelihood of successful valvotomy. Mitral Regurgitation

Two-dimensional echocardiography and Doppler techniques can be used to detect the presence of mitral regurgitation, to determine its severity, and also to determine the etiology of regurgitation and look for secondary effects. Mitral

Figure 7-50 M-mode echocardiogram recorded in a patient with typical mitral stenosis. Compare this mitral valve opening pattern to the mitral valve motion in Figure 7-1 . With mitral stenosis there is thickening at the leaflets and flattening of the E-F slope.

Figure 7-51 Transmitral Doppler recordings obtained in a patient with mitral stenosis at rest (top) and with exercise (bottom). Heart rate has increased from 85 to 110 beats/min, resulting in an increase in the mean pressure gradient from 6.3 to 13.6 mm Hg. Abbreviations are as per previous figures.

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Figure 7-52 Transesophageal echocardiogram recorded in a patient with severe mitral stenosis. Note the marked thickening of the mitral valve (arrows), including involvement of the chordal apparatus. The left ventricle and right ventricle are small, and the left atrium is massively dilated. Note the homogeneous echoes filling the right and left atria. In real-time scanning these are appreciated as a swirling, "smokelike" echo signal consistent with stagnant blood. Abbreviations are as per previous figures.

regurgitation can be due to a wide variety of cardiac conditions, some of which are presented in schematic form in Figure 7-46 . Typically, mitral regurgitation will first be documented using Doppler color flow imaging. In the presence of significant mitral regurgitation, volume overload of left ventricle and left atrium occurs, resulting in chamber dilation, the degree of which is dependent on both the severity and duration of mitral regurgitation.[88] The etiology of mitral regurgitation is determined by assessing the anatomy of the left ventricle and the mitral valve apparatus. Many forms of mitral regurgitation are due to intrinsic disease of the mitral valve, examples of which would be

mitral regurgitation concurrent with mitral stenosis, myxomatous degeneration with mitral valve prolapse, chordal rupture, endocarditis, and infarct-related papillary muscle rupture. Functional forms of mitral regurgitation also occur in which the mitral valve may be anatomically normal but fails to coapt because of dilation of the left ventricle. [88] This can occur due to either cardiomyopathy or coronary artery disease. In the vast majority of instances the anatomical and functional abnormality responsible for mitral regurgitation can be documented with TTE. On occasion, TEE is necessary to refine the anatomical assessment and may be particularly helpful in identifying rupture of a papillary muscle head and flail leaflets and in detecting smaller vegetations or perforations.[89] [90] ASSESSMENT OF SEVERITY.

Doppler color flow imaging is used to determine the severity of mitral regurgitation. The severity of mitral regurgitation is directly proportional to the size of the regurgitant jet within the left atrium.[91] [92] [93] Multiple studies have confirmed the relationship between the size of the regurgitant jet and the severity of regurgitation determined with angiography or other techniques. Typically, the size of the jet is indexed to the size of the left atrium. Figure 7-53 demonstrates examples of mitral regurgitation. Jets that are peripheral or impinging on a wall, rather than central, cause predictable problems with assessment of severity.[94] [95] Owing to the Coanda effect, a regurgitant jet impinging on a wall results in a smaller color flow area than an equivalent central regurgitant volume. The underlying

Figure 7-53 Four panels depicting varying degrees of mitral regurgitation; the two top panels are apical four-chamber transthoracic views showing, on the left, mild mitral regurgitation and, on the right, moderate to severe mitral regurgitation. On the left note the relatively narrow jet directed from the tips of the mitral valve toward the posterior left atrial wall. On the right note the larger jet, filling approximately 40 percent of the left atrial cavity. The two bottom panels are transesophageal echocardiograms. On the left note the mitral regurgitation occurring in two discrete jets and, on the right, the highly eccentric jet, which courses along the extreme lateral wall of the left atrium. Abbreviations are as per previous figures.

mechanism of this phenomenon is that a regurgitant volume "recruits" the adjacent blood flow into motion. As color Doppler flow detects cells in motion, irrespective of their origin, the visualized regurgitant jet is the sum of the regurgitant volume and the recruited blood cells. A centrally located jet recruits in all of its dimensions, whereas a jet adjacent to a wall recruits only on the free surface, hence being relatively smaller than an equal volume of central regurgitation. A jet impinging on a wall underestimates the regurgitant volume by approximately 40 percent. In cases of moderate and severe mitral regurgitation, flow in the pulmonary veins may reverse direction in systole. [96] A variation on this finding is attenuation of normal forward flow in the pulmonary vein during ventricular systole. More recently, three-dimensional reconstruction of mitral regurgitation jets has been shown to be feasible.[97] [98] The incremental value of this method has not yet been shown. Several characteristics of a regurgitant jet can give clues as to the etiology. In the

presence of chamber dilation due to cardiomyopathy, leaflet coaptation is abnormal and the leaflets are convex into the left ventricular cavity rather than concave ( Fig. 7-54 ). In extreme examples of this phenomenon the actual regurgitant orifice, owing to failure of coaptation, can be directly visualized. These jets are typically central in location. By using either color Doppler M-mode or careful interrogation of the spectral display, the timing of the mitral regurgitation jet can also be determined. Lesions such as mitral prolapse may result in regurgitation confined to mid and late systole. Anatomical disruption of any portion of the mitral valve will result in regurgitation. This can range from a few ruptured chordae with isolated prolapse of a single scallop to disruption of entire papillary muscle head with flail of an entire leaflet. TEE is often incrementally helpful in determining the precise degree of anatomical disruption of the valve (Fig. 7-55) . Irrespective of the etiology of a flail leaflet the resultant jet is often highly eccentric and its flow is directed opposite of the leaflet bearing the pathology; that is, a flail posterior mitral valve leaflet results in an anteriorly directed jet. An eccentric jet should lead to a higher index of suspicion of a flail leaflet. Three-dimensional echocardiography has shown promise for detailed assessment of mitral valve pathology in mitral regurgitation (Fig. 7-56) . Quantitation of mitral regurgitation is heavily dependent on the color Doppler flow area. Other techniques for quantifying mitral regurgitation rely on determining the width of the jet at its origin and on evaluation of the proximal isovelocity area. In general terms, for any given Nyquist limit, the larger the size of proximal isovelocity surface area the greater the degree of regurgitation. [99] Calculation of flow volume from proximal isovelocity surface area has already been discussed and can be applied to determine regurgitant volume. Mitral Valve Prolapse

The detection and characterization of mitral valve prolapse remains a common use of echocardiography. Early studies suggested a prevalence of prolapse of up to 21 percent in otherwise healthy young females. It should be emphasized

Figure 7-54 Apical four-chamber view in a patient with a dilated cardiomyopathy and severe mitral regurgitation due to a dilated annulus and abnormal mitral valve coaptation. The solid horizontal white line represents the plane of the mitral annulus. Note that the mitral valve closes well within the cavity of the left ventricle. The actual origin of the mitral regurgitation jet can be seen as it accelerates toward the regurgitant orifice (arrow) and is likewise displaced into the cavity of the left ventricle.

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Figure 7-55 Transesophageal echocardiogram recorded in a patient with a flail posterior mitral valve leaflet. The echocardiogram is recorded in a longitudinal view in which the left atrium, left ventricle, and

pulmonary artery are visualized. Because flail leaflets occur in atypical locations, it is often necessary to scan in unusual planes to identify the leaflet. In this projection a substantial portion of the posterior leaflet (arrow) can be seen to protrude into the left atrium, with the tip of the leaflet no longer attached to the chordal apparatus.

that many individuals identified as having mitral prolapse in these earlier studies are recognized today to simply have normal bowing of the mitral valve. The normal mitral valve closure pattern is for the tips of the leaflets to point toward the left ventricular apex and for there to be gentle bowing of the leaflet with a concavity toward the apex of the left ventricle. Based largely on these dimensional reconstruction techniques, the mitral valve annulus is known not to be a planar structure but rather to have complex three-dimensional geometry.[100] Depending on the tomographic plane of interrogation, a portion of one or both leaflets may bow behind the imaginary annular line. In the presence of otherwise anatomically normal thin leaflets, this represents a variation of normal and does not represent pathological mitral valve prolapse. The most extreme forms of mitral valve prolapse involve myxomatous degeneration of the valves with visible leaflet thickening (defined as greater than 3 to 5 mm in thickness) and either marked symmetrical bowing of the valve behind the majority of the annular plane or highly asymmetrical buckling of one or both leaflets into the plane of the left atrium (Figs. 7-57 and 7-58) . This will be associated with variable degrees of mitral regurgitation, which may be either wholly systolic or confined to mid to late systole. Because of the eccentric buckling of the myxomatous valve, the mitral regurgitation jet can be eccentric rather than central. The key aspects to the diagnosis of mitral valve prolapse rely not on the mere detection of a valve that buckles into the plane of the left atrium but on characterization of the valve morphology.[101] [102] As mentioned earlier, normal thin leaflets that bow gently into the left atrial plane probably represent no more than a variation of normal closure patterns. Patients with thickened redundant valves and myxomatous changes of the leaflet have a true form of structural heart disease. It is these individuals who are most at risk for endocarditis, spontaneous rupture of chordae, and progressive mitral regurgitation. It also appears that there is a higher than usual incidence of ventricular arrhythmias and neurological events in this subset of patients. Aortic Valve Disease Aortic Stenosis

Evaluation of patients with known or suspected aortic valve disease requires integration of anatomical information from two-dimensional echocardiography and physiological information from Doppler studies. Aortic stenosis is most commonly due to one of three pathological processes. These include a bicuspid aortic valve, rheumatic heart disease, and degenerative aortic stenosis. On rare occasions, aortic stenosis can be the result of endocarditis or radiation heart

Figure 7-56 Three-dimensional echocardiogram recorded in a patient with a partial flail mitral anterior leaflet. For both panels the orientation is a view of the mitral valve from within the left atrium. The left panel was recorded in diastole, and the unrestricted orifice can be seen. The right panel was recorded in

mid systole. Note the two scallops of the anterior leaflet that protrude into the left atrium (arrows).

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Figure 7-57 Parasternal long-axis view in diastole (top) and systole (bottom) in a patient with mitral valve prolapse and myxomatous changes. In the upper panel note the open mitral valve and the diffuse thickening of the posterior mitral valve leaflet (arrow). The lower panel was recorded in systole. Note that both leaflets prolapse behind the plane of the mitral valve annulus. The prolapse of the posterior leaflet is somewhat more prominent (arrow).

disease. Bicuspid aortic valve typically presents as a hemodynamically significant lesion in the fourth or fifth decade of life and calcific degenerative aortic stenosis in the seventh decade and beyond. Rheumatic aortic valve disease

Figure 7-58 M-mode echocardiogram of the mitral valve recorded in the same patient noted in Figure 7-55 . Note that the posterior leaflet is diffusely thickened and in systole prolapses posteriorly from the normal closure line (arrow).

will virtually always be seen in patients who have concurrent rheumatic mitral valve disease. The bicuspid aortic valve is the single most common congenital cardiac defect and occurs in approximately 2 percent of the population. There is a broad range of anatomical and physiological abnormalities associated with this condition. The bicuspid aortic valve is commonly thought of as a two-leaflet valve with roughly equal leaflet proportions. There is a range of abnormality in the "bicuspid valve" that includes nearly unicuspid valves and distribution of leaflet tissue other than 50/50 percent. Bicuspid aortic valves are commonly described as having either an anterior-posterior or a lateral orientation of the leaflets. In reality, virtually any direction of the major coaptation can be seen. TTE is a reliable method for detecting the bicuspid aortic valve. With the use of this technique, the hallmark of the bicuspid valve will be eccentric closure of the leaflets within the aorta. In approximately 80 percent of cases, two rather than three leaflets can be directly visualized (Fig. 7-59) . With closer scrutiny by way of TEE, what at first appears to be a true bicuspid valve often is found to represent a three-leaflet valve with unequal leaflet sizes and fusion of one of the three commissures, resulting in a functional bicuspid valve (Fig. 7-60) . It is important to examine the

Figure 7-59 Transthoracic echocardiogram in a patient with bicuspid aortic valve. In the upper panel, note that the leaflets of the aortic valve do not open all the way to the margins of the aorta but are "tethered" in lumen of the proximal aorta. The two bottom panels are recorded in the short-axis view at the base of the heart. The lower left panel was recorded in diastole and reveals the closed bicuspid valve with a single commissure oriented from 10 o'clock to 4 o'clock (arrows). The lower right panel is recorded

in systole, and the oval opening of the bicuspid valve can be appreciated within the circular aorta. Abbreviations are as per previous figures.

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Figure 7-60 Transesophageal echocardiogram recorded in a patient with an anatomical three-leaflet valve with a fused commissure resulting in a functional bicuspid aortic valve. In the top panel note the three cusps (N = noncoronary, L = left coronary, R = right coronary). The upper frame was recorded in diastole, and the closure lines would suggest presence of three leaflets. The lower panel is recorded in systole; and instead of opening fully to the margins of the aorta with a circular orifice, the valve opens with an oval, fishmouth-shaped orifice. Note the commissure between the right and left cusps is fused, resulting in a functionally bicuspid valve. Abbreviations are as per previous figures.

opening pattern of the aortic valve to determine that it is functionally bicuspid. There is a strong association between coarctation of the aorta and bicuspid valve. When either of these conditions is clinically suspected, the other should also be evaluated. Degenerative calcific valves appear as three-leaflet structures with marked thickening of the leaflets. Thickening and calcification may be more prominent at the base of the leaflets than at the tips. There is a broad range of immobility and stenosis, depending on the duration and severity of disease (Fig. 7-61) . Rheumatic aortic stenosis typically results in leaflet thickening along the commissural edges. It will be seen almost exclusively in the presence of rheumatic mitral stenosis. Once aortic stenosis is anatomically defined, secondary effects can also be evaluated. These include poststenotic dilation of the aorta and left ventricular hypertrophy. Assessment of left ventricular systolic function should also be undertaken. ASSESSMENT OF SEVERITY.

Doppler echocardiography is essential for assessment of the physiological significance of aortic stenosis (see Figs. 7-24 and 7-61) .[103] [103A] [103B] In clinically significant aortic stenosis the gradient is likely to exceed 50 mm Hg. This corresponds to a Doppler velocity of approximately 3.5 m/sec, which is out of the range for accurate quantitation using pulsed-wave Doppler. For this reason, continuous-wave Doppler is essential for quantitation. From continuous-wave Doppler both instantaneous peak and mean gradients can be determined using the Bernoulli equation. Either online or offline outlining of the spectral display and automatic calculation of these values can be performed. In some instances determination of the gradient at rest and with exercise may be beneficial. The gradients determined from Doppler echocardiography correlate very well with simultaneously determined invasive measurements.[103B] This correlation is maximal during simultaneous measurement and when micromanometer tip catheters are used (Fig. 7-62) . The commonly measured "peak to peak" gradient determined in the catheterization laboratory has no basis in physiological reality and will not correspond to either a peak instantaneous or mean gradient determined by either

micromanometer catheters or Doppler interrogation. In most instances, cardiac output and hence stroke volume are augmented in the catheterization laboratory compared with rest. For this reason Doppler-determined

Figure 7-61 Echocardiogram recorded in a patient with severe aortic stenosis. The top panel is a parasternal long-axis view recorded in systole. Left ventricular function is diminished. The aortic valve is markedly thickened and partially calcified. Its motion is markedly reduced and in systole it appears that the valve occludes the orifice (arrow). The lower panel is a continuous-wave Doppler recorded from the apex of the left ventricle along a line aimed through the stenotic aortic valve. Note the aortic stenosis signal below the zero crossing line. The peak velocity is 430 cm/sec, which corresponds to a maximum gradient of 77 mm Hg and a mean gradient of 49.4 mm Hg. Abbreviations are as per previous figures.

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Figure 7-62 Graphic comparison of Doppler- and catheterization-determined gradients in patients with aortic stenosis. On the left are simultaneously recorded gradients and on the right are nonsimultaneous gradients. Note the stronger correlation between Doppler and catheterization when gradients are obtained in a simultaneous manner. (From Currie PJ, Hagler DJ, Seward JB, et al: Instantaneous pressure gradient: A simultaneous Doppler and dual catheter correlative study. J Am Coll Cardiol 7:800-806, 1986.)

gradients in the echocardiography laboratory may be lower than a catheterization-determined gradient.[103B] On occasion, the Doppler gradient underestimates the gradient measured. This is common with nonsimultaneous recordings as noted earlier but also occurs when the angle of interrogation (theta) exceeds approximately 20 degrees. Off-angle interrogation is the single most common cause for underestimation of an aortic stenosis gradient. In instances in which there is a serial obstruction consisting of both valvular and subvalvular obstruction, both the V1 and V2 components of the Doppler equation must be incorporated. The actual valve orifice is usually not visualized to a reliable degree from TTE. TEE can be used to obtain a direct measurement of the aortic valve orifice in many patients with aortic stenosis. In severe aortic stenosis, the orifice may be highly irregular and not all portions of it may lie in the same plane. With scrupulous attention to detail it is possible in many instances to directly planimeter the area (Fig. 7-63) .[104] An additional method for determining the aortic valve area relies on the continuity equation.[105] [106] Typically, in aortic stenosis the left ventricular outflow tract area can be derived from the annulus diameter, assuming circular geometry. Pulsed Doppler is then used to determine the velocity of flow at that site. The product of the two is volumetric flow in the outflow tract. At the stenotic orifice continuous-wave Doppler is used to determine the average velocity. The algebraic equation can then be solved for the aortic

valve area. A modification of this technique uses mitral valve flow instead of left ventricular outflow. Because the velocity of flow increases at the restrictive orifice, several investigators have suggested using the V1/V2 ratio

Figure 7-63 Transesophageal echocardiogram recorded in a patient with severe aortic stenosis. In the left panel note the three aortic valve cusps (N = noncoronary, L = left coronary, R = right coronary). The leaflets are diffusely thickened and have restricted opening motion. The right-hand panel is the same systolic frame in which the stenotic area of the aortic valve has been planimetered. Note that the area of the aortic valve is calculated as 0.67 cm2 , consistent with severe aortic stenosis.

189

Figure 7-64 Composite of echocardiograms recorded in patients with aortic regurgitation. The two top panels were recorded in the same patient and show, on the left, an apical long-axis view and, on the right, a parasternal short-axis view. In the apical long-axis view note the fairly extensive confetti-like aortic regurgitation jet arising from the proximal aorta and traversing to the left ventricular apex. Note also that the aortic regurgitation jet velocities merge with the mitral inflow velocities, rendering quantitation problematic. The top right hand panel is recorded in the same patient and shows a central aortic regurgitation jet. The bottom left panel is a transesophageal echocardiogram recorded in a longitudinal view. Note the highly eccentric aortic regurgitation jet that appears to fill the entire width of the left ventricular outflow tract. This apparent filling of the left ventricular outflow tract is due to the posterior to anterior jet direction (white arrow) rather than to a substantial true width of the jet. The lower right panel is a color M-mode echocardiogram recorded in a patient with aortic insufficiency in which the normal systolic flow can be appreciated as well as a continuous diastolic flow in the lumen of the aorta that represents aortic insufficiency. The two downward pointing arrows denote the duration of systole, and the two upward pointing arrows indicate the duration of diastole.

as a marker of significant aortic stenosis.[105] Other methods for determining the severity of aortic stenosis involve calculation of aortic valve resistance [107] and using echo-Doppler data in variations of the Gorlin formula. From a practical standpoint it is often not necessary to determine an aortic valve area. In a patient with thickened restricted leaflets and a mean gradient exceeding 50 mm Hg, the presence of severe aortic stenosis is clinically assured. Likewise, in patients with normal ventricular function and with low gradients the likelihood of significant aortic stenosis becomes negligible. Patients with reduced left ventricular function, typically with ejection fractions of 25 to 35 percent, and a modest transvalvular gradient of 25 to 30 mm Hg are problematic. This situation may either represent mild aortic valve disease and unrelated left ventricular dysfunction or, conversely, critical aortic stenosis with secondary left ventricular dysfunction. In the latter situation, patients will benefit from aortic valve replacement, whereas for the former medical management is indicated. Dobutamine infusion, while monitoring left ventricular function and transvalvular

gradients, can be a useful means for separating these two entities.[108] [109] If left ventricular function augments with a dobutamine infusion and the gradient increases to clinically pertinent levels, the diagnosis is most likely severe aortic stenosis with secondary left ventricular dysfunction, and these patients will benefit from valve replacement. Conversely, if ventricular function improves without a change in the gradient it is less likely that the aortic stenosis is the limiting factor. Aortic Regurgitation

Detection and quantitation of aortic regurgitation relies predominantly on Doppler techniques.[110] [111] Using color flow imaging the regurgitant jet can be visualized in the left ventricular outflow tract from several different planes ( Fig. 7-64 ). In the majority of instances, there will be an underlying anatomical abnormality of the aortic valve such as endocarditis, disease of the aortic root, rheumatic valve disease, or a bicuspid valve. Several features of the regurgitant jet have been investigated as markers of the severity of aortic regurgitation. Unlike mitral regurgitation, in which the overall jet size correlates

Figure 7-66 Continuous-wave spectral recordings of patients with mild (top) and severe (bottom) aortic insufficiency. Note the relatively flat slope pressure decay in the mild instance and a steeper slope of pressure decay, denoting near equalization of aortic and left ventricular diastolic pressures, seen in severe aortic insufficiency.

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Figure 7-65 Parasternal long-axis two-dimensional echocardiograms in a patient with minimal (top) and moderate (bottom) aortic regurgitation. In the top panel note the thin color jet of aortic regurgitation that fills less than 10 percent of the left ventricular outflow tract, compared with the wider aortic insufficiency profile, filling over one third of the left ventricular outflow tract in the lower panel. Abbreviations are as per previous figures.

with regurgitation severity, neither the overall size nor depth of penetration of the aortic regurgitation jet correlate strongly with the severity of aortic regurgitation. This is in large part due to the difficulty in separating the regurgitant flow stream from mitral valve inflow. A greater degree of success has been obtained by measuring either the width or cross-sectional area of the regurgitant jet in the outflow tract and indexing this to the width or cross-sectional area of the outflow tract ( Fig. 7-65 ). These measurements are dependent on imaging the jet in its minor axis, and an eccentric jet, crossing across the outflow tract, will result in a disproportionately sized jet compared with its true dimension. TEE often provides more accurate visualization of the true direction and size

of the regurgitant jet. By using continuous-wave Doppler from the apex one can record the actual flow velocity profile of the regurgitant jet (Fig. 7-66) . The velocity of the regurgitant jet is directly related to pressure gradient between the aorta and left ventricle.[112] If this gradient remains high throughout diastole, the slope of velocity and pressure decay is relatively flat. This implies a relatively mild degree of aortic regurgitation in which there has been little equilibration of aortic and left ventricular diastolic pressures. Conversely, with severe aortic regurgitation there is a greater degree of equilibration of left ventricular and aortic diastolic pressures and the terminal aortic regurgitation velocities are relatively low, resulting in a fairly steep slope of velocity decay over the diastolic pressure curve. The pressure half time of the regurgitant jet, defined as the time in milliseconds required for the initial transvalvular diastolic gradient to decline to one half of its peak value, can be calculated and is inversely related to the severity of aortic regurgitation. A pressure half time less than 400 milliseconds correlates with severe aortic regurgitation. In high-quality studies the continuity equation can be used to calculate the aortic regurgitant volume.[113] Quantitation of aortic regurgitation has also been performed using the proximal isovelocity surface area method.[114] There are several secondary Doppler and anatomical features that should also be noted in aortic regurgitation. The proximal aorta often has progressive dilation with long-standing aortic regurgitation.[115] Left ventricular dilation is a natural consequence of long-standing hemodynamically significant aortic regurgitation.[116] [117] Left ventricular size can be normal in the acute phase. With moderate and severe aortic regurgitation, diastolic flow reversal in the descending thoracic aorta can frequently be detected from the suprasternal notch. Two-dimensional echocardiography often reveals an indentation of the anterior mitral valve leaflet during diastole. This is due to the impinging regurgitant jet that distorts the symmetrical opening pattern of the mitral leaflet. This is typically seen only in cases of moderate and severe aortic insufficiency. With M-mode echocardiography fine high-velocity flutter of the anterior mitral leaflet and occasionally the septum can be appreciated (Fig. 7-67) . TIMING OF SURGERY.

Echocardiography plays a significant role in the timing of surgery for aortic regurgitation.[116] [117] This decision is based largely on left ventricular size and performance rather than on the Doppler assessment of severity. Traditional echocardiographic findings that represent indications for surgery have included dilation of the left ventricle beyond 70 mm in diastole or beyond 55 mm in systole with a fractional shortening less than 25 percent. Additionally, progressive dilation of the left ventricle of 1.0 cm or more over a 12-month duration typically represents an indication for valve replacement.

Figure 7-67 M-mode echocardiogram recorded in a patient with aortic insufficiency. Note the fine fluttering of the mitral valve leaflet secondary to impingement by the aortic insufficiency jet. PW =

posterior wall.

Finally, left ventricular performance can be monitored with exercise, and a flat or falling ejection fraction likewise represents an indication for surgical intervention. Tricuspid Valve Disease TRICUSPID REGURGITATION.

Probably due to the complex closure pattern of the tricuspid valve, minimal and mild degrees of tricuspid regurgitation are commonly seen in normal individuals. The most common form of tricuspid valve disease is annular dilation due to right-sided heart overload, resulting in abnormal leaflet coaptation and tricuspid regurgitation. This is typically secondary to pulmonary hypertension, which most commonly is due to left-sided heart pathology. Tricuspid regurgitation due to annular dilation can be the result of virtually any form of heart disease, resulting in elevation of right ventricular pressure or volume. In these instances, the tricuspid valve typically appears anatomically normal but is found to be regurgitant. Quantitation of tricuspid regurgitation is done in a manner similar to that for mitral regurgitation and in clinical practice is a qualitative assessment (Fig. 7-68).[118] Minimal and mild degrees of tricuspid regurgitation are nearly ubiquitous in adult populations, even in the absence of identifiable structural heart disease.[118] Moderate and severe tricuspid regurgitation and tricuspid regurgitation associated with elevated right ventricular systolic pressure are typically associated with cardiac pathology. Primary tricuspid valve disease can result in tricuspid regurgitation as well. Involvement by rheumatic heart disease,[119] endocarditis, trauma with rupture of a papillary muscle,[120] Ebstein anomaly, radiation heart disease, carcinoid heart disease,[121] [122] and prolapse all have characteristic anatomical features that result in regurgitation. TEE can be useful in determining the feasibility of tricuspid valve repair. Carcinoid heart disease is a rare abnormality but has classic echocardiographic features (Fig. 7-69) . [121] [122] In this syndrome, the leaflets appear stiffened and immobile. The annulus is secondarily dilated and the leaflets may fail to coapt. This lesion is typically associated with severe tricuspid regurgitation without elevation in right ventricular systolic pressure.

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Figure 7-68 Two-dimensional echocardiograms with color flow imaging of patients with tricuspid regurgitation. Top, Echocardiogram is recorded in a patient with a mild degree of tricuspid insufficiency. Bottom, Echocardiogram of a patient with severe tricuspid regurgitation.

Irrespective of the cause of tricuspid regurgitation, one can capitalize on this lesion to accurately calculate right ventricular systolic pressure, as noted in the section on Doppler calculations. In the absence of obstruction to right ventricular outflow, this pressure equals pulmonary artery systolic pressure (see Fig. 7-29) . Calculation of right ventricular systolic pressure can be measured both at rest and with exercise and is a

valuable means of noninvasively determining pulmonary artery systolic pressures. TRICUSPID STENOSIS.

Isolated tricuspid stenosis is a very rare clinical entity. Tricuspid stenosis can be seen in individuals with rheumatic heart disease, in which case concurrent mitral stenosis will invariably be present.[119] The carcinoid syndrome can result in tricuspid stenosis as well. Calculation of transvalvular gradients across the tricuspid valve is done in a manner identical to that for the mitral valve. In the majority of cases, tricuspid valve stenosis is associated with regurgitation. Pulmonic Valve Disease (See Chaps. 43 and 44.)

Primary disease of the pulmonic valve is uncommon in adult patients. Occasional patients with pulmonic stenosis (Fig. 7-70) , either in isolation or in combination with other congenital lesions, may be encountered in the adult cardiology practice. Congenital pulmonic stenosis results in thickening of the leaflets and restricted motion on two-dimensional echocardiography. Because the orientation of the pulmonary outflow tract is anterior to posterior, Doppler interrogation is quite easily performed within an angle of integration (theta) close to 0 degrees. The degree of stenosis and regurgitation across the pulmonic valve is determined

Figure 7-69 Right ventricular inflow tract view recorded in a patient with carcinoid disease and tricuspid regurgitation. The right atrium and right ventricle are both visualized in this systolic frame. The tricuspid valve leaflets are abnormally dense and immobile. In this systolic frame the leaflets fail to coapt with the leaflet tip separated by approximately 2 cm. In real time the leaflets are nearly immobile.

Figure 7-70 Two-dimensional (A) and continuous-wave Doppler (B) recorded in a patient with valvular pulmonic stenosis. The two-dimensional study shows a thickened pulmonic valve with restricted motion (arrowheads). The continuous-wave Doppler shows a peak velocity of 4.4 m/sec, which is consistent with a systolic gradient of approximately 78 mm Hg. Abbreviations are as per previous figures. (From Feigenbaum H: Echocardiography. 5th ed. Malvern, PA, Lea & Febiger, 1994.)

in a manner analogous to that for the aortic valve. In the presence of pulmonic regurgitation, the pressure gradient between the pulmonary artery and right ventricle in diastole can be calculated, and from this an estimate of pulmonary artery diastolic pressure can be obtained.[123] This is done by calculating the end-diastolic pulmonary artery to right ventricular gradient and adding an assumed right ventricular diastolic pressure. Several characteristic patterns of pulmonary valve motion should be recognized on M-mode echocardiography. The first is that of pulmonic stenosis in which there is an augmented a wave but otherwise normal motion. In the presence of infundibular stenosis, coarse fluttering of the pulmonic valve is seen. In the presence of significant

pulmonary hypertension there is midsystolic notching of the pulmonic valve and loss of the pulmonary valve a wave (Fig. 7-71) . These findings are qualitative and may be seen only in the more advanced or severe forms of pathology. In modern practice, determination of pulmonary artery hemodynamics relies heavily on Doppler interrogation. Evaluation of the right ventricular outflow tract or pulmonary artery Doppler flow profile can provide valuable clues in patients with known or suspected pulmonary hypertension.[124] Normally, after the onset of ejection, pulmonary artery flow reaches its maximum velocity within 140 milliseconds of the onset of ejection. In pulmonary hypertension this acceleration time is progressively shortened (Fig. 7-72) . There is a linear and inverse correlation between the ejection time, defined as the time from onset of ejection to reaching peak velocity and pulmonary artery systolic and mean pressures. In general, a pulmonary artery acceleration time less than 70 milliseconds implies presence of a pulmonary artery systolic pressure exceeding 70 mm Hg. Other findings in pulmonary hypertension include notching of the pulmonary artery flow profile on spectral Doppler. Miscellaneous Valvular Heart Diseases

Several miscellaneous forms of valvular heart disease deserve comment. Recently, attention has been drawn to the association between the use of anorectic drugs, particularly the combination of phentermine and fenfluramine (PhenFen), and development of valvular heart disease.[125] [126] [127] [128] [128A] [128B] [128C] [128D] The exact incidence of drug-related valvular heart disease is unknown. Most studies have suggested that the predominant

192

Figure 7-71 M-mode echocardiograms of the pulmonic valve recorded in a normal individual (top) and in an individual with pulmonic stenosis (bottom). In the top tracing, note that the a wave is approximately 5 mm in depth. In contrast, in the patient with pulmonic stenosis, there is an exaggerated depth of the a wave (arrow) due to right ventricular pressure exceeding pulmonary artery diastolic pressure after atrial contraction.

lesions are similar to that seen in carcinoid or ergot heart disease. The leaflets of the mitral valve and chordae appear thickened and immobile, and mitral regurgitation is present. More commonly, aortic insufficiency has been noted in association with the use of these drugs, and it often appears out of proportion to the anatomical abnormalities noted on the aortic valve. Radiation therapy can result in valvular dysfunction, most often thickening and insufficiency. The severity of the valvular insufficiency is dependent on the degree of anatomical damage to the valve, and the precise valves involved are dependent entirely on the radiation portal and dose. Typically, more anterior structures are involved and

there may be concurrent myocardial dysfunction due to radiation myocarditis. Evaluation of Prosthetic Heart Valves (See also Chap. 46.)

Two-dimensional echocardiography can be used to determine the appropriate prosthesis size to implant in the aortic position.[129] [130] [131] The evaluation of prosthetic heart valves can be a complex and time-consuming process. Prosthetic heart valves can be divided into three basic groups: mechanical prostheses, such as single or dual disc valves or ball and cage valves; stented bioprostheses, which use either porcine aortic valves or bovine pericardium for valve leaflets; and a newer generation of stentless porcine valves that at this time are approved for use only in the aortic position. Each valve has unique echocardiographic characteristics, and different valves can be evaluated to varying degrees using TTE and TEE. Doppler echocardiography is obviously crucial for determining the presence of regurgitation and the flow characteristics of a valve.[132] [133] It is often not possible to fully evaluate a prosthetic valve with TTE, and TEE is often necessary. This is particularly true for visualization of mitral prostheses. Even with TEE, complete anatomical visualization of an aortic mechanical prosthesis can be problematic. For all but the new stentless aortic prosthesis the sewing ring is characteristically visualized as an echo-dense circular structure within the appropriate annulus. The ball and cage valve is typically visualized as an echo-dense sewing ring with three wire struts forming the cage and a ball moving within the cage. Depending on the composition of the ball, the ball itself may appear either as a spherical structure or as a single echo-dense line in motion. Single-disc mechanical prostheses are visualized as a sewing ring in which the disc can be seen to move. Typically from the transthoracic route all one sees is a single bright echo-dense line with phasic motion during the cardiac cycle above and into the plane of the sewing ring. The discs of a two-disc valve cast a smaller echo signature, and actual disc motion can be difficult to discern from TTE. Using TEE both leaflets of a two-disc valve are easily visualized in the mitral position and have a characteristic butterfly wing motion (Fig. 7-73) .[134] Identifying motion of both leaflets in the aortic position is more problematic. The stented porcine valves are visualized as a sewing ring, impinging on the actual orifice of the valve annulus in which three separate leaflets can be seen. These leaflets have the characteristics of a normal aortic valve. With fibrosis and degeneration or endocarditis the leaflets may become thickened and brighter than usual (Fig. 7-74) .[135] The newer stentless prosthesis and aortic homograft valves can be difficult to distinguish from a native aortic valve. Depending on the implantation technique, there may be few clues as to the presence of a stentless prosthesis other than subtle echodensities at the line of attachment in the annulus or, if implanted within the native aorta, a double-density aortic wall can be seen.[136] [137]

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Figure 7-72 Pulsed-wave Doppler in the right ventricular outflow tract demonstrating varying degrees of

pulmonary artery systolic pressure. A, Record of a normal individual. Note the normal acceleration time, defined as the time in milliseconds from onset of ejection to reaching peak velocity. In this instance the acceleration time is approximately 200 milliseconds. B, Record in a patient with modest pulmonary hypertension. Note the shortened acceleration. C, Record in a patient with severe pulmonary hypertension. Note the remarkably short acceleration time as well as the systolic notching in the flow pattern.

Complete evaluation of prosthetic valves requires detailed Doppler assessment. Color flow imaging is used to determine the presence and severity of regurgitation. [138] The combination of the sewing ring and/or the mechanical valve itself results in substantial reverberation and shadowing and dramatically reduces the ability to interrogate structures posterior to the mechanical prosthesis or sewing ring with Doppler. There is frequently a minimal amount of physiological regurgitation in mechanical prostheses that represents a combination of the closing velocity of the disc or ball and small physiological leaks at the closure lines. It is not uncommon to see minimal degrees of regurgitation in association with a stented or nonstented bioprosthesis. Valvular regurgitation in prosthetic valves can be quite eccentric, and one must use caution in applying rules for determining

Figure 7-75 Transesophageal echocardiogram recorded in a patient with a St. Jude mitral valve replacement and a paravalvular leak, resulting in moderate mitral regurgitation. Left, Recorded in systole. Note the two discs of the St. Jude prosthesis in their closed position (upward-pointing arrows). Immediately outside the boundary of the sewing ring is a distinct color jet (horizontal arrow) representing an eccentric mitral regurgitation jet arising from outside the border of the sewing ring. Right, The same image with color suppressed. Again note the closed leaflets of the St. Jude valve. With the color suppressed a distinct gap between the sewing ring and tissue (downward pointing arrow) can be seen, representing partial valve dehiscence.

severity of regurgitation. This is particularly true for paravalvular regurgitation ( Fig. 7-75 ). Spectral Doppler is used to determine pressure gradients across prosthetic valves. Stentless bioprostheses behave in a manner nearly identical to native aortic valves and typically have a peak gradient of less than 10 to 15 mm Hg.[136] [137] [139] Because of narrowing of the outflow tract by a sewing ring, a stented prosthesis has a higher transvalvular gradient.[139] The magnitude of this gradient is dependent on both flow and the size of the valve. Because of the wide range of anticipated gradients, it is crucial to establish a baseline for prosthetic valves at a time when they are known to be functioning normally. This avoids the problem of subsequent detection of a peak gradient that can be as high as 50 mm Hg. This may be due to the combination of a high flow state and a narrowed orifice due to the sewing ring and may not represent valve deterioration. Doppler evaluation for the gradient across a mechanical prosthesis is complicated by several factors, including phenomena of localized gradients and pressure recovery.[140] [141] As flow accelerates through the noncircular orifice of a mechanical prosthesis, there are areas of rapid flow acceleration that occur over very short distances. This acceleration results in instantaneous peak velocities of 3 to 4 m/sec, corresponding to gradients of 36 to 64 mm Hg. These pathological pressure

gradients occur over a very limited distance (1-2 mm) within the sewing ring and do not reflect the true left-ventricular-to-proximal-aorta pressure difference measured in the hemodynamic laboratory. As with a stented bioprosthesis, it is crucial to obtain an early baseline pressure gradient across a mechanical prosthesis at a time when it is known to function normally for subsequent comparison. This is best done by obtaining a full echocardiographic and Doppler examination at the time of the first follow-up visit after implantation. Dysfunction of prosthetic valves occurs due to valvular dehiscence, in which case a paravalvular leak can be seen (see Fig. 7-75 ), or there may be endocarditis (see Fig. 7-74) , thrombosis, or pannus interfering with motion of a mechanical valve. Typically, either stenosis or regurgitation can occur. If the mechanical valve becomes obstructed by pannus, vegetation, or thrombus, the transvalvular gradient typically will increase, although in some instances it may remain stable or even decline.[140] Regurgitation is usually seen in conjunction with restriction of the leaflet unless the leaflet has been restricted in a fully closed position. In suspected dysfunction of a prosthesis, TEE adds incremental value and is essential for complete evaluation. Assessment of Mitral Valve Repair

Transesophageal echocardiography has been instrumental in determining the success of mitral valve repair.[142] [143] The preoperative echocardiogram is highly reliable as a means for determining which patients are candidates for mitral valve repair, and intraoperative monitoring is an integral part of the surgical routine in determining success of repair. In general, patients with elongated redundant valves, those with pathology of the posterior leaflet, and those with smaller vegetations or perforations are excellent candidates for mitral valve repair. A rheumatic etiology and patients with fibrotic leaflets are less likely to have good long-term results. The intraoperative transesophageal echocardiogram is used to determine transvalvular gradients to exclude iatrogenic mitral stenosis and determine the degree, if any, of residual mitral regurgitation. Other adverse sequelae of mitral

194

Figure 7-73 Transesophageal echocardiogram of a patient with a normally functioning St. Jude mitral valve prosthesis. The scans are recorded at 0 degrees from behind the left atrium. The left panel is recorded in systole. Note the two closed leaflets of the prosthetic valve (arrows). The right-hand panel is recorded in diastole. Note the two leaflets now have a parallel position, pointing into the cavity of the left ventricle (arrows). Note the substantial shadowing from the sewing ring and discs, which reduces the ability to visualize the left ventricular cavity. Abbreviations are as per previous figures.

valve repair include development of dynamic left ventricular outflow tract obstruction, which likewise can be assessed with TEE before removing the patient from the operating room. Figures 7-55 and 7-76 are examples from a patient before and after

successful mitral valve repair. Infective Endocarditis (See Chap. 47.)

Infective endocarditis represents an invasive infection, usually by a bacterial organism of the endothelial lining of the heart, most commonly on one of the four cardiac valves. Left-sided valves are more commonly involved than right-sided valves. The echocardiographic hallmark of bacterial endocarditis is formation of a vegetation on a valvular surface. Pathologically, a vegetation consists of a combination of thrombus, necrotic valvular debris, inflammatory material, and bacteria. Over time, a vegetation may become sterilized, at which point only the residua of the inflammatory response with variable degrees of the thrombotic component persist. On echocardiography a vegetation has the appearance of an oscillating mass attached to a valve leaflet (Fig. 7-77) . Classically, these are seen on the downstream, low-pressure side of a valve. Therefore, one typically anticipates a vegetation on the left atrial side of the mitral valve and on the left ventricular outflow tract side of the aortic valve. In reality, larger vegetations can exist on both sides of a valve and atypical locations are not uncommon. In screening for vegetations, small unrelated masses or surface irregularities are not infrequently encountered, and thus the specificity for defining a vegetation is not 100 percent. Several large-scale studies have demonstrated that echocardiography may play an incremental role in rapidly establishing the diagnosis of endocarditis,[144] [145] [146] and at least one algorithm for defining endocarditis has used echocardiography as an intrinsic component of the diagnosis.[147] Noninfectious vegetation, such as those seen in association with connective tissue disease, are also detected with echocardiographic imaging.[148] [149] In addition to detection of a vegetation in patients with suspected endocarditis, echocardiography can be used to determine the functional significance and degree of anatomical impairment due to endocarditis and to evaluate complications of endocarditis. Typically, endocarditis results in valvular regurgitation and only rarely in significant valvular stenosis. Because of the variable location of vegetations and the highly variable degree to which the valvular surface may be interrupted, regurgitant lesions in endocarditis are more likely to be eccentric than in more classic forms of valvular heart disease. Several studies have attempted to use echocardiographic features of vegetations as a marker for the likelihood of requiring surgery or progressing to heart failure. In general, larger and more mobile vegetations are more likely to be associated with embolic events than are smaller sessile vegetations. Vegetations due to Staphylococcus aureus are more likely to result in abscess formation and less likely to be sterilized with antibiotics. COMPLICATIONS OF ENDOCARDITIS.

These include progressive valvular regurgitation leading to congestive heart failure, abscess formation, failure to sterilize, and embolic phenomena. Intracardiac abscesses are most commonly encountered in the relatively avascular areas of the heart. For aortic valve endocarditis this includes the aorta/mitral valve junction and for mitral and tricuspid valve disease the annular structures. Less commonly, intramyocardial abscess

or abscess within a papillary muscle is encountered. TRANSESOPHAGEAL ECHOCARDIOGRAPHY.

The relative diagnostic value of TTE and TEE has been evaluated in several studies.[150] [151] Because of the higher-quality, higher-resolution

195

Figure 7-74 Apical four-chamber (top) and parasternal short-axis views (lower panel) recorded in a patient with stented porcine bioprostheses in the mitral (top) and aortic (bottom) positions. In the upper panel, the horizontally oriented arrows denote the struts of the stented porcine valve that protrude in the cavity of the left ventricle. Within the struts note the echo-dense mass that represents vegetation. In the lower panel the three struts of the porcine bioprosthesis can be visualized at 2, 6, and 10 o'clock positions. Within the sewing ring of the bioprosthesis are noted several echo densities that represent vegetations. Abbreviations are as per previous figures.

imaging afforded by TEE, virtually all studies have demonstrated an increased sensitivity for detection of vegetations with TEE (Fig. 7-78) . Often the clinical diagnosis of endocarditis has included detection of vegetations, and, thus, many of these studies tend to overstate the sensitivity of TEE. Most studies have also suggested that when a high-quality, entirely normal transthoracic echocardiogram has been obtained in which there is no evidence of valvular mass or thickening and no evidence of pathological regurgitation, that the yield in proceeding to TEE is relatively low. Because TEE provides a high-resolution view of the heart, it also detects many limited areas of valvular thickening that are not related to an infectious process. Thus, its specificity for excluding the diagnosis of endocarditis may be less than optimal. There are several proven advantages to TEE in patients with endocarditis. Perhaps the most well established is the detection of abscesses, particularly in the aortic root (Fig. 7-79) .[152] [153] Data suggest that detection rates from the

Figure 7-76 Two-dimensional echocardiogram recorded in a patient after mitral valve repair and annuloplasty ring. The ring is seen as an echo-dense structure in the annulus (arrows). PV = pulmonary vein; DA = descending aorta.

transthoracic approach are under 30 percent, whereas sensitivity for detecting an abscess in the aortic root with TEE exceeds 95 percent. Additionally, TEE provides more accurate characterization of the size and mobility of vegetations

Figure 7-77 Parasternal long-axis view of patient with aortic valve vegetation. Note the relatively

echo-dense, irregular mass prolapsing into the left ventricular outflow tract in this diastolic frame (arrow). Abbreviations are as per previous figures.

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Figure 7-78 Transthoracic (top) and transesophageal echocardiogram (bottom) recorded in a patient with a mitral valve vegetation. In the transthoracic parasternal long-axis view, a highly mobile filamentous echo can be seen prolapsing into the left atrium during systole. This is consistent with a highly mobile vegetation. A systolic frame from the transesophageal echocardiogram is presented in the bottom panel. Again the highly filamentous mobile echo is noted (horizontal arrow). In addition there is a more sessile 8 mm diameter mass attached to the mitral valve (downward pointing arrow). Abbreviations are as per previous figures.

and detection of multiple vegetations in endocarditis. Finally, TEE is more accurate for determining the etiology of valvular regurgitation than is TTE. TEE can identify valvular perforations, ruptured chordae, and flail leaflets with a higher degree of reliability than can TTE.[154] Calcification of the Mitral Annulus

Fibrosis and calcification of the mitral annulus are common findings with increasing age and can be seen in younger patients with renal disease and other metabolic abnormalities that result in abnormal calcium metabolism (Fig. 7-80) . The degree of calcification can range from limited, focal deposits in the annulus to deposits resulting in a masslike effect.[155] [156] [157] In advanced degrees the basal aspects of the posterior mitral valve leaflet may be involved. In rare situations, annular calcification can result in functional restriction of the mitral valve orifice and a left atrial-left ventricular pressure gradient. Only in advanced and rare cases does the degree of obstruction result in pressure gradients likely to cause symptoms or result in secondary pulmonary hypertension. More commonly, mitral annular calcification is associated with varying degrees of mitral regurgitation. Heavy annular calcification may result in a lower likelihood

Figure 7-79 Transesophageal echocardiogram recorded in a patient with an aortic root abscess, obtained in a longitudinal orientation. Note the thickened aortic valve with superimposed vegetation (arrowhead) and the echo-free space (arrow) between the wall of the aorta and the right ventricular outflow tract, which represents a periaortic abscess. Abbreviations are as per previous figures.

of successful valve replacement and a situation in which paravalvular regurgitation is not uncommon after mitral valve replacement. [146] Statistically, it also has been associated with embolic events.[147]

CONGENITAL HEART DISEASE (See Chaps. 43 and 44.) Modern two-dimensional echocardiographic techniques provide a comprehensive means for evaluating virtually all

Figure 7-80 Two-dimensional echocardiogram recorded in a patient with renal insufficiency and calcification of the mitral annulus. Mitral annular calcium appears as an echo-dense mass in the mitral annulus.

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forms of congenital heart disease found in both adults and children.[158] [159] [160] Additionally, echocardiography can be used to evaluate repaired and palliated congenital heart disease. In the modern era it is unusual for cardiac catheterization or other techniques to be necessary for defining the anatomical anomaly in congenital heart disease.[152] Cardiac magnetic resonance imaging (MRI) may provide incremental information regarding pulmonary artery anatomy and complex venous and great artery connections. Doppler echocardiography often provides the majority of physiological information necessary for the clinical decision-making. It has become increasingly uncommon to make the diagnosis of congenital heart disease de novo in adult populations. Because of the increased access to well-trained pediatricians, family practitioners, and pediatric cardiologists, the majority of "significant" congenital heart lesions are detected in childhood and adolescence. Thus, the number and nature of lesions "escaping" detection until adulthood has changed over the past several decades. The single most common congenital lesion to be detected in adulthood, other than the bicuspid aortic valve, is the atrial septal defect. There are infrequent cases of ventricular septal defects and other anomalies that escape detection to adulthood. This chapter deals only with the more common entities likely to be encountered in adult populations and evaluation of the more common repaired and palliated lesions. Intracardiac Shunts

ATRIAL SEPTAL DEFECT.

The most common shunt lesion to be detected de novo in adulthood is the atrial septal defect. Because atrial septal defects result in a relatively innocent murmur, they are often overlooked in childhood and may escape detection until adolescence or adulthood. Atrial septal defects result in a left-to-right shunt at a level of the atrial septum and, consequently, a volume overload of the right ventricle in diastole. [18] [161] The volume overload pattern of the right ventricle is manifest as dilation of the right ventricle and usually the right atrium. Additionally, the septum is "flattened" and the left

ventricle, rather than assuming circular geometry, has a "D"-shaped geometry (see Fig. 7-21) . This septal flattening is present predominantly in diastole, and during systole the septum assumes its normal circular geometry. This right ventricular volume overload pattern that is typically seen in atrial septal defects is also seen in any other lesion resulting in right ventricular diastolic volume overload, including significant pulmonary insufficiency, tricuspid regurgitation, and anomalous pulmonary venous return. On M-mode echocardiography the right ventricular volume overload pattern is characterized as paradoxical septal motion. It is now recognized that this "paradoxical" septal motion actually represents restitution of normal circular geometry with the onset of ventricular systole. Detection of a right ventricular volume overload pattern may be the first clue to the presence of an atrial septal defect, after which further interrogation of the atrial septum should be undertaken to identify the location of the defect. The three most common locations of an atrial septal defect are secundum, primum, and sinus venosus, representing approximately 70 percent, 15 percent, and 15 percent of atrial septal defects, respectively. Rarer forms of atrial septal defect, including the unroofed coronary sinus, are also encountered. Whereas the secundum atrial septal defect is an isolated entity, there are strong associations between sinus venosus atrial septal defect and malalignment of the pulmonary veins, resulting in functional anomalous pulmonary venous return and abnormalities of the mitral valve seen with the primum atrial septal defect. A primum atrial septal defect is best considered a variant of endocardial cushion defect in which a small perimembranous ventricular septal defect and anomalies of the mitral valve may also

Figure 7-81 Transesophageal echocardiograms in two patients with atrial septal defects. In each case there is a distinct loss of tissue in the atrial septum, allowing direct communication between the left atrium and right atrium. The top panel is the same patient presented in the two left panels in Figure 7-82 , and the bottom panel is recorded in the same patient presented in the bottom right panel in Figure 7-82 .

be encountered. The classic mitral valve abnormality to be seen is a cleft mitral valve with varying degrees of mitral regurgitation. On occasion, a right ventricular volume overload pattern is encountered but no anatomical defect can be visualized. In these instances, contrast echocardiography using agitated saline can be a valuable means of detecting the right-to-left component of interatrial shunting.[42] [162] Of the three common types of atrial septal defect, the sinus venosus defect is most likely to escape direct visualization on a transthoracic echocardiogram. TEE is nearly 100 percent specific and sensitive in detection of all types of atrial septal defects, including sinus venosus defects (Fig. 7-81) .[163] With TEE, the atrial septal defect is visualized as a loss of tissue. The size of the defect can be accurately measured, and color flow imaging can be used to identify abnormal transatrial flow patterns (Figs. 7-81 and 7-82 ). [164] Often the diagnosis can be established with a degree of accuracy and confidence that catheterization is not necessary before surgical repair. Once identified, further characterization of the atrial septal defect can be undertaken

using two-dimensional echocardiography and Doppler techniques. Three-dimensional

Figure 7-82 Four illustrations of patients with atrial septal defects. Top left, Recorded from a subcostal transducer position in a patient with a small atrial septal defect (also illustrated in the lower left panel). From the subcostal transducer position the entire length of the atrial septum can be visualized. There is a defect approximately 7 mm in diameter in the secundum portion of the atrial septum with a color flow signal coursing from the left atrium into the right atrium (arrow) consistent with secundum septal defect. The lower left panel is the transesophageal echocardiogram from the same patient presented on the top left. The size of the defect can be more accurately appreciated, and again there is a distinct color flow image coursing from the left atrium into the right atrium. The upper right panel is a longitudinal view of the atrial septum showing a large patent foramen. Note the margins of the atrial septal tissue (arrows). The atrial septal tissue does not oppose, in this case leaving a 1-cm defect, through which flow shunts from the left atrium to the right atrium. SVC=superior vena cava. The lower right panel is recorded in a patient with a large secundum defect. Note the color flow image denoting a substantial flow from left atrium to right atrium. The defect is approximately 2 cm in diameter.

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echocardiography can provide valuable clues as to the complex shape of an atrial septal defect.[165] [166] TEE can be an invaluable technique for determining the integrity of the tissues surrounding the atrial septal defect and plays a valuable role in determining the feasibility of a percutaneous closure using a button or umbrella device.[167] [168] Defects less than 2 cm in diameter and with relatively firm tissue at the margins are more likely to be successfully closed, compared with large defects and those with fairly thin tissue at the margin or multiple perforations. Shunt Size.

Numerous attempts have been made to quantify the ratio of pulmonary and systemic flow in intracardiac shunt lesions, including atrial septal defect.[169] The majority of these attempts have been by calculating the instantaneous stroke volume of the pulmonary outflow tract and left ventricular outflow tract (see section on Doppler calculations). This calculation has been fairly reproducible and has correlated with hemodynamic assessment in the animal laboratory and in children. Because of the margin of error for measuring the dimension of the outflow tract, it has seen less use in adult patients. In general, the threshold for recommending closure of an atrial septal defect has diminished to a Qp/Qs (pulmonary/systemic flow ratio) of 1.5 or less. Detection of a right ventricular volume overload pattern in general denotes a shunt of at least this level, and thus the majority of detected atrial septal defects fall into the range that warrant closure. REPAIRED ATRIAL SEPTAL DEFECT.

Depending on the magnitude of the initial shunt and the age at which an atrial septal defect is repaired, the two-dimensional echocardiogram may revert to normal with respect to chamber sizes or show evidence of residual right-sided heart dilation. In

instances in which the defect was large and repaired only late, residual right ventricular dysfunction, varying degrees of pulmonary hypertension, and right ventricular hypertrophy may persist throughout adulthood. Depending on the nature of the repair technique, the atrial septum can appear anatomically normal or can reveal areas of echo density consistent with the type of patch material used. In general, the right ventricular volume overload pattern with paradoxical septal motion resolves but can be replaced by a postoperative septal motion pattern. OTHER ABNORMALITIES OF THE ATRIAL SEPTUM.

In addition to atrial septal defect anomalies such as aneurysm of the atrial septum,[170] [171] lipomatous atrial hypertrophy and patent foramen ovale[172] can be detected. The aneurysmal atrial septum is not infrequently associated with small perforations and minor degrees of either right-to-left or left-to-right atrial shunting (Fig. 7-83) . Contrast echocardiography can detect minor degrees of right-to-left shunting in both of these situations.[49] [173] ANOMALOUS PULMONARY VENOUS RETURN.

A final congenital lesion that results in a right ventricular volume overload pattern is anomalous pulmonary venous return. A variation on anomalous return is seen in patients with primum atrial septal defects who have functional anomalous return due to malalignment of the right superior pulmonary vein such that its flow is directed into the superior vena cava and right atrium. True anomalous pulmonary venous return often results in creation of a venous chamber posterior to the left atrium, which then drains to the right atrium.[174] [175] VENTRICULAR SEPTAL DEFECT.

Whereas the ventricular septal defect represents the most common congenital intracardiac shunt encountered in infants and children, it is a small percentage of those detected de novo in adults. A substantial number of small ventricular septal defects close spontaneously during childhood and thus are not present in adults, whereas the larger defects result in symptoms and are detected in childhood. Furthermore, the smaller persistent defects are associated with prominent pathological murmurs and unlikely to be confused for a flow murmur;

Figure 7-83 Apical four-chamber view recorded in a patient with an atrial septal aneurysm. Note the marked bulging of the atrial septum into the cavity of the left atrium (arrow). The right-hand panel is recorded after injection of saline contrast medium. Note the contrast medium has filled the right ventricular cavity, and there are numerous individual microbubbles seen in the cavity of both the left atrium and left ventricle, consistent with a right-to-left shunt through fenestrations in the atrial septal aneurysm. Abbreviations are as per previous figures.

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Figure 7-84 Schematic depicting the location of different ventricular septal defects compared with the different echocardiographic views. (From Feigenbaum H: Echocardiography. 5th ed. Malvern PA, Lea & Febiger, 1994.)

and, therefore, individuals come to medical attention promptly. On occasion, patients with small ventricular septal defects escape detection to adulthood, when the defects are found on the basis of a pathological murmur. Ventricular septal defects occur in several different locations, which are denoted echocardiographically in Figure 7-84 . The most common location is a small perimembranous septal defect; however, other locations, including supracristal, are not uncommonly encountered. Muscular defects can occur anywhere within the muscular septum, and small apical defects are frequently multiple. A ventricular septal defect can be visualized as a dropout of myocardial tissue with communication between the left and right ventricles.[176] The resolution of TTE, using 3and 5-MHz transducers, is such that most defects below a 3-mm size may not be directly visualized ( Fig. 7-85 ). It is uncommon to directly visualize small muscular defects that may take an angulated or serpiginous course through the ventricular septum. Color Doppler imaging over areas of the septum is a reliable means for detecting the abnormal transseptal flow.[177] [178] It is often necessary to scan in unusual and atypical planes to identify flow through the septum, especially when searching for a muscular defect. For the isolated small perimembranous defect, continuous-wave Doppler can be used to determine the velocity of flow from the left ventricle to the right ventricle and hence the transventricular pressure gradient.[179] This can then be subtracted from arm blood pressure to estimate right ventricular systolic pressure. With the use of this methodology the small restrictive ventricular septal defect can be characterized as a defect resulting in little or no chamber dilation, of small anatomical extent on two-dimensional scanning, and associated with a high transventricular gradient. Shunt Size.

The magnitude of shunting through a ventricular septal defect can be calculated using several Doppler techniques.[180] [181] Larger ventricular septal defects may be associated with substantial left-to-right shunts and development

Figure 7-85 Parasternal two-dimensional echocardiographic views in a patient with a moderate-sized perimembranous ventricular septal defect. The upper panel is recorded in a parasternal long-axis view and shows the proximal anterior septum. The lower panel is recorded in a short-axis view at the base of the heart. Note in each instance the distinct color jet arising on the left ventricular side of the ventricular septum and coursing in the right ventricular outflow tract. This is consistent with exclusive left-to-right

ventricular septal defect flow.

of secondary pulmonary hypertension. In this instance, the right ventricle will be dilated and hypertrophied. By using the tricuspid regurgitation signal, right ventricular systolic pressure can be calculated. In the presence of a ventricular septal defect it is important to look for associated anomalies of the right ventricular outflow tract and pulmonary valve. Pulmonic stenosis and right ventricular outflow tract obstruction are both protective of the pulmonary circuit and will lead to the scenario of elevated right ventricular systolic pressure with normal pulmonary artery pressures. This has obvious clinical implications with respect to surgical intervention. CLOSED AND REPAIRED VENTRICULAR SEPTAL DEFECT.

As noted earlier, many small ventricular septal defects close spontaneously in infancy and childhood. This occurs by way of two basic mechanisms. The first is adherence of a portion of the tricuspid leaflet to the ventricular septal defect. In this case, one may visualize a very thin membrane closing the actual ventricular septal defect.[182] The second mechanism appears to be growth of additional tissue from the margins of the ventricular septal defect. In this instance, there may be irregular tissue closing the ventricular septal defect, the extent of which can be highly variable. In many instances, a thin-walled aneurysm may be noted in the area of the previous ventricular septal defect. The aneurysm typically bows into the right ventricular outflow tract. A small residual left-to-right shunt may be encountered that often is of little hemodynamic significance but that may result in a murmur and pose a risk for endocarditis. TETRALOGY OF FALLOT.

Tetralogy of Fallot represents a complex of lesions including a ventricular septal defect with overriding aorta and obstruction to right ventricular outflow tract at either the infundibular or valvular level (Fig. 7-86) . The fourth component is a right-sided aortic arch. Before correction the lesion is characterized by a ventricular septal defect in which the edge of the ventricular septum is directed not at the anterior wall of the aorta but more at the aortic lumen. Varying degrees of right ventricular outflow tract obstruction including true valvular stenosis and infundibular muscular stenosis can be seen. Tetralogy of Fallot represents the most common cyanotic congenital

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Figure 7-86 Two-dimensional echocardiogram recorded in a patient with an unrepaired tetralogy of Fallot. Note the fairly large perimembranous ventricular septal defect and the overriding aorta. Because of the overriding aorta both right and left ventricular outflow is directed toward the aorta equally. Abbreviations are as per previous figures. (From Feigenbaum H: Echocardiography. 4th ed. Malvern PA,

Lea & Febiger, 1986.)

lesion to be encountered that is likely to result in survival to adulthood and, furthermore, the most common complex lesion to be encountered in the adult population after repair. Preoperatively, tetralogy of Fallot represents a broad spectrum of ventricular septal defect size and outflow tract obstruction. Postoperatively, varying degrees of residual abnormalities may be encountered, ranging from a nearly normal-appearing heart to one in which there are substantial degrees of right ventricular dysfunction and residual right ventricular outflow tract obstruction. [183] [184] Two-dimensional echocardiography and Doppler techniques can be a definitive means for following these individuals with respect to recovery of right ventricular function and development of complications such as recurrent right ventricular outflow tract obstruction and residual ventricular septal defect.[185] PULMONIC STENOSIS.

Isolated pulmonic stenosis is a relatively common congenital lesion. As with the bicuspid aortic valve, its hemodynamic severity ranges from negligible to severe and life threatening early in infancy. Because of the orientation of the proximal pulmonary artery and pulmonic valve, it is easily interrogated with Doppler. Underestimation of pulmonic valve gradients due to off-angle interrogation is uncommon. Anatomically, the stenotic pulmonary valve appears somewhat thickened and has "doming" motion (see Fig. 7-70) . On M-mode echocardiography there may be an accentuation of the pulmonic valve a wave. In adult patients it is not uncommon for valvular pulmonic stenosis to be associated with secondary infundibular hypertrophy with concurrent right ventricular outflow tract obstruction. Thus, it is important to evaluate both the subvalvular and valvular aspects of the pulmonary valve in adult patients. Less frequently, peripheral pulmonic stenosis will be encountered. Identification and characterization of the peripheral pulmonary arteries in adult populations can be quite problematic and is an area in which MRI can play an incremental and valuable role. Abnormalities of the Left Ventricular Outflow Tract

The most common abnormality of left ventricular outflow is the bicuspid aortic valve, which has been discussed previously. Additionally, both tunnel and discrete subaortic stenosis are occasionally encountered in adult patients. Tunnel aortic stenosis is visualized as a diffuse narrowing of the left ventricular outflow tract and more often is identified in children. Discrete, membranous subvalvular stenosis occasionally escapes detection until adulthood and is characterized by the presence of a thin membrane or ridge that encircles the left ventricular outflow tract (Fig. 7-87) .[186] Components of the membrane may be attached to the ventricular septum and to the anterior mitral valve leaflet. The membrane itself can be difficult to visualize from transthoracic transducer positions and may require TEE for complete visualization. The obstructing membrane results in turbulence in the left ventricular outflow tract, which can be detected with color Doppler flow imaging and eventually results in secondary pathology of the aortic valve with subsequent aortic insufficiency. M-mode echocardiography often reveals characteristic course systolic fluttering of the aortic valve leaflets. This finding can help

distinguish valvular from subvalvular obstruction. This should be contrasted to hypertrophic cardiomyopathy, in which anatomical abnormalities of the aortic valve and aortic insufficiency are uncommon. The etiology of subvalvular membranes is uncertain, and the lesion may progress from inconsequential and undetectable to significantly obstructive in adult patients. Additionally, if detected in childhood and surgically resected, there is a definite likelihood of recurrence of the lesion in adulthood. On occasion, discrete subvalvular membranes have been seen in association with spontaneously closed ventricular septal defects. Congenital Abnormalities of the Mitral Valve

Congenital abnormalities of the mitral valve, likely to be encountered in adult populations, include the previously mentioned cleft mitral valve, seen in association with a primum atrial septal defect as well as congenital mitral stenosis. The latter can occur either in the presence of a single papillary muscle, in which all chordae attach to a central point rendering an otherwise unremarkable valve functionally stenotic, or in a valve that is intrinsically stenotic

Figure 7-87 Transesophageal echocardiogram in a longitudinal plane of the left ventricular outflow tract demonstrating a small, discrete subaortic membrane (downward pointing arrow). The aortic leaflets are mildly thickened (horizontal arrows). This small membrane was not visualized from the transthoracic echocardiogram. Abbreviations are as per previous figures.

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Figure 7-88 Transthoracic echocardiogram recorded in a patient with cor triatum in the parasternal long-axis view (top) and apical views (bottom). A linear echo courses posteriorly from the area of the aorta. From the apical views the membrane can be seen to divide the left atrium into two chambers. PV = pulmonary vein; M = membrane; other abbreviations as per previous figures. (From Feigenbaum H: Echocardiography. 5th ed. Malvern, PA, Lea & Febiger, 1994.)

but with two papillary muscle attachments. Functionally, these patients will present in a manner nearly identical to that for rheumatic mitral stenosis. Awareness of the anatomical features of congenital mitral stenosis is necessary to separate it from rheumatic causes. In many instances the congenital lesion will be characterized by an obstructive but eccentrically directed mitral valve orifice without the characteristic chordal and leaflet thickening. Transvalvular gradients can be measured across the congenitally stenotic mitral valve but may require unusual transducer angulations and lines of interrogation. Cor triatriatum represents membrane within the body of the left atrium that likewise may be obstructive. TTE may suffice for identification of the membrane (Fig. 7-88) , but in

many instances TEE, which affords a more accurate view of the left atrium, is necessary.[187] [188] A final congenital abnormality of the mitral valve is the submitral ring or web. This represents a membrane attached near the mitral annulus within the left atrium that is obstructive to flow. Anomalies of the Tricuspid Valve

The most common congenital tricuspid valve anomaly to escape detection to adulthood is Ebstein anomaly. In this situation the lateral leaflet is elongated and tethered to the lateral wall of the right ventricle and the septal leaflet is relatively small and apically displaced.[189] This results in conversion of a portion of the right ventricle to an "atrialized" right ventricle (Figs. 7-89 and 7-90) . Tricuspid regurgitation is invariably present and results in dilation of the right side of the heart in general but predominantly of the right atrium and atrialized right ventricle. Atrial septal defect is a common association with Ebstein anomaly and

Figure 7-89 Schematic of the anatomical and echocardiographic abnormalities seen in Ebstein anomaly including apical displacement of the septal leaflet and elongation and tethering of the lateral leaflet. Both the functional (FRV) and atrialized right ventricle (AtRV) are noted. (From Feigenbaum H: Echocardiography. 5th ed. Malvern, PA, Lea & Febiger, 1994.)

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Figure 7-90 Two-dimensional echocardiogram recorded in a patient with Ebstein anomaly. Note the small, apically displayed septal leaflet and the elongated lateral leaflet that is tethered to the myocardium of the right ventricular lateral wall. (From Feigenbaum H: Echocardiography. 5th ed. Malvern, PA, Lea & Febiger, 1994.)

should be considered in all instances. Tricuspid regurgitation is present invariably and may provide one of the major clues to the presence of Ebstein anomaly. Because the closure of the tricuspid valve is displaced toward the apex of the right ventricle the apical location of the convergence zone of the tricuspid regurgitation jet may be one of the clues to the presence of this anomaly. Once identified, it is important to characterize several features of Ebstein anomaly that have direct relevance to the feasibility of surgical repair. Surgical repair can be undertaken in individuals with a relatively large functional right ventricle, compared with the atrialized portion, and in whom there is not extensive tethering of the lateral leaflet. This assessment can be made in a majority of patients using TTE. Tricuspid Atresia

Tricuspid atresia is usually detected in infancy but after palliation may allow survival to adulthood. In tricuspid atresia there is no functional tricuspid valve tissue, although the tricuspid annulus may be closed by a thin membrane with small perforations.[190] Because of the atretic tricuspid valve, right ventricular hypoplasia coexists. Obviously a complete form of tricuspid atresia is incompatible with life unless a concurrent atrial or ventricular septal defect is present. Persistent Ductus Arteriosus

Persistent ductus arteriosus represents persistence of the normal communication between the descending thoracic aorta and the left pulmonary artery. The size of the communication varies from 1 or 2 mm to a centimeter or more. The magnitude of left-to-right shunting is dependent on the size of the defect. Initially, persistent ductus results in a continuous left-to-right shunt at the great artery level that subsequently results in a left-sided heart volume overload early in childhood and adolescence. Because of the increased pulmonary flow, pulmonary hypertension may develop, in which case only the systolic component of the shunt persists. Echocardiographic detection of persistent ductus arteriosus is dependent on detection of left-sided heart enlargement and/or abnormal pulmonary artery flow.[191] With the use of suprasternal notch views it is occasionally possible to directly visualize the ductus (Fig. 7-91). More commonly, Doppler interrogation of the proximal pulmonary artery is the initial clue to the presence of a persistent ductus. By using either color Doppler flow imaging or pulsed Doppler one can detect continuous turbulent flow in the proximal pulmonary artery.[191] Further careful interrogation will frequently identify the origin of the abnormal flow from the descending aorta into the left main pulmonary artery.

Figure 7-91 Parasternal short-axis view at the level of the great vessels recorded in a patient with persistent ductus arteriosus. Note the dilated pulmonary artery and the abnormal color flow signal (large arrow) that originates from the area of descending thoracic aorta and flows into the pulmonary artery distal to the pulmonary valve. In this diastolic frame note the small pulmonic insufficiency jet (small white arrow). Abbreviations are as per previous figures. Coarctation of the Aorta

Narrowing or coarctation of the aorta occurs after the takeoff of the left subclavian artery. It results in reduction of systolic pressure distally and may present in adulthood as a secondary cause of systemic hypertension. The anatomical extent of coarctation may be visualized from the suprasternal notch, and continuous-flow Doppler can be used to determine the coarctation gradient.[192] There is a strong association between coarctation and bicuspid aortic valve; and whenever coarctation is discovered, efforts should be made to define the aortic valve anatomy. Transposition of the Great Arteries

Transposition refers to the situation in which there is ventricular-arterial discordance.

This is defined as a connection of the left ventricle to the pulmonary artery and the right ventricle to the aorta. There are two forms of transposition that may be encountered. D-transposition is an isolated malposition of the great vessels due to failure of the conotruncos to appropriately coil. In this situation the pulmonary artery is attached to the left ventricle, which receives blood from the left atrium. The aorta is attached to the right ventricle, which receives blood from the right atrium. This results in two parallel circulations and is obviously not compatible with life in the absence of an intracardiac shunt such as a persistent ductus or large ventricular or atrial septal defect. This lesion is invariably detected in infancy and is not encountered in adult patients in other than corrected forms. Surgical correction of transposition includes creation of an atrial septal defect early and subsequent surgical creation of a baffle that directs right atrial blood into the left ventricle and left atrial blood flow into the right ventricle. An anatomical switch of the great arteries has become the preferred surgical procedure. L-transposition occurs when there is both inversion of the ventricles and transposition of the great arteries (Fig. 7-92) .[193] In this situation, blood flows from the anatomical right atrium through an anatomical mitral valve into the anatomical left ventricle and then into the pulmonary artery. Blood returning to the left atrium flows through an anatomical tricuspid valve into an anatomical right ventricle and then to the aorta. This results in "corrected" transposition in which physiological blood flow is maintained. L-transposition is compatible with survival to the fifth or sixth decade and often is first detected in adults. In either type of transposition the great arteries no longer have the circular and crescent orientation but rather arise from the

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Figure 7-92 Transesophageal echocardiogram in an adult patient with L-transposition of the great vessels. In the top panel the connection of the anatomical right atrium to the anatomical left ventricle and the communication of the anatomical left atrium, through an anatomical tricuspid valve, into an anatomical right ventricle can be appreciated. Note the normal-appearing left atrial appendage (LAA). Note also the marked hypertrophy of the right ventricular trabeculations, which nearly obliterate the apex of the anatomical right ventricle (arrows). There is apical displacement of the atrioventricular valve contained within the anatomical right ventricle, compared with the atrioventricular (mitral) valve connecting the right atrium to the left ventricle. The lower panel depicts the parallel orientation of the pulmonary artery (PA) and aorta. The more anteriorly placed aorta is in communication with the anatomical right ventricle. Abbreviations are as per previous figures.

heart in a parallel fashion. In adult patients it can be difficult to directly visualize the parallel nature of the great vessels. Clues to the presence of congenitally "corrected" transposition include presence of a trabeculated ventricle with a more apically placed valve in a left and posterior position. L-transposition is compatible with survival into the fourth and fifth decade. After this period of time, substantial hypertrophy of the anatomical right ventricle occurs and right ventricular dysfunction is not uncommon. Regurgitation of the anatomical tricuspid valve in the systemic circuit is also quite common in adult patients.

Complex Congenital Heart Disease

The echocardiographic and clinical evaluation of complex congenital heart disease is best undertaken by individuals with specific interest and training in the area and is beyond the scope of this chapter. Three-dimensional echocardiography has been a valuable adjunct in evaluating the complex anatomy seen in complex lesions (Fig. 7-93) .[194] DISEASES OF THE PERICARDIUM (See Chap. 50.) PERICARDIAL EFFUSION.

Detection of pericardial effusion was one of the earliest utilizations of echocardiography, and modern ultrasound techniques remain the predominant diagnostic tool for detection, quantitation, and determination of the physiological significance of pericardial effusion.[195] [196] A pericardial effusion is viewed as an echo-free space surrounding the heart, most commonly seen posteriorly (Fig. 7-94) . Most clinical laboratories document the presence of pericardial effusion and quantify it as minimal, small, moderate, and large. A minimal effusion represents the 5 to 15 ml of normal pericardial fluid seen in disease-free individuals. This is most frequently noted as an echo-free space, confined to the posterior atrioventricular groove. A small pericardial effusion is defined as less than 5 mm in maximum dimension, which is visualized throughout the cardiac cycle. Moderate pericardial effusions typically are 10 to 15 mm in dimension and tend to be more circumferential. Large effusions are defined as those larger than 15 mm. Because patients are scanned in a supine or left lateral position the fluid tends to pool and to be mostly visible in the posterior aspects of the imaging planes. Numerous attempts have been made to quantify the amount of pericardial fluid but have not seen uniform acceptance.[197] The majority of laboratories use the semi-quantitative scheme noted earlier. Three-dimensional echocardiography has shown some promise for enhanced localization and quantitation of pericardial effusion.[198] The most commonly employed technique for quantifying the volume of effusion is to image the effusion in orthogonal planes and determine the intrapericardial volume using Simpson's rule. The entire cardiac silhouette can then likewise be traced and the total cardiac volume determined. The difference between the pericardial and cardiac volumes represents the volume of pericardial fluid. Although theoretically accurate, there are practical limitations to tracing both the cardiac and pericardial volumes that render this technique less than optimal and of little true clinical utility. Other aspects of a pericardial effusion also can be noted with echocardiography. The presence of soft tissue density masses, thickening of the visceral pericardium, and presence of fibrinous strands can all be identified. All of these features are more common in patients with marked inflammatory or malignant causes for pericardial effusion. Additionally, the nature of the fluid can be further characterized as clear or "cloudy." The hallmark of the benign, idiopathic effusion is a clear echo-free space, whereas malignancy, bacterial infection, and hemorrhagic effusions are more likely to

have solid components or stranding. Cardiac Tamponade.

Several echocardiographic findings are reliable indicators of elevated intrapericardial pressure, which in turn correlate with hemodynamic compromise or clinical tamponade. One of the earliest described was collapse of the right ventricular outflow tract during early diastole. This is best visualized in the parasternal views but can also be appreciated in the four-chamber view. The precise timing and duration of right ventricular collapse can best be determined with M-mode echocardiography. Cardiac tamponade occurs when pericardial effusion of sufficient magnitude has accumulated to result in equilibration of intrapericardial and passively determined intracardiac pressures. Immediately after mechanical systole the ventricle begins to relax, with a greater degree of active relaxation attributed to the left ventricle compared with the right. This results in disproportionate or favored filling of the left ventricle with a transient elevation in intrapericardial pressure. This results in early diastolic collapse of the highly compliant right ventricular outflow tract (Fig. 7-95) . Detection of transient outflow tract collapse is a reliable

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Figure 7-93 Three-dimensional echocardiogram of a patient with a ventricular septal defect, transposition, and double outlet right ventricle. Note the small right ventricular cavity and the parallel orientation of the two great vessels.

Figure 7-94 Transthoracic parasternal long-axis echocardiograms recorded in a patient with a small (top) pericardial effusion. In the top panel note the echo-free space confined to the area posterior to the heart (arrow). The bottom panel reveals a similar pattern but with a larger echo-free space. Abbreviations are as per previous figures.

marker that intrapericardial pressure is elevated and hemodynamic compromise is present. It is correlated with the presence of overt tamponade but also has been seen in patients who subsequently developed tamponade. The atrial corollary of this phenomenon is exaggerated atrial emptying. Because of elevated intrapericardial pressures, filling of the right ventricle is impeded in early diastole (a manifestation of which is early diastolic right ventricular collapse) and occurs to an exaggerated degree with atrial systole. This results in a delayed and exaggerated contraction of the right atrium with actual invagination of the atrial wall in late diastole (Fig. 7-96) . This echocardiographic sign of hemodynamic compromise is more sensitive than right ventricular diastolic collapse but less specific, because it occurs earlier in the course of intrapericardial pressure elevation. Right ventricular collapse may be absent even in the presence of elevated pericardial pressures in patients with right ventricular hypertrophy or significant pulmonary hypertension. In the presence of loculated effusion or in

complex situations, either right- or left-sided chambers may be differentially compressed.[199] [200] Doppler echocardiography can provide valuable clues as to the hemodynamic significance of pericardial effusions as well.[201] In hemodynamically significant effusions there is an exaggerated interplay between right and left ventricular filling, occurring with phases of the respiratory cycle. Clinically, this is manifest as an exaggerated pulsus paradoxus. Echocardiographically exaggerated respiratory variation can be documented by examining the left ventricular and right ventricular outflow tract flows in systole and noting exaggerated phasic variation in velocities and time velocity ventricles. Similarly, in a hemodynamically significant effusion, ventricular filling is impeded. The normal respiratory variation of the tricuspid valve is 25 percent, with a greater velocity in inspiration than expiration; and the normal mitral valve shows the opposite pattern with a variation of approximately 15 percent. In hemodynamically significant effusions there is a greater than usual variation in this respiratory pattern (Fig. 7-97) . CONSTRICTIVE PERICARDITIS.

Although chronic constrictive pericarditis remains an elusive diagnosis, echocardiography and Doppler evaluation can provide valuable clues as to its presence.[202] [203] [204] [204A] The classic form of constrictive pericarditis is calcific constrictive pericarditis after tuberculosis infection. In contemporary times, constriction

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Figure 7-95 Parasternal short-axis echocardiogram recorded in a patient with a pericardial effusion and evidence of hemodynamic compromise. A, Recorded in diastole. Note the normal shape and geometry of the right ventricular wall (RVW). B, Recorded in systole. Note that the tricuspid and pulmonic valves are both closed and that the right ventricular outflow tract has normal geometry. C, Recorded in early diastole. Note the tricuspid valve is now open and that the distal portion of the right ventricular outflow tract is compressed inward. Abbreviations are as per previous figures. (From Armstrong WF, Schilt BF, Helper DJ, et al: Diastolic collapse of the right ventricle with cardiac tamponade: An echocardiographic study. Circulation 65:1491-1496, 1982. Copyright 1982, American Heart Association.)

is more likely to be related to nontuberculous infections or hemorrhagic effusions or be secondary to trauma, cardiac surgery, or irradiation. The clinical presentation and echocardiographic appearance often vary from that classically described with calcific constriction. Numerous attempts have been made to quantify pericardial thickness using echocardiography. Routine transthoracic imaging has not been an accurate means for detecting pericardial thickening. TEE has shown more promise but has not seen clinical acceptance. Intracardiac ultrasonography does provide a high-resolution view of the pericardium but is an invasive

Figure 7-96 Apical four-chamber view recorded in a patient with a moderate pericardial effusion and evidence of hemodynamic compromise. The frame is recorded in early ventricular systole, immediately after atrial contraction. Note that the right atrial wall is indented inward and its curvature is frankly reversed (arrow), implying elevated intrapericardial pressure above right atrial pressure. Abbreviations are as per previous figures.

Figure 7-97 Pulsed-wave spectral Doppler recorded through the left ventricular outflow tract (top) and right ventricular outflow tract (bottom) in a patient with hemodynamic compromise due to pericardial effusion. Note the respirometry line on the bottom of each tracing. There is exaggerated respiratory velocity of flow in both the left ventricular and right ventricular outflow tracts. Note the reciprocal nature of the flow variation, with flow increasing during expiration and decreasing in early inspiration for the left ventricular outflow tract and the opposite pattern seen in the right ventricular outflow tract.

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Figure 7-98 Pulsed Doppler recording through the mitral valve (top) and tricuspid (bottom) in a patient with constrictive pericarditis. Note the respirometer tracing for each. There is exaggerated respiratory variation in inflow velocities in both the mitral and tricuspid valves. Note also that the deceleration time is shorter with inspiration (150 msec) than with expiration in the mitral tracing. Reciprocal changes are noted in the tricuspid valve flow patterns. (From Oh JK, Hatle LK, Seward JB, et al: Diagnostic role of Doppler echocardiography in constrictive pericarditis. J Am Coll Cardiol 23:154-162, 1994.)

procedure and has been validated in only a small number of patients. Determination of pericardial thickening is probably more accurately done with computed tomography (CT) or MRI. In the absence of direct ultrasound documentation of thickened pericardium there are indirect signs of pericardial constriction that should be evaluated in suspected cases. These include abnormalities of ventricular septal motion. The abnormalities of septal motion that occur are an exaggerated respiratory variation in septal position with marked bowing of the ventricular septum toward the left ventricle during inspiration. Additionally when viewed from the parasternal long-axis position an abnormality of septal motion is often detected. This frequently is seen as a downward motion of the ventricular septum in early systole, followed by a brief anterior motion, which can be confused with a conduction disturbance and is best detected with M-mode scanning. The Doppler hallmarks of cardiac constriction include exaggerated respiratory variation of mitral and tricuspid inflows with a pathologically elevated E to A ratio (Fig. 7-98) . Additionally, deceleration time is abnormally short and may vary to a disproportionate degree during the respiratory cycle. Examination of the IVC frequently reveals dilation. The normal multiphasic hepatic vein flow is replaced by monophasic flow, occurring predominantly in systole. The diagnosis of constrictive pericarditis in large part remains one of exclusion. From an

echocardiographic standpoint this diagnosis should be suspected in individuals with symptoms consistent with that diagnosis (i.e., edema, fatigue, and apparent low output state), normal left ventricular systolic function, and no valvular heart disease. Detection of abnormal septal motion, exaggerated respiratory variation, and an elevated E to A ratio provide the majority of the confirmatory evidence of this diagnosis. MISCELLANEOUS CONDITIONS OF THE PERICARDIUM.

Congenital absence of the pericardium occurs in both partial and complete forms. In the complete form there is a marked abnormality of septal motion with exaggerated intracardiac motion within the thorax. In the partial form, varying degrees of septal motion abnormality can be detected depending on the degree to which the pericardium is anatomically deficient. Pericardial cysts are detected as echo-free spaces adjacent to the heart. The diagnosis should probably be confirmed by CT or MRI as well. CARDIOMYOPATHIES (See Chap. 48.) Cardiomyopathies can be divided into three basic types: dilated cardiomyopathy of any etiology, hypertrophic cardiomyopathy, and restrictive cardiomyopathy. DILATED CARDIOMYOPATHY.

Irrespective of the cause of a dilated cardiomyopathy, left ventricular dilation with global systolic dysfunction is noted (Fig. 7-99) .[205] Depending on the duration of the disease, left atrial dilation likewise occurs; and if significant mitral regurgitation is present, secondary pulmonary hypertension with right-sided heart dilation is common. The range of systolic dysfunction in dilated cardiomyopathy is quite broad, and ejection fraction ranges from less than 10 percent to only mildly diminished. Although dilated cardiomyopathy is a global process, because of regional wall stress and loading conditions regional heterogeneity of function is seen.[206] Typically, the proximal portions of the inferoposterior and posterolateral walls have relatively preserved systolic function whereas the more distal walls, the ventricular septum, and apex appear more severely compromised. This pattern of wall motion may initially be confused with ischemic heart disease. The absence of frank scar or aneurysm and the absence of any truly normally functioning segments should lead the observer to appropriately make a diagnosis of nonischemic cardiomyopathy. The echocardiographic appearance of nonischemic cardiomyopathy is not dependent on its etiology, and patients with alcoholic, doxorubicin (Adriamycin)-induced, idiopathic, and postviral causes will all have a similar echocardiographic appearance. As a consequence of left ventricular dilation, the bullet-shaped geometry of the left ventricle is often distorted and the left ventricle becomes more spherical.[207] This has the effect of drawing the papillary muscles away from the mitral valve annulus and results in annular functional mitral regurgitation due to abnormal coaptation of the mitral valve (see Fig. 7-54 ). Mitral regurgitation severity may range from mild to severe; and, as a consequence, left atrial dilation to some degree is invariably present. Because of the diffuse nature of the initial insult, the right ventricle can be primarily affected with

dilation and hypokinesis and also secondarily affected due to subsequent pulmonary hypertension. Other complications of dilated cardiomyopathy that should be evaluated include presence of left ventricular thrombus and, in certain circumstances, development of left atrial thrombi. Detection of the latter requires TEE. The magnitude of secondary and pulmonary hypertension can be reliably determined from Doppler tracings of the tricuspid valve. Evaluation of diastolic properties of the left ventricle may provide valuable prognostic information.[208] [209] HYPERTROPHIC CARDIOMYOPATHY.

Hypertrophic cardiomyopathy comprises a heterogeneous disease in which there is inappropriate and pathological hypertrophy of the

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Figure 7-99 Transthoracic two-dimensional echocardiogram recorded in a patient with a dilated cardiomyopathy. The left panel is an apical four-chamber view showing dilation of all four cardiac chambers. Note that the mitral valve protrudes into the left ventricular cavity during systole consistent with papillary muscle dysfunction (arrows). There is also incomplete closure of the tricuspid valve due to annular dilation. The two right panels were recorded in a short-axis view in diastole (top) and systole (bottom). Note again the dilated right ventricle in the severe systole dysfunction with global hypokinesis of both chambers when diastolic and systolic frames are compared.

left ventricle and, less commonly, the right ventricle.[210] The classic form of hypertrophic cardiomyopathy has commonly been termed "idiopathic hypertrophic subaortic stenosis" [IHSS]. In this entity there is characteristic disproportionate hypertrophy of the ventricular septum with dynamic left ventricular outflow tract obstruction (Fig. 7-100) . Because hypertrophic cardiomyopathy is a heterogeneous disease the preferred terminology is hypertrophic cardiomyopathy, secondarily described as focal, concentric, apical, and with or without obstruction. Dynamic obstruction classically occurs in the left ventricular outflow tract. From an echocardiographic perspective it is associated with systolic anterior motion of the mitral valve. This results in development of a systolic gradient that develops in the left ventricular outflow tract over the course of systole (Fig. 7-101) .[211] [212] [213] Thus, the maximum gradient is in late systole as opposed to early or mid systole, which is characteristic of a fixed valvular or discrete obstruction. Systolic anterior motion of the mitral valve can be detected either with two-dimensional echocardiography, typically from the parasternal long-axis view, and also with M-mode echocardiography (Fig. 7-102) . Although Doppler echocardiography remains the definitive examination for detection and quantification of outflow tract obstruction, secondary evidence of outflow tract obstruction can be obtained from the M-mode echocardiogram. Systolic anterior motion of the mitral valve that actually remains in contact with the septum for 40 percent of the systolic cycle is more likely to be associated with significant hemodynamic obstruction. Additionally, the outflow tract obstruction results in a characteristic systolic notching pattern on the aortic valve that is best visualized with M-mode echocardiography.

Mitral regurgitation is common in patients with obstructive hypertrophic cardiomyopathy, and the continuous wave of Doppler spectral profile of the mitral regurgitation may occasionally be confused with outflow tract obstruction. It should be kept in mind that the mitral regurgitation velocity will peak relatively early whereas the outflow tract obstruction has a characteristic late-peaking "dagger-like" appearance. Other variants of hypertrophic cardiomyopathy include mid-cavity obstruction, in which case the maximum gradient is typically at the papillary muscle level. Other distributions of hypertrophy include nearly concentric left ventricular hypertrophy that may have no associated outflow tract obstruction. In this instance, patients can be highly symptomatic because of a relatively small left ventricular cavity with markedly elevated diastolic pressures.[214] Additionally, the small cavity, even with supernormal systolic functions, results in a low stroke volume and cardiac output. A final variant of hypertrophic cardiomyopathy is the apical variant, which is more common in Asian populations.[215] Deep T wave inversions across the precordium are seen in this variant. By definition it is not obstructive. Two-dimensional echocardiography and Doppler imaging can be used to follow the status of outflow tract gradients at rest or exercise and after either drug, surgical, or, more recently, transcutaneous ablative therapy.[216] A reduction in both the outflow tract gradient and the severity of mitral regurgitation can be documented after successful therapy. On occasion, patients present with what appears to be a "burned-out" hypertrophic cardiomyopathy. In this instance, unexplained pathological hypertrophy is present with a relatively normal-sized left ventricle that is diffusely hypokinetic. Frequently, systolic function has deteriorated to the point that there is no longer an outflow tract gradient. Any of the forms of hypertrophic cardiomyopathy can result in long-standing elevation of diastolic pressure and secondary pulmonary hypertension. RESTRICTIVE AND INFILTRATIVE CARDIOMYOPATHY.

Restrictive cardiomyopathies are a family of diseases in which systolic function is relatively preserved until very

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Figure 7-100 Parasternal long-axis views recorded in a patient with a hypertrophic cardiomyopathy. The top panel is diastole and the bottom panel is systole. (Note this image has been recorded in tissue harmonic imaging and therefore myocardial signatures and brightness are increased. No assumptions regarding tissue characterization should be made from a tissue harmonic image.) In the top panel note the marked thickening of the ventricular septum (white arrows), which measures approximately 3 cm in thickness. The posterior wall was only mildly hypertrophied. The bottom panel was recorded in systole, and systolic anterior motion of the mitral valve (arrow) is clearly seen.

late stages but ventricular myocardium is pathologically stiff, leading to chronic elevation

of diastolic pressure. Symptoms result because of the elevated diastolic pressures. By definition, obstruction is not present, nor is there a primary cause for abnormal myocardial relaxation. The most common form of restrictive cardiomyopathy is the idiopathic restrictive cardiomyopathy in which both atria are dilated, wall thickness tends to be at the upper normal or mildly hypertrophied, systolic function is within normal limits or only mildly depressed, and there is Doppler evidence of abnormal ventricular relaxation. Typically, this is manifest as an elevated E to A ratio without exaggerated respiratory variation. Other causes of restrictive physiology include infiltrative cardiomyopathies, the most common of which is cardiac amyloidosis. Other rarer etiologies include the glycogen storage diseases[217] and association with other systemic diseases.[218] Cardiac amyloidosis may present as either a primary or a secondary entity and is often associated with amyloid deposits in other organs. Amyloid deposition in the myocardium results in hypertrophy in the absence of hypertension and abnormal myocardial texture, which is noted as a bright "speckling" appearance (Fig. 7-103) .[219] Caution is advised when using second harmonic imaging because this type of instrumentation leads to the appearance of an abnormal myocardial signature as well. There is often evidence of diastolic dysfunction.[220] In the early phases a reduced E to A ratio with a flat deceleration slope is seen. Later, an elevated E to A ratio occurs, associated with a short deceleration time. This pattern has been associated with a worse prognosis. In advanced amyloid, virtually all cardiac structures, including valve leaflets, are involved. In late phases, systolic dysfunction is seen. DISTINCTION OF RESTRICTIVE AND CONSTRICTIVE PHYSIOLOGY.

The distinction between constrictive pericarditis and a restrictive cardiomyopathy is often clinically problematic. Echocardiography can play several valuable roles in this clinical situation. The first is in the exclusion of primary valvular disease, left ventricular dysfunction, and pulmonary hypertension, which may have resulted in the clinical presentation. Typically, patients in whom this dilemma arises have preserved right and left ventricular

Figure 7-101 Continuous-wave Doppler recorded from the apex of the left ventricle with the interrogation being directed through the left ventricular outflow tract in a patient with an obstructive hypertrophic cardiomyopathy. Note the late peaking systolic gradient with a peak velocity of approximately 3.8 m/sec (corresponding to a peak pressure gradient of 58 mm Hg. Additionally (small arrow), there is evidence of presystolic forward flow in the left ventricular outflow tract, following atrial systole. This is consistent with a hypertrophied and noncompliant ventricle in which atrial contraction results in presystolic flow in the outflow tract.

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Figure 7-102 M-mode echocardiogram recorded in the same patient depicted in Figure 7-100 . Note the markedly thickened ventricular septum. The mitral valve as seen directly below the ventricular septum and the E and A waves in diastole are noted. Note in systole there is anterior motion of the mitral valve (black/white arrow).

systolic function with signs and symptoms of biventricular heart failure. Other than detection of cardiac amyloid or patients in whom there are classic findings of constriction, the separation of these two entities relies heavily on Doppler echocardiography. In both cases the E to A ratio is elevated, but in constriction there is a greater than usual respiratory variation in inflow velocities.[221] [222] Deceleration time is short in both but varies to a greater degree in restrictive than in constrictive processes. Examination of pulmonary and hepatic vein flow can be helpful as well. In both instances vein flow is monophasic, but in restriction there is a greater degree of flow reversal in late diastole coincident with inspiration.[223] Newer techniques such as Doppler tissue imaging to interrogate the velocity of myocardial relaxation can also play a role.[224] Most patients with restrictive disease have delayed relaxation and delayed motion of the annulus compared with patients with constrictive pericarditis. The diagnosis of constrictive pericarditis and its separation from restrictive diseases remains problematic even in experienced hands, and many atypical cases of each process exist. Both processes can also coexist, and this combination is not uncommon after radiation therapy, in which there may be a constrictive component in the pericardium but a restrictive component to the right ventricle due to radiation injury. ISCHEMIC HEART DISEASE (See Chaps. 35 , 36 , and 37 .) BASIC PRINCIPLES.

Myocardial ischemia and infarction result in regional disturbances of ventricular contraction. After acute reduction in coronary flow, both diastolic[225] and systolic dysfunction occur. Normal systolic contraction consists of both myocardial thickening and inward motion of the endocardium (see Figs. 7-3 and 7-5) . Immediately after the onset of ischemia, myocardial thickening ceases and, depending on the size of the anatomical area and the severity of ischemia, the wall can become frankly dyskinetic (Figs. 7-104 and 7-105) . If blood flow is not restored, myocardial necrosis results and the wall motion abnormality becomes fixed. Over a period of approximately 6 weeks, actual tissue loss occurs and there is replacement by fibrous tissue and a scar forms. MYOCARDIAL INFARCTION.

As noted earlier, myocardial necrosis, once established, results in a permanent wall motion abnormality. The degree of transmural involvement required before wall motion becomes abnormal is approximately 20 percent.[226] The implication of this is that non-Q-wave myocardial infarction will result in hypokinesis or akinesis of the wall even though the majority of the myocardial mass may still be perfused and viable. A tethering effect of nontransmural infarction or ischemia results in dysfunction of the entire wall thickness. Because the balance of the myocardium is intrinsically normal, it is capable of overriding this effect during either pharmacological stimulation or stress, therefore resulting in substantial cardiovascular reserve in segments that may be akinetic at rest.

The regional wall motion score is directly related to the size of the myocardial infarction; however, because of the tethering phenomenon, wall motion abnormalities overestimate the true anatomical extent. Tethering occurs in several different forms. The most common occurs in substantial size myocardial infarction where the infarcted area may be frankly dyskinetic. During systole the dyskinetic segment drags the normal myocardium outward. Thus, this normal myocardium, which intrinsically has the capacity to contract, is tethered to the abnormal myocardium and is functionally abnormal. The opposite phenomenon can occur in relatively small infarctions where, during cardiovascular stress, the normal healthy adjacent myocardium contracts more vigorously and drags the abnormal segment with it, thus masking the

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Figure 7-103 Two-dimensional echocardiogram recorded in a patient with cardiac amyloid. In both the parasternal long-axis view (top) and short-axis view (bottom) note the homogeneous echo intensity of the myocardium. Both the mitral and aortic valves are also thickened. In real time the myocardium takes on a speckled appearance.

wall motion abnormality. A final form of tethering is "vertical" tethering in which ischemic or infarcted subendocardial layers exert a disproportion of effect on overall myocardial contractility. Because only 20 percent of the myocardium needs to be involved in the ischemic or infarction process for the entire wall to become dysfunctional, nontransmural (non-Q-wave myocardial infarction) results in a wall motion abnormality that is indistinguishable from that of transmural infarction. Depending on the location and size of the necrotic area, ventricular remodeling will also occur. Remodeling takes several forms and ranges from formation of a frank aneurysm (Fig. 7-106) to progressive left ventricular dilation. Echocardiographically, an aneurysm is defined as a noncontracting area of myocardium with abnormal geometry in both diastole and systole. In clinical echocardiography a regional wall motion abnormality, conforming to a known coronary distribution, is the hallmark of acute ischemia or myocardial infarction. Detection of a wall motion abnormality with echocardiography can be a valuable adjunct in the diagnosis of ischemia in patients who are presenting with chest pain. After successful reperfusion, wall motion abnormalities typically will resolve. The time course over which the resolve occurs is variable and may range from 12 hours to 2 weeks. Typically, wall motion abnormalities recover within 72 hours if blood flow has been restored in a timely fashion.[227] At the time of presentation with acute myocardial infarction there are several echocardiographic findings that relate to patient prognosis. As with all imaging techniques, the greater the degree of left ventricular dysfunction, the greater the

likelihood of complications such as development of heart failure and death.[228] [229] The size of the myocardial infarction can be approximated with echocardiography by calculating a wall motion score or by calculation of an ejection fraction. Both of these values can be tracked over time to determine the status of recovery. Evaluation of the mitral valve inflow with Doppler echocardiography provides valuable prognostic information as well.[230] [231] Because myocardial ischemia causes immediate diastolic abnormalities, mitral valve inflow patterns become abnormal

Figure 7-104 Transthoracic echocardiogram recorded in a patient with an acute anterior septal myocardial infarction in a parasternal long-axis view. Note the dyskinesis of the anterior septum (upward arrows) when diastolic (top) and systolic (bottom) frames are compared. Downward arrow indicates normal septum movement.

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Figure 7-105 Two-dimensional echocardiogram recorded in a patient with an inferior myocardial infarction complicated by right ventricular infarction. The two left panels are parasternal short-axis views recorded at the level of the papillary muscles. The top left panel is recorded in diastole. Note the full-thickness myocardium and the circular geometry of the left ventricle. In systole (bottom panel) the inferior wall (arrows) becomes frankly dyskinetic and fails to show normal systolic thickening whereas the remaining walls thickened appropriately and moved inward. The right panel is an apical four-chamber view demonstrating a dilated right ventricle that is globally hypokinetic in real time. This is consistent with right ventricular involvement.

early in the course of myocardial infarction. One may anticipate an abnormal (typically reduced) E to A ratio in myocardial ischemia. With more substantial areas of ischemia and greater degrees of diastolic dysfunction, an increased E to A ratio, suggesting restrictive physiology, may be seen. The latter is of more ominous prognostic significance. COMPLICATIONS OF MYOCARDIAL INFARCTION.

Table 7-3 outlines the complications of myocardial infarction

Figure 7-106 Apical two-chamber view of a patient with an inferior myocardial infarction. The proximal third of the inferior wall is thin, with distorted geometry consistent with a basilar aneurysm. The right panel was recorded in systole, and this area can be seen to bulge further compared with the remaining ventricular walls, which contract normally. Abbreviations are as per previous figures.

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Figure 7-107 Apical four-chamber views recorded in two different patients with anterior infarct and left ventricular thrombus. The top panel denotes a large laminar thrombus filling a substantial portion of the apex and adherent to the ventricular septum (arrows). The bottom panel denotes a smaller, more spherical thrombus in the apex of the patient with a more limited apical myocardial infarction (arrows). Abbreviations are as per previous figures.

that can be reliably detected using two-dimensional echocardiography. Virtually all mechanical complications are accurately identified. Left ventricular thrombi may form in the first 24 hours after myocardial infarction and are most commonly seen in anterior infarctions with large areas of apical dyskinesis.[232] [233] They are far less common in inferior wall myocardial infarction. Thrombi can present either as laminar, pedunculated, or mobile masses (Fig. 7-107) . There is a substantially greater likelihood of subsequent embolization in mobile and pedunculated thrombi than in sessile and laminar thrombi. Infarct expansion is defined as progressive dilation of the infarct zone without recurrent myocardial necrosis.[234] [235] This can occur either acutely, after myocardial infarction, in which case it can be confused with reinfarction, or more chronically over the first 3 to 6 months. When infarct expansion occurs acutely it is seen in the substrate of necrotic and highly friable myocardium. Acute infarct expansion presents as an aneurysm appearing in the first 72 hours, is the anatomical precursor of free wall rupture and ventricular septal defect, and carries a grave prognosis. Chronic infarct expansion occurs over several months, and the likelihood of mechanical complications is low. It does result in tethering of normal walls and progressive chamber dilation with reduction in overall systolic performance. It has been linked to development of both arrhythmias and progressive congestive heart failure. Pericardial effusion occurs in approximately 40 percent of patients with transmural myocardial infarction. It is often asymptomatic and detected only with echocardiographic scanning. A pericardial effusion occurring in the presence of acute infarct expansion is far more worrisome and may be one of the earlier signs of partial myocardial rupture. MYOCARDIAL RUPTURE.

The myocardium can rupture in one of three locations. In each case, infarct expansion usually precedes rupture. Free wall rupture complicates approximately 3 percent of acute myocardial infarction and is usually not a survivable event. Clinically, these patients present with recurrent pain and rapidly develop pericardial effusion and tamponade, and death results. In rare instances, echocardiography has been used to document the presence of free wall rupture and allow emergency corrective surgery.[236] A pseudoaneurysm forms when a partial rupture spontaneously seals off, resulting in an extra cardiac chamber the walls of which consist of pericardium and thrombus. It

typically connects to the left ventricle with a narrow mouth, distinguishing it from a true aneurysm, which communicates with the left ventricular cavity by way of a wide opening.[237] [238] Rupture of either a papillary muscle or the ventricular septum results in signs and symptoms of heart failure and a prominent holosystolic murmur, owing to acute mitral regurgitation or ventricular septal defect ( (Figs. 7-108 ). Two-dimensional echocardiography is a highly accurate technique for separating the two entities.[239] [240] Because of the critically ill nature of these individuals, many of them are intubated and TEE may be necessary to establish a diagnosis. Once the diagnosis is established, the degree of mechanical disruption can be determined. Additionally, echocardiography can be used to assess left and right TABLE 7-3 -- COMPLICATIONS OF MYOCARDIAL INFARCTION DETECTED BY ECHOCARDIOGRAPHY EARLY Pericardial effusion Infarct expansion Thrombus formation Myocardial rupture Free wall Ventricular septal defect Papillary muscle Functional mitral regurgitation Right ventricular infarction LATE Infarct expansion Left ventricular aneurysm Left ventricular thrombus Pericardial effusion Functional mitral regurgitation

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Figure 7-108 Apical four-chamber view recorded in a patient with acute anteroapical myocardial infarction and an infarct-related septal defect. Note the color flow, traversing the apical portion of the

septum and due to the ventricular septal defect. Abbreviations are as per previous figures.

ventricular function. Both of these are critical components of risk assessment when planning surgical intervention. Ventricular septal defect with concurrent right ventricular dysfunction carries a substantially greater mortality and morbidity. RIGHT VENTRICULAR INFARCTION.

Some degree of right ventricular dysfunction accompanies a large proportion of patients with inferior infarction due to occlusion of the proximal right coronary artery. Both systolic and diastolic dysfunction occur, and variable degrees of tricuspid regurgitation are common. Depending on which right ventricular branches are involved, the right ventricular wall motion or abnormality can be either apical or more laterally located. Frequently, all that is noted is right ventricular dilation with fairly uniform hypokinesis of the right ventricle.[241] In many instances, right ventricular ischemia is a transient phenomenon and recovery is anticipated. An additional complication of right ventricular infarction is the opening of a patent foramen ovale with subsequent right-to-left shunting. Shunts of significant size can result in arterial oxygen desaturation. The presence of a right-to-left shunt can be reliably documented with saline contrast echocardiography. In patients with severe multivessel disease, an ischemic cardiomyopathy can develop. This term refers to diffuse global left ventricular systolic dysfunction as a consequence of severe, multivessel coronary artery disease. In many instances there have been multiple unrecognized acute myocardial infarctions. This type of cardiomyopathy presents as a nearly globally hypokinetic ventricle, often with patchy areas of wall thinning but without distinct aneurysm. Secondary mitral regurgitation is common and is due to papillary muscle dysfunction and dilation of the mitral valve annulus. MYOCARDIAL STUNNING AND HIBERNATION.

There are two phenomena that result in potentially reversible myocardial dysfunction.[242] [243] [244] The first of these is myocardial stunning, which occurs after a severe acute ischemic insult. In this scenario, flow is restored and there is no myocardial necrosis. The exact physiological causes of myocardial stunning are not fully understood, but the syndrome results in spontaneous recovery of myocardial function after restitution of blood flow. Typically, myocardial function recovers in 1 to 7 days. Echocardiography can be used to track recovery of function in this syndrome, and dobutamine stress echocardiography is an excellent means of predicting viability. Myocardial hibernation is a similar phenomenon seen in a chronic situation.[245] [246] In this situation there is no identifiable recent acute event but diffuse myocardial dysfunction is seen in the presence of normal or near-normal resting blood flow. In many instances what has been termed "myocardial hibernation" may actually represent repetitive stunning. In this scenario, functional recovery of the myocardium occurs after successful revascularization. As in stunning, dobutamine stress echocardiography is an

excellent means for detecting hibernating myocardium. STRESS ECHOCARDIOGRAPHY.

Stress echocardiography is a family of examinations in which two-dimensional echocardiographic monitoring is undertaken before, during, and after cardiovascular stress. It has been shown to be a cost-effective means for evaluating patients presenting with chest pain. The form of cardiovascular stress can include exercise with treadmill[247] [248] [249] [250] [251] [252] [252A] or bicycle ergometry.[253] [254] [255] [256] By evaluating wall motion at rest and then comparing myocardial performance at stress, one obtains indicators of inducible ischemia that can be assigned to specific coronary territory (Figs. 7-18 and 7-109) . Although treadmill exercise is often more familiar to patients, it is limited by the need to image only at rest and after exercise. It is not possible to successfully image an upright walking individual. Bicycle exercise provides the opportunity to image at each sequential stage of stress, and therefore peak exercise images are available. For patients incapable of physical exercise, pharmacological stress, most commonly employing a dobutamine infusion, can be used.[251] [257] [258] [259] [260] [261] [262] [262A] [262B] [262C] These protocols typically rely on an incremental infusion protocol of 10, 20, 30, and 40 mug/kg/min, augmented by atropine to obtain an adequate heart rate when necessary. Images can be obtained at each stage of dobutamine infusion. Patients with significant obstructive coronary disease develop regional wall motion abnormalities identical to those seen during physical stress. The safety record of dobutamine has been excellent,[262D] and its accuracy appears equivalent to that of exercise echocardiography. An alternative to dobutamine is dipyridamole infusion, which relies on provocation of ischemia by differential vasodilation in normal and descended arteries.[263] [264] All of the different exercise echocardiography modalities have been validated against coronary arteriography as a standard and appear to have accuracy equivalent to the competing radionuclide procedures (Table 7-4) . In general, the sensitivity of thallium scintigraphy tends to be slightly higher than that of exercise echocardiography, whereas the specificity of exercise echocardiography typically has been higher than that of thallium. As with all other forms of cardiovascular stress, exercise echocardiography has distinct advantages and disadvantages. Even in experienced laboratories there may be a 5 percent failure rate due to suboptimal imaging and patients in whom adequate levels of cardiovascular stress have not been obtained will not have positive studies, even in the presence of coronary disease. The clinical utility and value of stress echocardiography has been specifically evaluated in female populations. In female populations it appears to be an effective clinical tool for diagnosis and prognosis, however with a slightly lower overall accuracy than seen in male patients.[265] [266] In addition to the diagnosis of coronary disease, stress echocardiography has been used extensively for determining patient prognosis in general populations[267] [268] [269] [270] [270A] and after myocardial infarction[271] [272] [273] as well as in tracking results of percutaneous interventions.[274] It plays a major role in determining myocardial viability in suspected stunning or hibernation.[275] [276] [276A] [276B] [276C] [276D] [276E] [276F] Dobutamine stress echocardiography has seen substantial success in determining preoperative risk

assessment in patients undergoing noncardiac surgery. Its accuracy for predicting cardiac events of myocardial infarction and death before major vascular surgery exceeds that of competing thallium scintigraphic techniques.[277] MYOCARDIAL CONTRAST ECHOCARDIOGRAPHY.

This technique relies on use of newly developed contrast agents.[278] [279] [280] [280A] These agents, once injected into the circulation, perfuse the myocardium in a manner parallel to red blood cells. This technique should be considered investigational and still in evolution at this point, but it has shown tremendous promise for detection of coronary stenosis. Multiple technologies are under development for detection of contrast medium within the myocardium, no one of which has been uniformly accepted. Technologies to detect contrast in the myocardium have included routine gray scale imaging, power Doppler imaging,[280B] second harmonic imaging, and pulse inversion imaging, and numerous others are being developed. It may also be necessary to compare perfused and nonperfused frames by using the ultrasound instrument itself to destroy contrast in the myocardium, thereby allowing creation of baseline frames immediately adjacent to perfused frames ( (Figs. 7-110 ). Demonstration of myocardial perfusion with contrast echocardiography has

214

Figure 7-109 Exercise echocardiogram recorded in a patient with a disease of the right coronary artery. The two left panels were recorded at rest and the two right panels immediately after treadmill exercise; the top panels show diastole and the bottom panels show systole. In each panel the arrows note the location of the inferior wall endocardium at end diastole. At rest there is appropriate thickening and inward motion of the inferior wall that can be seen to move inward through the body of the arrows. Immediately after exercise the proximal inferior wall (lower two arrows) becomes frankly dyskinetic and the mid and diastole portion of the inferior wall is akinetic. Note that there is no incursion of the endocardium into the previously placed arrows.

also been suggested as a means of detecting myocardial viability. DIRECT VISUALIZATION OF CORONARY ARTERIES.

Using high-frequency transducers, it is possible to directly visualize the proximal portions of the left main and right coronary arteries (Fig. 7-111) .[281] [282] [283] [284] This can be done to identify their takeoff and to exclude anomalous origin of a coronary artery. With scrupulous attention to detail one can visually characterize the wall of the left main and proximal left interior descending coronary artery and detect areas of atherosclerotic involvement and calcification. Detection of calcification within the proximal left anterior descending TABLE 7-4 -- ACCURACY OF STRESS ECHOCARDIOGRAPHY FOR DETECTION OF CORONARY ARTERY DISEASE

STRESS

NO. OF PATIENTS

SENSITIVITY SPECIFICITY %

No.

%

No.

Armstrong, et al.[247]

TME

123

88

Crouse, et al.[248]

TME

228

97

170/175

64

34/35

Marwick, et al.[249]

TME

150

84

96/114

86

31/36

TME

150

83

50/60

62

56/90

TME

136

88

105/119

82

14/17

TME

112

74

64/86

88

22/26

Bike

309

91

193/211

77

76/98

Cohen, et al.

Bike

52

78

29/37

87

13/15

Hecht, et al.[255]

Bike

180

93

127/137

86

37/43

Luotolahti, et al.[256]

Bike

118

93

101/108

70

7/10

Marwick, et al.[259]

DSE

217

72

102/142

83

62/75

Ling, et al.

DSE

183

93

151/162

62

13/21

Marcovitz and Armstrong[261]

DSE

141

96

105/109

66

21/32

Beleslin, et al.[251]

DSE

136

82

98/119

77

13/17

Takeuchi, et al.[262]

DSE

120

85

63/74

93

43/46

[250]

Roger, et al.

Beleslin, et al.

[251]

Quinones, et al.[252] Ryan, et al.

[253] [254]

[260]

86

DSE = dobutamine stress echocardiography; TME = treadmill exercise.

215

Figure 7-110 Transthoracic two-dimensional echocardiogram recorded after intravenous injection of a perfluorocarbon-based contrast agent. A fill-destruction technique has been used in which the ventricular myocardium can be seen to be opacified by the contrast agent in the left panel. After sequential ultrasound pulses contrast medium is destroyed; the nonenhanced frame appears on the right. There is homogeneous opacification of the entire ventricular myocardium in this normal example.

coronary artery appears to be a potentially reliable marker that significant obstructive coronary artery disease is present. Proximal coronary artery aneurysms can also be detected in children with Kawasaki disease.[285] Either from the transesophageal or transthoracic approach it is also possible to place a Doppler sample volume in the coronary artery lumen and to quantify phasic flow in the coronary artery. [286] [287] It is also possible to use Doppler echocardiography to determine the velocity of flow in the coronary sinus. This can be done both under basal conditions and after vasodilation.

DISEASES OF THE AORTA (See Chap. 40.) Transthoracic echocardiography visualizes the proximal 3 to 5 cm of the ascending aorta and portions of the descending thoracic aorta behind the left atrium from parasternal positions. In the majority of patients a substantial portion of the aortic arch can be visualized from the suprasternal transducer position. The sensitivity for detecting aortic disease is relatively poor from the transthoracic approach. If disease of the aorta is suspected, TEE is necessary. TEE provides a high-resolution view of the ascending aorta and descending thoracic aorta as far as the gastroesophageal junction but does not visualize the abdominal aorta. Additionally, there is a very limited area of the aortic arch that may be suboptimally viewed. In many centers, TEE has become the preferred and standard examination for evaluation of patients with suspected aortic disease. AORTIC DISSECTION.

Acute aortic dissection is a life-threatening disease requiring emergent surgical intervention. TTE can be used for early screening and is valuable for detecting the presence of aortic dilation, secondary aortic insufficiency, and left ventricular function. Its accuracy for actual detection of the aortic dissection flap and determining its extent is not adequate as a stand-alone technique. TEE has proven to be a highly accurate and reliable technique for diagnosing and excluding aortic dissection, determining its extent, identification of communication points, and assessment of the severity of aortic insufficiency, and obviously determining complications such as rupture and adventitial hematoma. The accuracy for detection of acute aortic dissection is equivalent to that of CT and MRI (Table 7-5) .[288] [289] [290] [291] [292] [293] [294] [295] [296] [297] [298] Aortic dissection is classified by several schemes, all of which are designed to distinguish dissection of ascending aorta from that confined to the descending thoracic aorta. A dissection flap appears as a linear echo within the lumen of the aorta (Fig. 7-112) . In patients with connective tissue disease and relatively nonatherosclerotic aortas, the intimal flap is frequently highly mobile. It may take a spiral course as it courses through the descending thoracic aorta. More chronic dissections appear as a linear echo dividing the aorta into two or more lumens. In this instance the intimal flap may appear more rigid and less mobile than in the acute setting. In acute dissection of the ascending aorta,

Figure 7-111 Transthoracic echocardiogram of the left coronary artery. The left main (LM), left anterior descending (LAD), and a proximal portion of the circumflex (CX) coronary artery are clearly visualized.

dilation of the ascending aorta is seen in virtually all instances. Other echocardiographic findings of acute aortic dissection include presence of pleural effusion and of adventitial hematoma, which appears as a homogeneous echo-dense mass outside the wall of the aorta tracking along its course.

Specific cardiac features to be noted in aortic dissection include the presence or absence of pericardial effusion and of aortic insufficiency. Aortic insufficiency can be due either to annular dilation with abnormal coaptation, direct extension of the dissection into the annulus, disrupting the support for the aortic valve, or, less commonly, prolapse of a portion of the intimal flap through the aorta, resulting in a conduit for insufficiency.[298A] AORTIC ANEURYSM.

Aneurysm of the ascending aorta, arch, and descending thoracic aorta can be diagnosed and characterized with TEE.[298] Characteristics of the aneurysm as fusiform or discrete and the extent of atherosclerotic involvement and secondary thrombus formation can all be determined. Because thoracic aneurysm without dissection is a chronic process requiring serial evaluation, most centers rely more heavily on CT or MRI for elective follow-up of chronic thoracic aortic aneurysms. ATHEROSCLEROTIC DISEASE.

The transesophageal echocardiogram is an excellent tool for determining the extent and nature of atherosclerotic involvement of the thoracic aorta (Fig. 7-113) . Atherosclerotic disease can be characterized as focal or diffuse and further characterized as mild, moderate, and severe. Complex and mobile components likewise can be noted and have relevance for embolic phenomena.[299] [300] [300A] [300B] [300C] The phenomenon of intramural hematoma has recently received much attention.[301] [302] Intramural hematoma occurs in the setting of underlying atherosclerotic disease and results in spontaneous rupture and lysis in the medial layers TABLE 7-5 -- ACCURACY OF TRANSESOPHAGEAL ECHOCARDIOGRAPHY FOR DETECTION OF AORTIC DISSECTION AUTHOR YEAR NO. OF WITH SENSITIVITY SPECIFICITY PATIENTS DISSECTION Erbel, et al.[289]

1989

164

82

81/82 (99%)

80/82 (98%)

Hashimoto, et al.[294]

1989

22

22

22/22 (100%)

N/A

Ballal, et al.[292]

1991

61

34

33/34 (97%) 27/27 (100%)

Nienaber, et al.[293]

1993

110

44

43/44 (98%)

216

20/26 (77%)

Figure 7-112 Transesophageal echocardiogram recorded in a patient with an acute type A dissection of the aorta. The top panel is a longitudinal view of the ascending aorta. Note the dilation of the proximal aorta and the thin linear echo present in both in the lumen of the aorta, a portion of which prolapses through the aortic valve into the left ventricular outflow tract (arrows). The white arrowheads denote the actual margins of the aortic annulus. The bottom panel is recorded in a view orthogonal to the upper panel and reveals the external diameter of the aorta (black arrowheads) as well as the open three leaflet aortic valve (small white arrows). Within the actual orifice of the aortic valve is a portion of the dissection tear (large white arrow). Abbreviations are as per previous figures.

of the aorta. The syndrome of acute intramural hemorrhage is virtually identical to acute dissection from the standpoint of clinical presentation. Intramural hemorrhage may be a focal process resulting in local breakdown in the medial layers with ulcer formation or can result in creation of a dissection plane through the media. In this instance, rather than seeing a thin intimal flap due to classic dissection a heavily diseased atherosclerotic aorta is seen with a dissection plane through the diseased medial tissue. MARFAN SYNDROME AND DISEASE OF THE PROXIMAL AORTA.

Marfan syndrome is a heritable disorder of connective tissue that results in abnormalities in the proximal aorta. The underlying pathology is cystic medial necrosis, which results in characteristic dilation of the proximal aorta, most prominent in the sinuses of Valsalva. There is secondary effacement of the sinotubular junction and dilation of the ascending aorta. Because the predominant area of dilation is in the proximal aorta, TTE often suffices for screening in these patients (Fig. 7-114) . Complications of the aortic process in Marfan syndrome include progressive dilation with secondary aortic insufficiency and development of aortic dissection. Echocardiography has seen tremendous success in the serial evaluation of these individuals and in the timing of elective surgery.[303] [304] SINUS OF VALSALVA ANEURYSM.

In addition to the characteristic symmetrical dilation seen in Marfan syndrome, aneurysms can arise in the sinus of Valsalva. These range from relatively small and discrete to large "windsock" aneurysms that protrude into the right ventricular outflow tract.[305] [306] On occasion, rupture occurs, leading to a continuous shunt from the aorta into the downstream chamber. The most common site for a sinus of Valsalva aneurysm to rupture is into the right atrium or the right ventricular outflow tract. In this instance, remnants of the aneurysm can be seen prolapsing into the right ventricular outflow tract and high velocity turbulent flow is noted in the downstream chamber. Because of the rupture, coarse fluttering of the right coronary cusp of the aortic valve may be noted. CARDIAC MASSES (See Chap. 49.) CARDIAC TUMORS.

Echocardiography is the primary screening tool for patients with known or suspected intracardiac tumors.[307] [308] Cardiac tumors can be divided into those that are primary to

the heart and those that are secondary or metastatic. They can be further divided into benign and malignant types. ATRIAL MYXOMA.

The most common benign primary tumor of the heart is the atrial myxoma. Approximately 75 percent of atrial myxomas are isolated, pedunculated tumors in the left atrium attached to the area of the foramen ovale by a stalk (Fig. 7-115) . Less common locations include the right atrium, either ventricle, or pulmonary vein or vena cava. The classic left atrial myxoma is a smooth, relatively homogeneously echo-dense mass with substantial mobility.[309] It moves into the orifice of the mitral valve in diastole and prolapses back into the left atrium in systole. Depending on its size, it may result in functional obstruction of the mitral valve, thereby mimicking mitral stenosis. Concurrent mitral regurgitation is not uncommon. In the presence of a typical appearance of a myxoma, the diagnosis is virtually certain from an echocardiographic standpoint and no further evaluation may be necessary. Because of the tendency to cause obstruction of the mitral valve, secondary pulmonary hypertension can occur. Additionally, emboli from the surface of the myxoma are not uncommon. OTHER PRIMARY CARDIAC TUMORS.

Cardiac lipomas are benign primary cardiac tumors with a broad range of appearance. They are most common in the body of the left ventricle and occasionally may be present as pedunculated masses.[310] Although unlikely to embolize, they can be associated with superimposed thrombus, which can embolize. Echocardiography is useful for identification of the mass but is unable to precisely identify it as lipomatous tissue. MRI has substantially succeeded in tissue characterization of these masses. PAPILLOMA.

Benign papillomas occasionally occur on valvular structures. These appear as homogeneous, usually spherical masses, typically less than 1 cm in diameter. They may appear on the mitral valve chordae and occasionally

217

Figure 7-113 Transesophageal echocardiograms recorded in three different patients, visualizing the descending thoracic aorta. The upper left panel is recorded in a normal, disease-free aorta. Notice the circular geometry and the lack of any thickening or irregularity in the wall of the aorta. The top right panel was recorded in a patient with a large descending thoracic aortic aneurysm measuring approximately 6 cm in its greatest dimension. Note the substantial atherosclerosis present as well as the vague, smokelike echoes in the lumen of the aorta representing stagnant blood. There is also a lucency posterior to the wall representing spontaneous intramural hemorrhage. The lower two panels were recorded in a patient with moderately severe atherosclerotic disease of the thoracic aorta. The panel on the left was recorded in the transverse view of the aorta. Note the irregular contour of the lumen, which is due to

atherosclerotic involvement of the wall. The panel on the right was recorded at the same level of the aorta but in a longitudinal projection. The upper pointing arrows denote the outer wall of the aorta. Note the irregularity in the aortic lumen and the protruding atheroma (arrows).

Figure 7-114 Transthoracic echocardiogram in a patient with Marfan syndrome. Note the marked dilation of the sinuses of proximal aorta (arrow).

on the aortic valve. As with other cardiac tumors, they have been associated with emboli. The main differential diagnosis is between benign papilloma and vegetation. CARDIAC MALIGNANCIES.

The majority of cardiac malignancies represent metastatic disease, most commonly from breast, esophagus, or lung. Diffuse malignancy, such as lymphoma, can also involve the heart either primarily or secondarily. Metastatic disease of the heart is virtually always associated with pericardial involvement as well. The appearance of metastatic disease in the heart is typically of mobile echo-dense masses attached to the endothelium (Fig. 7-116) , although isolated intramural masses and diffuse myocardial invasion have also been noted.[311] [312] There are several primary malignant tumors of the heart, including angiosarcoma and rhabdomyoma. Rhabdomyoma is more common in children. Cardiac malignancies are relatively rare occurrences and can appear in virtually any chamber. There is a greater prevalence of sarcoma and rhabdomyoma in the right atrium (Fig. 7-117) and right ventricle and involving the veins or great vessels than the actual body of the heart in adults. INTRACARDIAC THROMBUS.

Thrombi can occur in any chamber of the heart but are most common in the left ventricular apex (see Fig. 7-107) after myocardial infarction

218

Figure 7-115 Transthoracic (top) and transesophageal (bottom) echocardiogram recorded in a patient with an atrial myxoma. Note the vague echo-dense mass and the transthoracic echocardiogram that is more clearly defined in the transesophageal echo. Additionally, a thin stalk connecting the mass to the atrial septum is seen in the transesophageal echocardiogram.

or in the setting of cardiomyopathy and in the left atrium in the setting of mitral stenosis or atrial fibrillation. Ventricular thrombi have been discussed previously.

Atrial thrombi appear as echo-dense masses within the body of the left atrium but more commonly in the left atrial appendage. The left atrial appendage has a fine muscular ridgelike network that can be confused with small thrombi. Because thrombi occur in the presence of stasis, frequently spontaneous contrast with "smokelike" echoes is seen in the left atrium and left atrial appendage as well. SPECIFIC CLINICAL UTILIZATION OF ECHOCARDIOGRAPHY The previous discussion represents an outline of the diagnostic capabilities of echocardiography. There are several specific clinical situations in which echocardiography can be used and which should be understood by the clinician. Table 7-6 outlines the role of different echocardiographic modalities in clinical problem solving. EVALUATION OF DYSPNEA AND CONGESTIVE HEART FAILURE.

Two-dimensional echocardiography is recommended as an initial part of the evaluation in patients with known or suspected congestive heart failure.[312A] Evaluation of ventricular function can be undertaken, and determination of both primary and secondary valvular abnormalities can likewise be accurately assessed. Doppler echocardiography can play a valuable role with respect to determining diastolic function and establishing the diagnosis of diastolic heart failure. Heart failure with normal systolic function but abnormal diastolic relaxation comprises 30 to 40 percent of patients presenting with congestive heart failure. Because the therapy of this is distinctly different from that of systolic dysfunction, establishing the appropriate etiology and diagnosis is essential. This can be effectively done with the combination of two-dimensional echocardiography and Doppler echocardiography. CARDIAC SOURCE OF EMBOLUS.

It has become increasingly recognized that many neurological events and large artery occlusions are the result of embolization from the heart or other major vascular structures. Identifying which patients are most likely to have a cardiac source of embolus has been problematic, but, in general, any patient with abrupt occlusion of a major vessel or younger individual with a neurological event (typically younger than 45 years of age) should be suspected of having a potential cardiac etiology. Additionally, older individuals with neurological events but who do not have identifiable vascular disease require screening for a cardiac etiology. Several large-scale surveillance studies have demonstrated prevalence and range of abnormalities associated with neurological and embolic events.[313] [314] [315] One of the more common abnormalities to identify in this situation is a patent foramen ovale with or without a right-to-left shunt identified by contrast echocardiography (see Fig. 7-83) . TEE is often required for

Figure 7-116 Transesophageal echocardiogram recorded in a long-axis view of the left atrium and left ventricle in a patient with an intracardiac tumor. Note the approximate 1 cm diameter spherical mass

attached to the posterior wall of the left ventricle by a thin stalk (arrow).

219

Figure 7-117 Apical four-chamber view (top) and transesophageal echocardiogram (bottom) in a patient with a large right atrial mass. In the top panel the mass can be seen arising from the area of the inferior vena cava and essentially filling the right atrium. A similar appearance is seen in the transesophageal echocardiogram (bottom) where the mass appears adjacent to the atrial septum. Abbreviations are as per previous figures.

complete evaluation because TTE is not sufficient to exclude left atrial thrombus or evaluate the thoracic aorta for atherosclerotic degree. A potential cardiac source of embolus will be identified in many patients with neurological and other events, but the identification of such a lesion does not necessarily prove cause and effect. The degree to which atherosclerotic disease of the aorta and patent foramen ovale are causative rather than coexistent with other etiologies often remains unproven. In a substantial number of patients, highly mobile strands and areas of fibrosis may be noted on either the aortic or mitral valve. The clinical implication of these anomalies is unknown. ATRIAL FIBRILLATION.

Echocardiography plays a crucial role in the evaluation of patients with atrial fibrillation.[316] [317] [318] [319] [320] [320A] [320B] Patients with atrial fibrillation should be characterized as having underlying heart disease or having a structurally normal heart, in which case a diagnosis of lone atrial fibrillation can be made. Determination of the underlying cardiac anatomy is essential for decision-making regarding likelihood of conversion to and maintenance of sinus rhythm and for determining the embolic potential and hence the need for long-term anticoagulation. In general, patients with normal cardiac anatomy are unlikely to sustain an embolic event and highly likely to revert to sinus rhythm and have sinus rhythm maintained. Conversely, patients with cardiomyopathy and severe mitral stenosis are less likely to be maintained in sinus rhythm and have a higher likelihood of embolic events. Thus, these individuals are candidates for long-term anticoagulation. TEE has also been proposed as a management tool in determining the timing for elective cardioversion. Immediately after electrical cardioversion there is an increased likelihood of embolization. Embolization in this setting arises either from

Figure 7-118 Transesophageal echocardiogram recorded in a patient with a recent neurological event. In the top panel there is vague echo mass, which in real time has a swirling smokelike appearance (downward pointing arrow). At a slightly different transducer position, the actual apex of the left atrial appendage can be seen to contain a filling defect consistent with thrombus, noted between the two vertically oriented arrows. Abbreviations are as per previous figures.

220

TABLE 7-6 -- CLINICAL UTILITY OF ECHOCARDIOGRAPHY 2D DOPPLER CFD CONTINUOUS TEE STRESS WAVE Pericardial disease

1

2

3

4

4

N/A

Murmur

1

1

1

3

4

N/A

Mitral stenosis

1

1

1

--

3

3

Mitral regurgitation

1

1

1

--

3

N/A

Aortic stenosis/regurgitation 1

1

1

--

3

3

1

1

1

--

2

N/A

Chest pain syndrome

1

3

3

4

4

1

Rule out coronary artery disease

1

3

3

4

4

1

Diagnose acute myocardial infarction

1

3

3

4

4

N/A

Aneurysm

1

3

3

4

4

N/A

Thrombus

1

3

3

4

4

N/A

Ventricular septal defect/papillary muscle rupture

1

1

1

3

2

N/A

Assess left ventricular function

1

1

2

4

4

3

Congenital heart disease

1

1

1

3

3

3

1

1

1

2

2

4

Dilated

1

1

1

4

4

3

Hypertrophic

1

1

1

4

4

3

1

1

1

4

2

N/A

1

1

1

2

3

3


Prosthetic heart valve dysfunction Coronary artery disease

Complications of infarction

Atrial septal defect Cardiomyopathy

Endocarditis Pulmonary hypertension Known

Occult

1

1

1

2

3

2

Congestive heart failure

1

1

1

4

4

3

Stroke/source of embolus

1

2

2

1

2

N/A

Aortic dissection

2

2

1

4

1

N/A

Dyspnea evaluation

1

1

1

1

4

1

1 = Indicated and essential; 2 = often required--may add, informative; 3 = necessary in select instances for specific question; 4 = rarely necessary; 2D = two-dimensional; CFD = color flow Doppler; TEE = transesophageal echocardiography; N/A = not available. From Armstrong WF: Echocardiography. In Kelly's Textbook of Medicine. 4th ed. Philadelphia, Lippincott-Raven, 2000. a preexisting thrombus or from atrial stunning with subsequent thrombus formation (Fig. 7-118) . A strategy of TEE to exclude left atrial thrombus, followed immediately by cardioversion, has been proposed as an efficient means of restoring sinus rhythm without requiring long-term pre-cardioversion anticoagulation. After cardioversion, atrial stunning occurs and the likelihood of new thrombus formation is actually transiently enhanced. For this reason, anticoagulation is clinically indicated in virtually all patients immediately after cardioversion. PULMONARY EMBOLUS (See also Chap. 52) .

Patients with pulmonary embolus often present with atypical symptoms. In this instance, TEE and TTE can provide valuable clinical information.[321] [322] In a patient presenting with a combination of chest pain and dyspnea, with or without evidence of venous stasis, detection of right-sided heart dilation and dysfunction and/or elevation of pulmonary artery pressures can be valuable clues to the nature of the underlying process. Direct visualization of large pulmonary emboli is occasionally possible from either TTE but more usually TEE.[323] Additionally, by using either technique, embolus in transit can be detected as a highly mobile serpiginous mass, typically entrapped in the tricuspid valve apparatus and less commonly spanning a patent foramen ovale. Detection of typical serpiginous mass in the right atrium identifies a patient at substantial risk for further embolization and is a clinical situation requiring emergent therapy (Fig. 7-119) . PULMONARY HYPERTENSION (See also Chap. 53) .

Pulmonary hypertension represents an elusive diagnosis. Clinically, pulmonary hypertension can occur either as a primary phenomenon or secondary to a variety of either cardiac or pulmonary processes. The majority of patients with established pulmonary hypertension have identifiable abnormalities on echocardiography, including variable degrees of right ventricular enlargement and hypertrophy ( (Figs. 7-120 ). [324] [325] As noted earlier, pulmonary artery pressures can be estimated from the velocity of the tricuspid regurgitation jet (see Fig. 7-29) . In patients with only mild elevation of

pulmonary pressure, exercise echocardiography to track pulmonary artery pressures with stress can also be performed and provides valuable information regarding the presence of occult, exercise-induced pulmonary hypertension. Doppler echocardiography can also be used to follow pulmonary artery pressures with therapy. FETAL ECHOCARDIOGRAPHY.

Because cardiac ultrasonography carries no risk to the pregnant women or fetus and is fully noninvasive it can be used to make the antepartum diagnosis of congenital heart disease.[326] This should be undertaken only by pediatric echocardiographers with appropriate experience in the technique. Many major intracardiac abnormalities can be detected at the end of the first trimester, and the majority of physiologically significant abnormalities can be detected in utero in the second trimester. This technique has seen substantial use in identifying fetuses with congenital heart defects who may warrant urgent transfer to a neonatal intensive care unit or an emergent intervention for life-threatening cardiac problems immediately after birth. EVALUATION AND MONITORING OF INVASIVE AND INTERVENTIONAL PROCEDURES.

Two-dimensional echocardiography, often using TEE, has seen substantial success as a means of monitoring invasive procedures. This includes direct online monitoring of pericardiocentesis[327] and assistance in localization and placement of catheters for electro

Figure 7-120 Transthoracic echocardiogram recorded in a parasternal long- and short-axis view in a patient with severe pulmonary hypertension. Note the dilation and hypertrophy of the right ventricle and the abnormal geometry of the left ventricle in which the ventricular septum is concave toward the right ventricle.

221

Figure 7-119 Transesophageal echocardiogram recorded in a patient with pulmonary embolus, found to have "thromboembolism in transit." The top panel is recorded at 0 degrees. The dilated right atrium and right ventricle are obvious. Three highly mobile components of a long serpiginous thrombus can be seen in the right atrium (arrows). The bottom panel is recorded at 106 degrees and visualizes the right atrium. The serpiginous nature of the thrombus can be appreciated, and it is noted to coil on itself in the cavity of the right atrium. Abbreviations are as per previous figures.

physiological ablation as well as online monitoring of endomyocardial biopsy specimens.[328] [329] [330] Additionally, TEE is an instrumental component of transcatheter closure of atrial septal defects in the catheterization laboratory [330A] and often used in other procedures where a transatrial approach is necessary for therapy, such as mitral balloon valvotomy.[331] [332] [333]

REFERENCES Thomas JD: The DICOM image formatting standard: What it means for echocardiographers. J Am Soc Echocardiogr 8:319-327, 1995. 1.

Trippi JA, Lee KS, Kopp G, et al: Emergency echocardiography telemedicine: An efficient method to provide 24-hour consultative echocardiography. J Am Coll Cardiol 27:1748-1752, 1996. 2.

EXAMINATION AND APPEARANCE OF THE NORMAL HEART; ANATOMICAL VARIANTS Stoddard MF, Liddell NE, Longacker RA, et al: Transesophageal echocardiography: Normal variants and mimickers. Am Heart J 124:1587-1598, 1992. 3.

Veinot JP, Harrity PJ, Gentile F, et al: Anatomy of the normal left atrial appendage: A quantitative study of age-related changes in 500 autopsy hearts: Implications for echocardiographic examination. Circulation 9:3112-3115, 1996. 4.

Wong M, Bruce S, Joseph D, et al: Estimating left ventricular ejection fraction from two-dimensional echocardiograms: Visual and computer-processed interpretations. Echocardiography 8:1-7, 1991. 5.

Waggoner AD, Miller JG, Perez JE: Two-dimensional echocardiographic automatic boundary detection for evaluation of left ventricular function in unselected adult patients. J Am Soc Echocardiogr 7:459-464, 1994. 6.

Huwez FU, Houston AB, Watson J, et al: Age and body surface area related normal upper and lower limits of M-mode echocardiographic measurements and left ventricular volume and mass from infancy to early adulthood. Br Heart J 72:276-280, 1994. 7.

Chuang ML, Hibberd MG, Salton CJ, et al: Importance of imaging method over imaging modality in noninvasive determination of left ventricular volumes and ejection fraction. J Am Coll Cardiol 35:477-484, 2000. 7A.

Yvorchuk KJ, Davies RA, Chang KL: Measurement of left ventricular ejection fraction by acoustic quantification and comparison with radionuclide angiography. Am J Cardiol 74:1052-1056, 1994. 8.

Gorcsan J, Denault A, Gasior TA, et al: Rapid estimation of left ventricular contractility from end-systolic relations by echocardiographic automated border detection and femoral arterial pressure. Anesthesiology 81:553-562, 1994. 9.

Gorcsan J, Romand JA, Mandarino WA, et al: Assessment of left ventricular performance of on-line pressure-area relations using echocardiographic automated border detection. J Am Coll Cardiol 23:242-252, 1994. 10.

Devereux RB, Alonson DR, Lutas EM, et al: Echocardiographic assessment of left ventricular hypertrophy: Comparison to necropsy findings. Am J Cardiol 57:450-458, 1986. 11.

11A. Palmieri

V, Dahlof B, DeQuattro V, et al: Reliability of echocardiographic assessment of left ventricular structure and function. The PRESERVE Study. J Am Coll Cardiol 34:1625-1632, 1999. 12.

Byrd BF, Finkbeiner W, Bouchard A, et al: Accuracy and reproducibility of clinically acquired

two-dimensional echocardiographic mass measurements. Am Heart J 118:133-137, 1989. Weyman AE, Franklin TD, Hogan RD, et al: Importance of temporal heterogeneity in assessing the contraction abnormalities associated with acute myocardial ischemia. Circulation 70:102-112, 1984. 13.

Bourdillon PDV, Broderick TM, Sawada SG, et al: Regional wall motion index for infarct and noninfarct regions after reperfusion in acute myocardial infarction: Comparison with global wall motion index. J Am Soc Echocardiogr 2:398-407, 1989. 14.

McGillem MJ, Mancini GBJ, DeBoe SF, et al: Modification of the centerline method for assessment of echocardiographic wall thickening and motion: A comparison with areas of risk. J Am Coll Cardiol 11:861-866, 1988. 15.

Windle JR, Armstrong WF, Miles WM, et al: Determination of the earliest site of ventricular activation in Wolff-Parkinson-White syndrome: Application of digital continuous loop two-dimensional echocardiography. J Am Coll Cardiol 7:1286-1294, 1986. 16.

Voelkel AG, Pietro DA, Folland ED, et al: Echocardiographic features of constrictive pericarditis. Circulation 58:871-875, 1978. 17.

Ryan T, Petrovic O, Dillon JC, et al: An echocardiographic index for separation of right ventricular volume and pressure overload. J Am Coll Cardiol 5:918-927, 1985. 18.

Lehmann KG, Lee FA, McKenzie WB, et al: Onset of altered interventricular septal motion during cardiac surgery. Circulation 82:1325-1334, 1990. 19.

DOPPLER PRINCIPLES AND EQUATIONS Handshoe R, DeMaria AN: Doppler assessment of intracardiac pressures. Echocard Rev Cardiovasc Ultrasound 2:127-139, 1985. 20.

Bom K, de Boo J, Rijsterborgh H: On the aliasing problem in pulsed Doppler cardiac studies. J Clin Ultrasound 12:559-567, 1984. 21.

Stewart WJ, Galvin KA, Gillam LD, et al: Comparison of high pulse repetition frequency and continuous wave Doppler echocardiography in the assessment of high flow velocity in patients with valvular stenosis and regurgitation. J Am Coll Cardiol 6:565-571, 1985. 22.

Stevenson JG: Appearance and recognition of basic concepts in color flow imaging. Echocardiography 6:451-466, 1989. 23.

Ritter SB: Red, green and blue: The flag of Doppler color flow mapping: Flow mapping 1989. Echocardiography 6:369-370, 1989. 24.

Tramarin R, Torbicki A, Marchandise B, et al: Doppler echocardiographic evaluation of pulmonary artery pressure in chronic obstructive pulmonary disease: A European multicentre study. Eur Heart J 12:103-111, 1991. 25.

222

Lazarus M, Dang TY, Gardin JM, et al: Evaluation of age, gender, heart rate and blood pressure changes and exercise conditioning on Doppler measured aortic blood flow acceleration and velocity during upright treadmill testing. Am J Cardiol 62:439-443, 1988. 26.

Moulinier L, Venet T, Schiller NB, et al: Measurement of aortic blood flow by Doppler echocardiography: Day to day variability in normal subject and applicability in clinical research. J Am Coll Cardiol 17:1326-1333, 1991. 27.

Miller WE, Richards KL, Crawford MH: Accuracy of mitral Doppler echocardiographic output determinations in adults. Am Heart J 119:620-626, 1990. 28.

Taylor R: Evolution of the continuity equation in the Doppler echocardiographic assessment of the severity of valvular aortic stenosis. J Am Soc Echocardiogr 3:326-330, 1990. 29.

Shiota T, Jones M, Teien DE, et al: Evaluation of mitral regurgitation using a digitally determined color Doppler flow convergence "centerline" acceleration method. Circulation 89:2879-2887, 1994. 30.

Grayburn PA, Fehske W, Omran H, et al: Multiplane transesophageal echocardiographic assessment of mitral regurgitation by Doppler color flow mapping of the vena contract. Am J Cardiol 74:912-917, 1994. 31.

Chen C, Rodriguez L, Lethor J-P, et al: Continuous wave Doppler echocardiography for noninvasive assessment of left ventricular dP/dt and relaxation time constant from mitral regurgitant spectra in patients. J Am Coll Cardiol 23:970-976, 1994. 32.

Kawai H, Yokato Y, Yokoyama M: Noninvasive evaluation of contractile state by left ventricular dP/dtmax divided by end-diastolic volume using continuous-wave Doppler and M-mode echocardiography. Clin Cardiol 17:662-668, 1994. 33.

Sherrid MV, Chu CK, Delia E, et al: An echocardiographic study of the fluid mechanics of obstruction in hypertrophic cardiomyopathy. J Am Coll Cardiol 22:816-825, 1993. 34.

Oh JK, Appleton CP, Hatle LK, et al: The noninvasive assessment of left ventricular diastolic function with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 10:246-270, 1997. 35.

Nishimura RA, Tajik AJ: Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician's Rosetta Stone. J Am Coll Cardiol 30:8-18, 1997. 36.

Kozan O, Nazli C, Kinay O, et al: Use of intraventricular dispersion of the peak diastolic flow velocity as a marker of left ventricular diastolic dysfunction in patients with atrial fibrillation. J Am Soc Echocardiogr 11:1036-1043, 1998. 37.

37A. Wachtell

K, Smith G, Gerdts E, et al: Left ventricular filling patterns in patients with systemic hypertension and left ventricular hypertrophy (the LIFE study). Am J Cardiol 85:466-472, 2000. Konecke LL, Feigenbaum H, Chang S, et al: Abnormal mitral valve motion in patients with elevated left ventricular diastolic pressures. Circulation 47:989-996, 1973. 38.

Rossvoll O, Hatle LK: Pulmonary venous flow velocities recorded by transthoracic Doppler ultrasound: Relation to left ventricular diastolic pressures. J Am Coll Cardiol 21:1687-1696, 1993. 39.

40.

Masuyama T, Lee JM, Nagano R, et al: Doppler echocardiographic pulmonary venous flow-velocity

pattern for assessment of the hemodynamic profile in acute congestive heart failure. Am Heart J 129:107-113, 1995.

SPECIFIC IMAGING FORMATS AND TECHNIQUES Seward JB, Khandheria BK, Edwards WD, et al: Biplanar transesophageal echocardiography: Anatomic correlations, image orientation and clinical applications. Mayo Clin Proc 65:1193-1213, 1990. 41.

Marcovitz PA, Bach DS, Segar DS, et al: Impact of B-mode color encoding on rapid detection of ultrasound targets: An in vitro study. J Am Soc Echocardiogr 6:382-386, 1993. 42.

Senior R, Soman P, Khattar RS, et al: Improved endocardial visualization with second harmonic imaging compared with fundamental two-dimensional echocardiographic imaging. Am Heart J 138:163-168, 1999. 43.

Skolnick DG, Sawada SG, Feigenbaum H, et al: Enhanced endocardial visualization with noncontrast harmonic imaging during stress echocardiography. J Am Soc Echocardiogr 12:559-563, 1999. 44.

Spencer KT, Bednarz J, Rafter PG, et al: Use of harmonic imaging without echocardiographic contrast to improve two-dimensional image quality. Am J Cardiol 82:794-799, 1998. 45.

45A. Mulvagh

SL, DeMaria AN, Feinstein SB, et al: Contrast echocardiography: Current and future applications. J Am Soc Echocardiog 13:331, 2000. 45B. Spencer

KT, Bednarz J, Mor-Avi V, et al: The role of echocardiographic harmonic imaging and contrast enhancement for improvement of endocardial border delineation. J Am Soc Echocardiogr 13:131-138, 2000. Garcia MJ, Smedira NG, Greenberg NL, et al: Color M-mode Doppler flow propagation velocity is a preload insensitive index of left ventricular relaxation: Animal and human validation. J Am Coll Cardiol 35:201-208, 2000. 45C.

Derumeaux G, Ovize M, Loufova J, et al: Assessment of nonuniformity of transmural myocardial velocities by color-coded tissue Doppler imaging: Characterization of normal, ischemic and stunned myocardium. Circulation 101:1390, 2000. 45D.

Goldberg BB, Liu JB, Forsberg F: Ultrasound contrast agents: A review. Ultrasound Med Biol 20:319-333, 1994. 46.

Bommer WJ, Shah PM, Allen H, et al: The safety of contrast echocardiography: Report of the committee on contrast echocardiography for the American Society of Echocardiography. J Am Coll Cardiol 3:6-13, 1984. 47.

Meltzer RS, Tickner EG, Popp RL: Why do the lungs clear ultrasound. Ultrasound Med Biol 6:263-269, 1980. 48.

Serruys PW, Van Den Brand M, Hugenholtz PG, et al: Intracardiac right-to-left shunts demonstrated by two-dimensional echocardiography after peripheral vein injection. Br Heart J 42:429-437, 1979. 49.

Feinstein SB, Cheirif J, Ten Cate FJ, et al: Safety and efficacy of a new transpulmonary ultrasound contrast agent: Initial multicenter clinical results. J Am Coll Cardiol 16:316-324, 1990. 50.

51.

Grayburn PA, Weiss JL, Hack TC, et al: Phase III multicenter trial comparing the efficacy of 2%

dodecafluoropentane emulsion (EchoGen) and sonicated 5% human albumin (Albunex) as ultrasound contrast agents in patients with suboptimal echocardiograms. J Am Coll Cardiol 32:230-236, 1998. Cohen JL, Cheirif J, Segar DS, et al: Improved left ventricular endocardial border delineation and opacification with OPTISON (FS069), a new echocardiographic contrast agent. J Am Coll Cardiol 32:746-752, 1998. 52.

Main ML, Grayburn PA: Clinical applications of transpulmonary contrast echocardiography. Am Heart J 137:144-153, 1999. 53.

53A. Reilly

JP, Tunick PA, Timmermans RJ, et al: Contrast echocardiography clarifies uninterpretable wall motion in intensive care unit patients. J Am Coll Cardiol 35:485-490, 2000. Von Bibra H, Becher H, Firschke C, et al: Enhancement of mitral regurgitation and normal left atrial color Doppler flow signals with peripheral venous injection of a saccharide-based contrast agent. J Am Coll Cardiol 22:521-528, 1993. 54.

Von Bibra H, Sutherland G, Becher H, et al: Clinical evaluation of left heart Doppler contrast enhancement by a saccharide-based transpulmonary contrast agent. J Am Coll Cardiol 25:500-508, 1995. 55.

55A. Thanigaraj

S, Schechtman KB, Perez JE: Improved echocardiographic delineation of left ventricular thrombus with the use of intravenous second-generation contrast image enhancement. J Am Soc Echocardiogr 12:1022-1026, 1999. 55B. Takeuchi

M, Ogunyankin K, Pandian NG, et al: Enhanced visualization of intravascular and left atrial appendage thrombus with the use of a thrombus-targeting ultrasonographic contrast agent (MRX-408A1): In vivo experimental echocardiographic studies. J Am Soc Echocardiogr 12:1015-1021, 1999. Skyba DM, Price RJ, Linka AZ, et al: Direct in vivo visualization of intravascular destruction of microbubbles by ultrasound and its local effects on tissue. Circulation 98:290-293, 1998. 56.

Porter TR, Xie F, Li S, et al: Increased ultrasound contrast and decreased microbubble destruction rates with triggered ultrasound imaging. J Am Soc Echocardiogr 9:599-605, 1996. 57.

Wei K, Skyba DM, Firschke C, et al: Interactions between microbubbles and ultrasound: In vitro and in vivo observations. J Am Coll Cardiol 29:1081-1088, 1997. 58.

Gopal AS, Shen Z, Sapin PM, et al: Assessment of cardiac function by three-dimensional echocardiography compared with conventional noninvasive methods. Circulation 92:842-853, 1995. 59.

Siu SC, Levine RA, Rivera JM, et al: Three-dimensional echocardiography improves noninvasive assessment of left ventricular volume and performance. Am Heart J 130:812-822, 1995. 60.

Salustri A, Spitaels S, McGhie J, et al: Transthoracic three-dimensional echocardiography in adult patients with congenital heart disease. J Am Coll Cardiol 26:759-767, 1995. 61.

Ota T, Fleishman CE, Strub M, et al: Real-time, three-dimensional echocardiography: Feasibility of dynamic right ventricular volume measurement with saline contrast. Am Heart J 137:958-966, 1999. 62.

Takuma S, Zwas DR, Fard A, et al: Real-time, 3-dimensional echocardiography acquires all standard 2-dimensional images from 2 volume sets: A clinical demonstration in 45 patients. J Am Soc Echocardiogr 12:1-6, 1999. 63.

Collins M, Hsieh A, Ohazama CJ, et al: Assessment of regional wall motion abnormalities with real-time 3-dimensional echocardiography. J Am Soc Echocardiogr 12:7-14, 1999. 64.

Chuang ML, Parker RA, Riley MF, et al: Three-dimensional echocardiography improves accuracy and compensates for sonographer inexperience in assessment of left ventricular ejection fraction. J Am Soc Echocardiogr 12:290-299, 1999. 65.

65A. Schmidt

MA, Ohazama CJ, Agyeman KO, et al: Real-time three-dimensional echocardiography for measurement of left ventricular volumes. Am J Cardiol 84:1434-1439, 1999. Bruce CJ, Packer DL, Seard JB: Transvascular imaging: Feasibility study using a vector phased array ultrasound catheter. Echocardiography 16:425-430, 1999. 66.

Fu M, Hung JS, Lo PH, et al: Intracardiac echocardiography via the transvenous approach with use of 8F 10-MHz ultrasound catheter. Mayo Clin Proc 74:775-783, 1999. 67.

Gerber TC, Erbel R, Gorge G, et al: Extent of atherosclerosis and remodeling of the left main coronary artery determined by intravascular ultrasound. Am J Cardiol 73:666-671, 1994. 68.

Pinto FJ, Chenzbraum A, Botas J, et al: Feasibility of serial intracoronary ultrasound imaging for assessment of progression of intimal proliferation in cardiac transplant recipients. Circulation 90:2348-2355, 1994. 69.

223

Ge J, Erbel R, Gerber T, et al: Intravascular ultrasound imaging of angiographically normal coronary arteries: A prospective study in vivo. Br Heart J 71:572-578, 1994. 70.

Nakamura S, Colombo A, Galione A, et al: Intracoronary ultrasound observations during stent implantation. Circulation 89:2026-2034, 1994. 71.

71A. Hong

MK, Park SW, Mintz GS, et al: Intravascular ultrasonic predictors of angiographic restenosis after long coronary stenting. Am J Cardiol 85:441-445, 2000. 71B. de

Feyter PJ, Kay P, Disco C, et al: Reference chart derived from post-stent-implantation intravascular ultrasound predictors of 6-month expected restenosis on quantitative coronary angiography. Circulation 100:1777-1783, 1999. Kern MJ, Aguirre FV, Donohue TJ, et al: Continuous coronary flow velocity monitoring during coronary interventions: Velocity trend patterns associated with adverse events. Am Heart J 128:426-434, 1994. 72.

DiMario C, Krams R, Gil R, et al: Slope of the instantaneous hyperemic diastolic coronary flow velocity-pressure relation: A new index for assessment of the physiological significance of coronary stenosis in humans. Circulation 90:1315-1324, 1994. 73.

McPherson DD: Tissue characterization by ultrasound: What is possible now? What will be possible? Echocardiography 8:77-91, 1991. 74.

Bach DS, Armstrong WF, Donovan CL, et al: Quantitative Doppler tissue imaging for assessment of regional myocardial velocities during transient ischemia and reperfusion. Am Heart J 132:721-725, 1996. 75.

Garcia MJ, Rodriguez L, Ares M, et al: Myocardial wall velocity assessment by pulsed Doppler tissue imaging: Characteristic findings in normal subjects. Am Heart J 132:648-656, 1996. 76.

76A. Pasquet

A, Armstrong G, Rimmerman C, et al: Correlation of myocardial Doppler velocity response to exercise with independent evidence of myocardial ischemia by dual-isotope single-photon emission computed tomography. Am J Cardiol 85:536-542, 2000. 76B. Derumeaux

G, Ovize M, Loufoua J, et al: Assessment of nonuniformity of transmural myocardial velocities by color-coded tissue Doppler imaging. Circulation 101:1390-1395, 2000. Pasquet A, Armstrong G, Beachler L, et al: Use of segmental tissue Doppler velocity to quantitate exercise echocardiography. J Am Soc Echocardiogr 12:901-912, 1999. 76C.

Stewart WJ, Aurigemma GP, Bierman FZ, et al: Task Force 4: Training in echocardiography. J Am Coll Cardiol 25:16-19, 1995. 77.

Cheitlin MD, Alpert JS, Armstrong WF, et al: ACC/AHA guidelines for the clinical application of echocardiography. Circulation 95:1686-1744, 1997. 78.

ACQUIRED VALVULAR HEART DISEASE Nishimura RA, Rihal CS, Tajik AJ, et al: Accurate measurement of the transmitral gradient in patient with mitral stenosis: A simultaneous catheterization and Doppler echocardiographic study. J Am Coll Cardiol 24:152-158, 1994. 79.

79A. Wang

A, Ryan T, Kisslo KB, et al: Assessing the severity of mitral stenosis: Variability between noninvasive and invasive measurements in patients with symptomatic mitral valve stenosis. Am Heart J 138:777-784, 1999. Leavitt JI, Coats MH, Falk RH: Effects of exercise on transmitral gradient and pulmonary artery pressure in patients with mitral stenosis or a prosthetic mitral valve: A Doppler echocardiographic study. J Am Coll Cardiol 17:1520-1526, 1991. 80.

Fredman CS, Pearson AC, Labovitz AJ, et al: Comparison of hemodynamic pressure half-time method and Gorlin formula with Doppler and echocardiographic termination of mitral valve area in patients with combined mitral stenosis and regurgitation. Am Heart J 119:121-129, 1990. 81.

Loperfido F, Laurenzi F, Gimigliano F, et al: A comparison of the assessment of mitral valve area by continuous wave Doppler and by cross sectional echocardiography. Br Heart J 57:348-355, 1987. 82.

Loyd D, Ask P, Wranne B: Pressure half-time does not always predict mitral valve area correctly. J Am Soc Echocardiogr 1:313-321, 1988. 83.

Thomas JD, Wilkins GT, Choong CYP, et al: Inaccuracy of mitral pressure half-time immediately after percutaneous mitral valvotomy: Dependence on transmitral gradient and left atrial and ventricular compliance. Circulation 78:980-993, 1988. 84.

Robson DJ, Flaxman JC: Measurement of the end-diastole pressure gradient and mitral valve area in mitral stenosis by Doppler ultrasound. Eur Heart J 5:660-667, 1984. 85.

Hernandez R, Banuelos C, Alfonso F, et al: Long-term clinical and echocardiographic follow-up after percutaneous mitral valvuloplasty with the Inoue balloon. Circulation 99:1580-1586, 1999. 86.

Padial LR, Abascal VM, Moreno PR, et al: Echocardiography can predict the development of severe mitral regurgitation after percutaneous mitral valvuloplasty by the Inoue technique. Am J Cardiol 83:1210-1231, 1999. 87.

Burwash IG, Blackmore GL, Koilpillai CJ: Usefulness of left atrial and left ventricular chamber sizes as predictors of the severity of mitral regurgitation. Am J Cardiol 70:774-779, 1992. 88.

Himelman RB, Kusumoto F, Oken K, et al: The flail mitral valve: Echocardiographic findings by precordial and transesophageal imaging and Doppler color flow mapping. J Am Coll Cardiol 17:272-279, 1991. 89.

Shyu KG, Lei MH, Hwang JJ, et al: Morphologic characterization and quantitative assessment of mitral regurgitation with ruptured chordae tendineae by transesophageal echocardiography. Am J Cardiol 70:1152-1156, 1992. 90.

Rivera JM, Vandervoort PM, Morris E, et al: Visual assessment of valvular regurgitation: Comparison with quantitative Doppler measurements. J Am Soc Echocardiogr 7:480-487, 1994. 91.

Castello R, Fagan L, Lenzen P, et al: Comparison of transthoracic and transesophageal echocardiography for assessment of left-sided valvular regurgitation. Am J Cardiol 68:1677-1680, 1991. 92.

Tribouilloy C, Shen WF, Slama MA, et al: Non-invasive measurement of the regurgitant fraction by pulsed Doppler echocardiography in isolated pure mitral regurgitation. Br Heart J 66:290-294, 1991. 93.

Chao K, Moises VA, Shandas R, et al: Influence of the Coanda effect on color Doppler jet area and color encoding: In vitro studies using color Doppler flow mapping. Circulation 85:333-341, 1992. 94.

Rivera JM, Mele D, Vendervoort PM, et al: Physical factors determining mitral regurgitation jet area. Am J Cardiol 74:515-516, 1994. 95.

Enriquez-Sarano M, Dujardin KS, Tribouilloy CM, et al: Determinants of pulmonary venous flow reversal in mitral regurgitation and its usefulness in determining the severity of regurgitation. Am J Cardiol 83:535-541, 1999. 96.

De Simone R, Glombitza G, Vahl CF, et al: Three-dimensional color Doppler: A clinical study in patients with mitral regurgitation. J Am Coll Cardiol 33:1646-1654, 1999. 97.

De Simone R, Glombitza G, Vahl CF, et al: Three-dimensional color Doppler: A new approach for quantitative assessment of mitral regurgitant jets. J Am Soc Echocardiogr 12:173-185, 1999. 98.

Chen C, Koschyk D, Brockhoff C, et al: Noninvasive estimation of regurgitant flow rate and volume in patients with mitral regurgitation by Doppler color mapping of accelerating flow field. J Am Coll Cardiol 21:374-383, 1993. 99.

Levine RA, Stathogiannis E, Newell JB, et al: Reconsideration of echocardiographic standards for mitral valve prolapse: Lack of association between leaflet displacement isolated to the apical four chamber view and independent echocardiographic evidence of abnormality. J Am Coll Cardiol 11:1010-1019, 1988. 100.

101.

Freed L, Levy D, Levine R, et al: Prevalence and clinical outcome of mitral-valve prolapse. N Engl J

Med 341:1-7, 1999. Gilon D, Buonanno F, Joffe M, et al: Lack of evidence of an association between mitral-valve prolapse and stroke in young patients. N Engl J Med 341:8-13, 1999. 102.

Otto CM, Pearlman AS, Kraft CD, et al: Physiologic changes with maximal exercise in asymptomatic valvular aortic stenosis assessed by Doppler echocardiography. J Am Coll Cardiol 20:1160-1167, 1992. 103.

Currie PJ, Hagler DJ, Seward JB, et al: Instantaneous pressure gradient: A simultaneous Doppler and dual catheter correlative study. J Am Coll Cardiol 7:800-806, 1986. 103A.

Garcia D, Pibarot P, Dumesnil JG, et al: Assessment of aortic valve stenosis severity: A new index based on the energy loss concept. Circulation 101:765, 2000. 103B.

Tribouilloy C, Shen WF, Peltier M, et al: Quantitation of aortic valve area in aortic stenosis with multiplane transesophageal echocardiography: Comparison with monoplane transesophageal approach. Am Heart J 128:526-532, 1994. 104.

Zoghbi WA, Farmer KL, Soto JG, et al: Accurate noninvasive quantification of stenotic aortic valve area by Doppler echocardiography. Circulation 73:452-459, 1986. 105.

Taylor R: Evaluation of the continuity equation in the Doppler echocardiographic assessment of the severity of valvular aortic stenosis. J Am Soc Echocardiogr 3:326-330, 1990. 106.

107.

Ford LE, Feldman T, Carroll JD: Valve resistance. Circulation 89:893-895, 1994.

Lin SS, Roger VL, Pascoe R, et al: Dobutamine stress Doppler hemodynamics in patients with aortic stenosis: Feasibility, safety, and surgical correlations. Am Heart J 136:1010-1016, 1998. 108.

deFilippi CR, Willett DL, Brickner ME, et al: Usefulness of dobutamine echocardiography in distinguishing severe from nonsevere valvular aortic stenosis in patients with depressed left ventricular function and low transvalvular gradients. Am J Cardiol 75:191-194, 1995. 109.

Nishimura RA, Vonk GD, Rumberger JA, et al: Semiquantitation of aortic regurgitation by different Doppler echocardiographic techniques and comparison with ultrafast computed tomography. Am Heart J 124:995-1001, 1992. 110.

Bouchard A, Yock P, Schiller NB, et al: Value of color Doppler estimation of regurgitant volume in patients with chronic aortic insufficiency. Am Heart J 117:1099-1105, 1989. 111.

Samstad S, Hegrenaes L, Skjaerpe T, et al: Half time of the diastolic aortoventricular pressure difference by continuous wave Doppler ultrasound: A measure of the severity of aortic regurgitation? Br Heart J 61:336-343, 1989. 112.

Yeung AC, Plappert T, St. John Sutton MG: Calculation of aortic regurgitation orifice area by Doppler echocardiography: An application of the continuity equation. Br Heart J 68:236-240, 1992. 113.

Nishigami K, Yoshikawa J, Yoshida K, et al: Quantification of aortic regurgitant stroke volume by Doppler color flow proximal isovelocity surface area method. Jpn J Med Ultrasonics 19:9, 1992. 114.

Padial LR, Oliver A, Sagie A, et al: Two-dimensional echocardiographic assessment of the progression of aortic root size in 127 patients with chronic aortic regurgitation: Role of the supraaortic 115.

ridge and relation to the progression of the lesion. Am Heart J 134:814-821, 1997.

224

Bonow RO, Dodd JT, Maron BJ, et al: Long-term serial changes in left ventricular function and reversal of ventricular dilatation after valve replacement for chronic aortic regurgitation. Circulation 78:1108-1120, 1988. 116.

Bonow RO, Lakatos E, Maron BJ, et al: Serial long-term assessment of the natural history of asymptomatic patients with chronic aortic regurgitation and normal left ventricular systolic function. Circulation 84:1625-1635, 1991. 117.

Mugge A, Danile WG, Herrmann G, et al: Quantification of tricuspid regurgitation by Doppler color flow mapping after cardiac transplantation. Am J Cardiol 66:884-887, 1990. 118.

Parris TM, Panidis IP, Ross J, et al: Doppler echocardiographic findings in rheumatic tricuspid stenosis. Am J Cardiol 60:1414-1416, 1987. 119.

Winslow T, Redberg R, Schiller NB: Transesophageal echocardiography in the diagnosis of flail tricuspid valve. Am Heart J 123:1682-1684, 1992. 120.

Pellikka PA, Tajik JA, Khandheria BK, et al: Carcinoid heart disease: Clinical and echocardiographic spectrum in 74 patients. Circulation 87:1188-1196, 1993. 121.

Lundin L, Landelius J, Andren B, et al: Transoesophageal echocardiography improves the diagnostic value of cardiac ultrasound in patients with carcinoid heart disease. Br Heart J 64:190-194, 1990. 122.

Stephen B, Dalal P, Berger M, et al: Noninvasive estimation of pulmonary artery diastole pressure in patients with tricuspid regurgitation by Doppler echocardiography. Chest 116:73-77, 1999. 123.

Stevenson JG: Comparison of several noninvasive methods for estimation of pulmonary artery pressure. J Am Soc Echocardiogr 2:157-171, 1989. 124.

Connolly HM, Crary JL, McGoon MD, et al: Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 337:581-588, 1997. 125.

Khan MA, Herzog CA, St. Peter JV, et al: The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite-suppressant drugs. N Engl J Med 339:713-718, 1998. 126.

Weissman NJ, Tighe JF, Gottdiener JS, et al: An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine, sustained-release dexfenfluramine, or placebo. N Engl J Med 339:725-732, 1998. 127.

Burger AJ, Sherman HB, Charlamb MJ, et al: Low prevalence of valvular heart disease in 226 phentermine-fenfluramine protocol subjects prospectively followed for up to 30 months. J Am Coll Cardiol 34:1153-1158, 1999. 128.

128A.

Kimmel SE, Keane MG, Crary JL, et al: Detailed examination of fenfluramine-phentermine users

with valve abnormalities identified in Fargo, North Dakota. Am J Cardiol 84:304-308, 1999. Burger AJ, Sherman HB, Charlamb MJ, et al: Low prevalence of valvular heart disease in 226 phentermine-fenfluramine protocol subjects prospectively followed for up to 30 months. J Am Coll Cardiol 34:1153-1158, 1999. 128B.

Shively BK, Roldan CA, Gill EA, et al: Prevalence and determinants of valvulopathy in patients treated with dexfenfluramine. Circulation 100:2161-2167, 1999. 128C.

Kancherla MK, Salti HI, Mulderink TA, et al: Echocardiographic prevalence of mitral and/or aortic regurgitation in patients exposed to either fenfluramine-phentermine combination or to dexfenfluramine. Am J Cardiol 84:1335-1338, 1999. 128D.

EVALUATION OF PROSTHETIC HEART VALVES Abraham TP, Kon ND, Nomeir AM, et al: Accuracy of transesophageal echocardiography in preoperative determination of aortic anulus size during valve replacement. J Am Soc Echocardiogr 10:149-154, 1997. 129.

Bridgman PG, Bloomfield P, Reid JH, et al: Prediction of stentless aortic bioprosthesis size with transesophageal echocardiography and magnetic resonance imaging. J Heart Valve Disease 6:487-489, 1997. 130.

Oh CC, Click RL, Orszulak TA, et al: Role of intraoperative transesophageal echocardiography in determining aortic annulus diameter in homograft insertion. J Am Soc Echocardiogr 11:638-642, 1998. 131.

Prasad NK, Alam M, Rosman HS, et al: Serial Doppler gradients are predictive of future bioprosthetic valve degeneration. Echocardiography 15:337-344, 1998. 132.

Gueret P, Vignon P, Fournier P, et al: Transesophageal echocardiography for the diagnosis and management of nonobstructive thrombosis of mechanical mitral valve prosthesis. Circulation 91:103-110, 1995. 133.

Alam M, Rosman HS, Sun I: Transesophageal echocardiographic evaluations of St. Jude Medical and bioprosthetic valve endocarditis. Am Heart J 123:236-239, 1992. 134.

Rothbart RM, Castriz JL, Harding LV, et al: Determination of aortic valve area by two-dimensional and Doppler echocardiography in patients with normal and stenotic bioprosthetic valves. J Am Coll Cardiol 15:817-824, 1990. 135.

Hasegawa J, Kitamura S, Taniguchi S, et al: Comparative rest and exercise hemodynamics of allograft and prosthetic valves in the aortic position. Ann Thorac Surg 64:1753-1756, 1997. 136.

Westaby S, Huysmans HA, David TE: Stentless aortic bioprotheses: Compelling data from the second international symposium. Ann Thorac Surg 65:235-240, 1998. 137.

Chambers J, Monaghan M, Jackson G: Colour Doppler mapping in the assessment of prosthetic valve regurgitation. Br Heart J 62:1-8, 1989. 138.

Pibarot P, Dumesnil JG, Jobin J, et al: Hemodynamic and physical performance during maximal exercise in patients with an aortic bioprosthetic valve. J Am Coll Cardiol 34:1609-1617, 1999. 139.

140.

Vandervoort PM, Greenberg NL, Pu M, et al: Pressure recovery in bileaflet heart valve prostheses:

Localized high velocities and gradients in central and side orifices with implications for Doppler-catheter gradient relation in aortic and mitral position. Circulation 92:3464-3472, 1995. Baumgartner H, Khan S, DeRobertis M, et al: Effect of prosthetic aortic valve design on the Doppler-catheter gradient correlation: An in vitro study of normal St. Jude, Medtronic-Hall, Starr-Edwards and Hancock valves. J Am Coll Cardiol 19:324-332, 1992. 141.

Stewart WJ, Currie PJ, Salcedo EE, et al: Evaluation of mitral leaflet motion by echocardiography and jet direction by Doppler color flow mapping to determining the mechanisms of mitral regurgitation. J Am Coll Cardiol 20:1353-1361, 1992. 142.

Freeman WK, Schaff HV, Khandheria BK, et al: Intraoperative evaluation of mitral valve regurgitation and repair by transesophageal echocardiography: Incidence and significance of systolic anterior motion. J Am Coll Cardiol 20:599-609, 1992. 143.

Lindner JR, Case A, Dent JM, et al: Diagnostic valve of echocardiography in suspected endocarditis: An evaluation based on the pretest probability of disease. Circulation 93:730-736, 1996. 144.

Heinle S, Wilderman N, Harrison JK, et al: Value of transthoracic echocardiography in predicting embolic events in active infective endocarditis. Am J Cardiol 74:799-801, 1994. 145.

Yvorchuk KJ, Chan KL: Application of transthoracic and transesophageal echocardiography in the diagnosis and management of infective endocarditis. J Am Soc Echocardiogr 7:294-308, 1994. 146.

Durack DT, Lukes AS, Bright DK, et al: New criteria for diagnosis of infective endocarditis: Utilization of specific echocardiographic findings. Am J Med 96:200-209, 1994. 147.

CONGENITAL HEART DISEASE Blanchard DG, Ross RS, Dittrich HC: Non-bacterial thrombotic endocarditis: Assessment by transesophageal echocardiography. Chest 102:954-956, 1992. 148.

Appelbe AF, Olson D, Mixon R, et al: Libman-Sacks endocarditis mimicking intracardiac tumor. Am J Cardiol 68:817-818, 1991. 149.

Lowry RW, Zoghbi WA, Baker WB, et al: Clinical impact of transesophageal echocardiography in the diagnosis and management of infective endocarditis. Am J Cardiol 73:1089-1091, 1994. 150.

Sochowski RA, Chan KL: Implication of negative results on a monoplane transesophageal echocardiographic study in patients with suspected infective endocarditis. J Am Coll Cardiol 21:216-221, 1993. 151.

Aguado JM, Gonzalez-Vilchez F, Martin-Duran R, et al: Perivalvular abscesses associated with endocarditis: Clinical features and diagnostic accuracy of two-dimensional echocardiography. Chest 104:88-93, 1993. 152.

Leung DYC, Cranney GB, Hopkins AP, et al: Role of transesophageal echocardiography in the diagnosis and management of aortic root abscess. Br Heart J 72:175-181, 1994. 153.

Ballal RS, Mahan EF, Nanda NC, et al: Aortic and mitral valve perforation: Diagnosis by transesophageal echocardiography and Doppler color flow imaging. Am Heart J 121:214-217, 1991. 154.

155.

Nestico RF, DePace NL, Morganroth J, et al: Mitral annular calcification: Clinical, pathophysiologic,

and echocardiographic review. Am Heart J 107:989-996, 1984. Meltzer RS, Martin RP, Robbins BS, et al: Mitral annular calcification: Clinical and echocardiographic features. Acta Cardiol 35:189-202, 1980. 156.

Nair CK, Thomson W, Ryschon K, et al: Long-term follow-up of patients with echocardiographically detected mitral annular calcium and comparison with age- and sex-matched control subjects. Am J Cardiol 63:465-470, 1989. 157.

Hoppe UC, Dederichs B, Deutsch HJ, et al: Congenital heart disease in adults and adolescents: Comparative value of transthoracic and transesophageal echocardiography and MR imaging. Radiology 199:669-677, 1996. 158.

Simpson IA, Sahn DJ: Adult congenital heart disease: Use of transthoracic echocardiography versus magnetic resonance imaging scanning. Am J Cardiac Imaging 9:29-37, 1995. 159.

O'Leary PW, Hagler DJ, Seward JB, et al: Biplane intraoperative transesophageal echocardiography in congenital heart disease. Mayo Clin Proc 70:317-326, 1995. 160.

Mehta RH, Helmcke F, Nanda NC, et al: Uses and limitations of transthoracic echocardiography in the assessment of atrial septal defect in the adult. Am J Cardiol 67:288-294, 1991. 161.

Konstantinides S, Kasper W, Geibel A, et al: Detection of left-to-right shunt in atrial septal defect by negative contrast echocardiography: A comparison of transthoracic and transesophageal approach. Am Heart J 126:909-917, 1993. 162.

Watanabe F, Takenaka K, Suzuki J, et al: Visualization of sinus venous-type atrial septal defect by biplane transesophageal echocardiography. J Am Soc Echocardiogr 7:179-181, 1994. 163.

Hausmann D, Daniel WG, Mugge A, et al: Value of transesophageal color Doppler echocardiography for detection of different types of atrial septal defects in adults. J Am Soc Echocardiogr 5:481-488, 1992. 164.

Dall'Agata A, McGhie J, Taams MA, et al: Secundum atrial septal defect is a dynamic three-dimensional entity. Am Heart J 137:1075-1081, 1999. 165.

225

Tantengco MV, Bates JR, Ryan T, et al: Dynamic three-dimensional echocardiographic reconstruction of congenital cardiac septation defects. Pediatr Cardiol 18:184-190, 1997. 166.

Banerjee A, Bengur AR, Li JS, et al: Echocardiographic characteristics of successful deployment of the Das AngelWings atrial septal defect closure device: Initial multicenter experience in the United States. Am J Cardiol 83:1236-1241, 1999. 167.

Magni G, Hijazi ZM, Pandian NG, et al: Two- and three-dimensional transesophageal echocardiography in patient selection and assessment of atrial septal defect closure by the new DAS-Angel Wings device: Initial clinical experience. Circulation 96:1722-1728, 1997. 168.

169.

Okura H, Yoshikawa J, Yoshida K, et al: Quantification of left-to-right shunts in secundum atrial septal

defect by two-dimensional contrast echocardiography with use of Albunex. Am J Cardiol 75:639-642, 1995. Ilercil A, Meisner JS, Vijayaraman P, et al: Clinical significance of fossa ovalis membrane aneurysm in adults with cardioembolic cerebral ischemia. Am J Cardiol 80:96-98, 1997. 170.

Mugge A, Daniel WG, Angerman C, et al: Atrial septal aneurysm in adult patients: A multicenter study using transthoracic and transesophageal echocardiography. Circulation 91:2785-2792, 1995. 171.

Sun JP, Stewart WJ, Hanna J, et al: Diagnosis of patent foramen ovale by contrast versus color Doppler by transesophageal echocardiography: Relation to atrial size. Am Heart J 131:239-244, 1996. 172.

Stoddard MD, Keedy DL, Dawkins PR, et al: The cough test is superior to the Valsalva maneuver, the delineation of right-to-left shunting through a patent foramen ovale during contrast transesophageal echocardiography. Am Heart J 125:185-189, 1993. 173.

Ammash NM, Seward JB, Warnes CA, et al: Partial anomalous pulmonary venous connection: Diagnosis by transesophageal echocardiography. J Am Coll Cardiol 29:1351-1358, 1997. 174.

Goswami KC, Shrivastava S, Saxena A, et al: Echocardiographic diagnosis of total anomalous pulmonary venous connection. Am Heart J 126:433-440, 1993. 175.

Tee SD, Shiota T, Weintraub R, et al: Evaluation of ventricular septal defect by transesophageal echocardiography: Intraoperative assessment. Am Heart J 127:585-592, 1994. 176.

Sommer RJ, Golinko RJ, Ritter SB: Intracardiac shunting in children with ventricular septal defect: Evaluation with Doppler color flow mapping. J Am Coll Cardiol 16:1437-1444, 1990. 177.

Sutherland GS, Smyllie JH, Ogilvie BC, et al: Colour flow imaging in the diagnosis of multiple ventricular septal defects. Br Heart J 62:43-49, 1989. 178.

Houston AB, Lim MK, Doig WB, et al: Doppler assessment of the interventricular pressure drop in patients with ventricular septal defects. Br Heart J 60:50-56, 1988. 179.

Moises VA, Maciel BC, Hornberger LK, et al: A new method for noninvasive estimation of ventricular septal defect shunt flow by Doppler color flow mapping: Imaging of the laminar flow convergence region on the left septal surface. J Am Coll Cardiol 18:824-832, 1991. 180.

Moises VA, Maciel BC, Hornberger LK, et al: A new method for noninvasive estimation of ventricular septal defect shunt flow by Doppler color flow mapping: Imaging of the laminar flow convergence. J Am Coll Cardiol 18:833-836, 1991. 181.

Ramaciotti C, Keren A, Silverman NH: Importance of (perimembranous) ventricular septal aneurysm in the natural history of isolated perimembranous ventricular septal defect. Am J Cardiol 57:268-272, 1986. 182.

Sharma S, Anand R, Kanter KR, et al: The usefulness of echocardiography in the surgical management of infants with congenital heart disease. Clin Cardiol 15:891-897, 1992. 183.

Atallah-Yunes NH, Kavey RE, Bove BL, et al: Postoperative assessment of a modified surgical approach to repair of tetralogy of Fallot: Long-term follow-up. Circulation 94:II22-II26, 1996. 184.

185.

Santoro G, Marino B, DiCarlo D, et al: Echocardiographically guided repair of tetrology of Fallot. Am J

Cardiol 73:808-811, 1994. Gnanapragasam JP, Houston AB, Doig WB, et al: Transesophageal echocardiographic assessment of fixed subaortic obstruction in children. Br Heart J 66:281-284, 1991. 186.

Sadiq M, Sreeram N, Silove ED: Congenitally divided left atrium: Diagnostic pitfalls in cross-sectional echocardiography. Int J Cardiol 48:99-101, 1995. 187.

Bartel T, Muller S, Geibel A: Preoperative assessment of cor triatriatum in an adult by dynamic three dimensional echocardiography was more informative than transesophageal echocardiography or magnetic resonance imaging. Br Heart J 72:498-499, 1994. 188.

Roberson DA, Silverman NH: Ebstein's anomaly: Echocardiographic and clinical features in the fetus and neonate. J Am Coll Cardiol 14:1300-1307, 1989. 189.

Van Praagh S, Vangi V, Hee Sul J, et al: Tricuspid atresia or severe stenosis with partial common atrioventricular canal: Anatomic data, clinical profile and surgical considerations. J Am Coll Cardiol 17:932-943, 1991. 190.

Milne MJ, Sung RYT, Fok TF, et al: Doppler echocardiographic assessment of shunting via the ductus arteriosus in newborn infants. Am J Cardiol 64:102-105, 1989. 191.

Rao PS, Carey P: Doppler ultrasound in the prediction of pressure gradients across aortic coarctation. Am Heart J 118:299-307, 1989. 192.

Meissner MD, Panidis IP, Eshaghpour E, et al: Corrected transposition of the great arteries: Evaluation by two-dimensional and Doppler echocardiography. Am Heart J 111:599-601, 1986. 193.

Vogel M, Losch S: Dynamic three-dimensional echocardiography with a computed tomography imaging probe: Initial clinical experience with transthoracic application in infants and children with congenital heart defects. Br Heart J 71:462-467, 1994. 194.

DISEASES OF THE PERICARDIUM Levine MJ, Lorell BH, Diver DJ, et al: Implications of echocardiographically assisted diagnosis of pericardial tamponade in contemporary medical patients: Detection before hemodynamic embarrassment. J Am Coll Cardiol 17:59-65, 1991. 195.

Chuttani K, Pandian NG, Mohanty PK, et al: Left ventricular diastolic collapse: An echocardiographic sign of regional cardiac tamponade. Circulation 83:1999-2006, 1991. 196.

D'Cruz IA, Hoffman PK: A new cross sectional echocardiographic method for estimating the volume of large pericardial effusions. Br Heart J 66:448-451, 1991. 197.

Vazquez de Prada JA, Jiang L, Handschumacher MD, et al: Quantification of pericardial effusions by three-dimensional echocardiography. J Am Coll Cardiol 24:254-259, 1994. 198.

Torelli J, Marwick TH, Salcedo EE: Left atrial tamponade: Diagnosis by transesophageal echocardiography. J Am Soc Echocardiogr 4:413-414, 1991. 199.

Fusman B, Schwinger ME, Charney R, et al: Isolated collapse of left-sided heart chambers in cardiac tamponade: Demonstration by two-dimensional echocardiography. Am Heart J 121:613-616, 1991. 200.

Burstow DJ, Oh JK, Bailey KR, et al: Cardiac tamponade: Characteristic Doppler observations. Mayo Clin Proc 64:312-324, 1989. 201.

Klein AL, Cohen GI, Pietrolungo JF, et al: Differentiation of constrictive pericarditis from restrictive cardiiomyopathy by Doppler transesophageal echocardiographic measurements of respiratory variations in pulmonary venous flow. J Am Coll Cardiol 22:1935-1943, 1993. 202.

Vaitkus PT, Kussmaul WG: Constrictive pericarditis versus restrictive cardiomyopathy: A reappraisal and update of diagnostic criteria. Am Heart J 122:1431-1441, 1991. 203.

Oh JK, Hatle LK, Seward JB, et al: Diagnostic role of Doppler echocardiography in constrictive pericarditis. J Am Coll Cardiol 23:154-162, 1994. 204.

Myers RBH, Spodick DH: Constrictive pericarditis: Clinical and pathophysiologic characteristics. Am Heart J 138:219-232, 1999. 204A.

CARDIOMYOPATHIES Rihal CS, Nishimura RA, Hatle LK, et al: Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated cardiomyopathy. Circulation 90:2772-2779, 1994. 205.

Bach DS, Beanlands RSB, Schwaiger M, et al: Heterogeneity of ventricular function and myocardial oxidative metabolism in nonischemic dilated cardiomyopathy. J Am Coll Cardiol 25:1258-1262, 1995. 206.

Munt BI, Leotta DF, Bolson EL, et al: Left ventricular shape analysis from three-dimensional echocardiograms. J Am Soc Echocardiogr 11:761-769, 1998. 207.

Hurrell DG, Nishimura RA, Ilstrup DM, et al: Utility of pre-load alteration in assessment of left ventricular filling pressure by Doppler echocardiography: A simultaneous catheterization and Doppler echocardiographic study. J Am Coll Cardiol 30:459-467, 1997. 208.

Xie GY, Berk MR, Smith MD, et al: Prognostic value of Doppler transmitral flow patterns in patients with congestive heart failure. J Am Coll Cardiol 24:132-139, 1994. 209.

Lewis JF, Maron BJ: Hypertrophic cardiomyopathy characterized by marked hypertrophy of the posterior left ventricular free wall: Significance and clinical implications. J Am Coll Cardiol 18:421-428, 1991. 210.

Panza JA, Maris TJ, Maron BJ: Development and determinants of dynamic obstruction to left ventricular outflow in young patients with hypertrophic cardiomyopathy. Circulation 85:1398-1405, 1992. 211.

Panza JA, Petrone RK, Fananapazir L, et al: Utility of continuous wave Doppler echocardiography in the noninvasive assessment of left ventricular outflow tract pressure gradient in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 19:91-99, 1992. 212.

Schwammental E, Block M, Schwartzkopff B, et al: Prediction of the site and severity of obstruction in hypertrophic cardiomyopathy by flow mapping and continuous wave Doppler echocardiography. J Am Coll Cardiol 20:964-972, 1992. 213.

Spirito P, Maron BJ: Relation between extent of left ventricular hypertrophy and diastolic filling abnormalities in hypertrophic cardiomyopathy. J Am Coll Cardiol 15:808-813, 1990. 214.

Ko YL, Lei MH, Chiang FT, et al: Apical hypertrophic cardiomyopathy of the Japanese type: Occurrence with familial hypertrophic cardiomyopathy in a family. Am Heart J 124:1626-1630, 1992. 215.

Faber L, Seggewiss H, Ziemssen P, et al: Intraprocedural myocardial contrast echocardiography as a routine procedure in percutaneous transluminal septal myocardial ablation: Detection of threatening myocardial necrosis distant from the septal target area. Cathet Cardiovasc Interven 7:462-466, 1999. 216.

Gross DM, Williams JC, Caprilio C, et al: Echocardiographic abnormalities in the mucopolysaccharide storage diseases. Am J Cardiol 61:170-176, 1988. 217.

Spirito P, Lupi G, Melevendi C, et al: Restrictive diastolic abnormalities identified by Doppler echocardiography in patients with thalassemia major. Circulation 82:88-94, 1990. 218.

Simons M, Isner JM: Assessment of relative sensitivities of noninvasive tests for cardiac amyloidosis in documented cardiac amyloidosis. Am J Cardiol 69:425-427, 1992. 219.

226

Klein AL, Hatle LK, Taliercio CP, et al: Prognostic significance of Doppler measures of diastolic function in cardiac amyloidosis: A Doppler echocardiography study. Circulation 83:808-816, 1991. 220.

Oh JK, Hatle LK, Seward JB, et al: Diagnostic role of Doppler echocardiography in constrictive pericarditis. J Am Coll Cardiol 23:154-162, 1994. 221.

Schiavone WA, Calafiore PA, Salcedo EE: Transesophageal Doppler echocardiographic assessment of pulmonary venous flow velocity in restrictive cardiomyopathy and constrictive pericarditis. Am J Cardiol 63:1286-1288, 1990. 222.

Klein AL, Cohen GI, Pietrolungo JF, et al: Differentiation of constrictive pericarditis from restrictive cardiomyopathy by Doppler transesophageal echocardiographic measurements of respiratory variations in pulmonary venous flow. J Am Coll Cardiol 22:1935-1943, 1993. 223.

Garcia MJ, Rodriguez L, Ares M, et al: Differentiation of constrictive pericarditis from restrictive cardiomyopathy: Assessment of left ventricular diastolic velocities in longitudinal axis by Doppler tissue imaging. J Am Coll Cardiol 27:108-114, 1996. 224.

ISCHEMIC HEART DISEASE Stoddard MF, Pearson AC, Kern MJ, et al: Left ventricular diastolic function: Comparison of pulsed Doppler echocardiographic and hemodynamic indexes in subjects with and without coronary artery disease. J Am Coll Cardiol 13:327-336, 1989. 225.

Homans DC, Asinger R, Elsperger J, et al: Regional function and perfusion at the lateral border of ischemic myocardium. Circulation 71:1038-1047, 1985. 226.

Nidorf SM, Siu SC, Galambos G, et al: Benefit of late coronary reperfusion on ventricular morphology and function after myocardial infarction. J Am Coll Cardiol 21:683-691, 1993. 227.

Sabia P, Abbott RD, Afrookitech A, et al: Importance of two-dimensional echocardiographic assessment of left ventricular systolic function in patients presenting to the emergency room with cardiac-related symptoms. Circulation 84:1615-1624, 1991. 228.

Jugdutt BI: Identification of patients prone to infarct expansion by the degree of regional shape distortion on an early two-dimensional echocardiogram after myocardial infarction. Clin Cardiol 13:28-40, 1990. 229.

Oh JK, Ding ZP, Gersh BJ, et al: Restrictive left ventricular diastolic filling identifies patients with heart failure after acute myocardial infarction. J Am Soc Echocardiogr 5:497-503, 1992. 230.

Pipilis A, Meyer TE, Ormerdo O, et al: Early and late changes in left ventricular filling after acute myocardial infarction and the effect of infarct size. Am J Cardiol 70:1397-1401, 1992. 231.

Keren A, Goldberg S, Gottlieb S, et al: Natural history of left ventricular thrombi: Their appearance and resolution in the posthospitalization period of acute myocardial infarction. J Am Coll Cardiol 15:790-800, 1990. 232.

Delemarre BJ, Visser CA, Bot H, et al: Prediction of apical thrombus formation in acute myocardial infarction based on left ventricular spatial flow pattern. J Am Coll Cardiol 15:355-360, 1990. 233.

Abernethy M, Sharpe N, Smith H, et al: Echocardiographic prediction of left ventricular volume after myocardial infarction. J Am Coll Cardiol 17:1527-1532, 1991. 234.

Picard MH, Wilkins GT, Gillam LD, et al: Immediate regional endocardial surface expansion following coronary occlusion in the canine left ventricle: Disproportionate effects of anterior versus inferior ischemia. Am Heart J 121:753-762, 1991. 235.

Deshmukh HG, Khosla S, Jefferson KK: Direct visualization of left ventricular free wall rupture by transesophageal echocardiography in acute myocardial infarction. Am Heart J 126:475-477, 1993. 236.

Bansal RC, Pai RG, Hauck AJ, et al: Biventricular apical rupture and formation of pseudoaneurysm: Unique flow patterns by Doppler and color flow imaging. Am Heart J 124:497-500, 1992. 237.

Burns CA, Paulsen W, Arrowood JA, et al: Improved identification of posterior left ventricular pseudoaneurysms by transesophageal echocardiography. Am Heart J 124:796-799, 1992. 238.

Ballal RS, Sanyal RS, Nanda NC, et al: Usefulness of transesophageal echocardiography in the diagnosis of ventricular septal rupture secondary to acute myocardial infarction. Am J Cardiol 71:367-370, 1993. 239.

Hanlon JT, et al: Echocardiography recognition of partial papillary muscle rupture. J Am Soc Echocardiogr 6:101-103, 1993. 240.

Goldberger JJ, Himelman RB, Wolfe CL, et al: Right ventricular infarction: Recognition and assessment of its hemodynamic significance by two-dimensional echocardiography. J Am Soc Echocardiogr 4:140-146, 1991. 241.

242.

Marban E: Myocardial stunning and hibernation. Circulation 83:681-688, 1991.

Kloner RA, Bolli R, Marban E, et al: Medical and cellular implications of stunning, hibernation, and preconditioning: An NHLBI workshop. Circulation 97:1848-1867, 1998. 243.

Camici PG, Wijns W, Borgers M, et al: Pathophysiological mechanisms of chronic reversible left ventricular dysfunction due to coronary artery disease. Circulation 96:3205-3214, 1997. 244.

245.

Heusch G, Schulz R: Hibernating myocardium: A review. J Mol Cell Cardiol 28:2359-2372, 1996.

Vanoverschelde JJ, Wijns W, Depre C, et al: Mechanisms of chronic regional postischemic dysfunction in humans. Circulation 87:1513-1523, 1993. 246.

Armstrong WF, O'Donnell J, Ryan T, et al: Effect of prior myocardial infarction and extent and location of coronary disease on accuracy of exercise echocardiography. J Am Coll Cardiol 10:531-538, 1987. 247.

Crouse LJ, Harbrecht JJ, Vacek JL, et al: Exercise echocardiography as a screening test for coronary artery disease and correlation with coronary arteriography. Am J Cardiol 67:1213-1218, 1991. 248.

Marwick TH, Nemec JJ, Pashkow FJ, et al: Accuracy and limitations of exercise echocardiography in a routine clinical setting. J Am Coll Cardiol 19:74-81, 1992. 249.

Roger VL, Pellikka PA, Oh JK, et al: Identification of multivessel coronary artery disease by exercise echocardiography. J Am Coll Cardiol 24:109-114, 1994. 250.

Beleslin BD, Ostojic M, Stepanovic J, et al: Stress echocardiography in the detection of myocardial ischemia. Circulation 90:1168-1176, 1994. 251.

Quinones MA, Verani MS, Haichin RM, et al: Exercise echocardiography versus 201 Tl single-photon emission computed tomography in evaluation of coronary artery disease: Analysis of 292 patients. Circulation 85:1026-1031, 1992. 252.

Peteiro J, Monserrat L, Martinez D, et al: Accuracy of exercise echocardiography to detect coronary artery disease in left bundle branch block unassociated with either acute or healed myocardial infarction. Am J Cardiol 85:890-893, 2000. 252A.

Ryan T, Segar DS, Sawada SG, et al: Detection of coronary artery disease with upright bicycle exercise echocardiography. J Am Soc Echocardiogr 6:186-197, 1993. 253.

Cohen JL, Ottenweller JE, George AK, et al: Comparison of dobutamine and exercise echocardiography for detecting coronary artery disease. Am J Cardiol 72:1226-1231, 1993. 254.

Hecht HS, DeBord L, Shaw R, et al: Digital supine bicycle stress echocardiography: A new technique for evaluating coronary artery disease. J Am Coll Cardiol 21:950-956, 1993. 255.

Luotolahti M, Saraste M, Hartiala J: Exercise echocardiography in the diagnosis of coronary artery disease. Ann Med 28:73-77, 1996. 256.

Mertes H, Sawada SG, Ryan T, et al: Symptoms, adverse effects, and complications associated with dobutamine stress echocardiography: Experience in 1118 patients. Circulation 88:15-19, 1993. 257.

Bremer ML, Monahan KH, Stussy VL, et al: Safety of dobutamine stress echocardiography supervised by registered nurse sonographers. J Am Soc Echocardiogr 11:601-605, 1998. 258.

Marwick T, D'Hondt AM, Baudhuin T, et al: Optimal use of dobutamine stress for the detection and evaluation of coronary artery disease: Combination with echocardiography or scintigraphy, or both? J Am 259.

Coll Cardiol 22:159-167, 1993. Ling LH, Pellikka PA, Mahoney DW, et al: Atropine augmentation in dobutamine stress echocardiography: Role and incremental value in a clinical practice setting. J Am Coll Cardiol 28:551-557, 1996. 260.

Marcovitz PA, Armstrong WF: Accuracy of dobutamine stress echocardiography in detecting coronary artery disease. Am J Cardiol 69:1269-1273, 1992. 261.

Takeuchi M, Araki M, Nakashima Y, et al: Comparison of dobutamine stress echocardiography and stress thallium-201 single-photon emission computed tomography for detecting coronary artery disease. J Am Soc Echocardiogr 6:593-602, 1993. 262.

Elhendy A, van Domburg RT, Bax JJ, et al: Accuracy of dobutamine technetium 99m sestamibi SPECT imaging for the diagnosis of single-vessel coronary artery disease: Comparison with echocardiography. Am Heart J 139:224-230, 2000. 262A.

Fragasso G, Lu C, Dabrowski P, et al: Comparison of stress/rest myocardial perfusion tomography, dipyridamole and dobutamine stress echocardiography for the detection of coronary disease in hypertensive patients with chest pain and positive exercise test. J Am Coll Cardiol 34:441-447, 1999. 262B.

Smart SC, Knickelbine T, Malik F, et al: Dobutamine-atropine stress echocardiography for the detection of coronary artery disease in patients with left ventricular hypertrophy. Circulation 101:258-263, 2000. 262C.

Mathias W, Arruda A, Santos FC, et al: Safety of dobutamine-atropine stress echocardiography: A prospective experience of 4033 consecutive studies. J Am Soc Echocardiogr 12:785-791, 1999. 262D.

Severi S, Picano E, Michelassi C, et al: Diagnostic and prognostic value of dipyridamole echocardiography in patients with suspected coronary artery disease. Circulation 89:1160-1173, 1994. 263.

Ostojic M, Picano E, Beleslin B, et al: Dipyridamole-dobutamine echocardiography: A novel test for the detection of milder forms of coronary artery disease. J Am Coll Cardiol 23:1115-1122, 1994. 264.

Kwok Y, Kim C, Grady D, et al: Meta-analysis of exercise testing to detect coronary artery disease in women. Am J Cardiol 83:660-666, 1999. 265.

Lewis JF, Lin L, McGorray S, et al: Dobutamine stress echocardiography in women with chest pain. J Am Coll Cardiol 33:1462-1468, 1999. 266.

Chuah SC, Pellikka PA, Roger VL, et al: Role of dobutamine stress echocardiography in predicting outcome in 860 patients with known or suspected coronary artery disease. Circulation 97:1474-1480, 1998. 267.

Krivokapich J, Child JS, Walter DO, et al: Prognostic value of dobutamine stress echocardiography in predicting cardiac events in patients with known or suspected coronary artery disease. J Am Coll Cardiol 33:708-716, 1999. 268.

Poldermans D, Fioretti PM, Boersma E, et al: Long-term prognostic value of dobutamine-atropine stress echocardiography in 1737 patients with known or suspected coronary artery disease. Circulation 99:757-762, 1999. 269.

227

Syed MA, Al-Malki Q, Kazmouz G, et al: Usefulness of exercise echocardiography in predicting cardiac events in an outpatient population. Am J Cardiol 82:569-573, 1998. 270.

Pingitore A, Picano E, Varga A, et al: Prognostic value of pharmacological stress echocardiography in patients with known or suspected coronary artery disease. J Am Coll Cardiol 34:1769-1777, 1999. 270A.

Carlos ME, Smart SC, Wynsen JC, et al: Dobutamine stress echocardiography for risk stratification after myocardial infarction. Circulation 95:1402-1410, 1997. 271.

Sicari R, Picano E, Landi P, et al: Prognostic value of dobutamine-atropine stress echocardiography early after acute myocardial infarction. J Am Coll Cardiol 29:254-260, 1997. 272.

Shaw LJ, Peterson ED, Kesler K, et al: A meta-analysis of predischarge risk stratification after acute myocardial infarction with stress electrocardiographic, myocardial perfusion, and ventricular function imaging. Am J Cardiol 78:1327-1337, 1996. 273.

Mertes H, Erbel R, Nixdorff U, et al: Exercise echocardiography for the evaluation of patients after nonsurgical coronary artery revascularization. J Am Coll Cardiol 21:1087-1093, 1993. 274.

Bax JJ, Poldermans D, Elhendy A, et al: Improvement of left ventricular ejection fraction, heart failure symptoms and prognosis after revascularization in patients with chronic coronary artery disease and viable myocardium detected by dobutamine stress echocardiography. J Am Coll Cardiol 34:163-169, 1999. 275.

276.

Bonow RO: Identification of viable myocardium. Circulation 94:2674-2680, 1996.

Bolognese L, Buonamici P, Cerisano G, et al: Early dobutamine echocardiography predicts improvement in regional and global left ventricular function after reperfused acute myocardial infarction without residual stenosis of the infarct-related artery. Am Heart J 139:153-163, 2000. 276A.

Amanullah AM, Chaudhry FA, Heo J, et al: Comparison of dobutamine echocardiography, dobutamine sestamibi, and rest-redistribution thallium-201 single-photon emission computed tomography for determining contractile reserve and myocardial ischemia in ischemic cardiomyopathy. Am J Cardiol 84:626-631, 1999. 276B.

Samady H, Elefteriades JA, Abbott BG, et al: Failure to improve left ventricular function after coronary revascularization for ischemic cardiomyopathy is not associated with worse outcome. Circulation 100:1298-1304, 1999. 276C.

Monin JL, Garot J, Scherrer-Crosbie M, et al: Prediction of functional recovery of viable myocardium after delayed revascularization in postinfarction patients. J Am Coll Cardiol 34:1012-1019, 1999. 276D.

Dionisopoulos P, Smart SC, Sagar KB: Dobutamine stress echocardiography predicts left ventricular remodeling after acute myocardial infarction. J Am Soc Echocardiogr 12:777-784, 1999. 276E.

276F. Hoffer

EP, Dewe W, Celentano C, et al: Low-level exercise echocardiography detects contractile reserve and predicts reversible dysfunction after acute myocardial infarction. J Am Coll Cardiol

34:989-997, 1999. Shaw LJ, Eagle KA, Gersh BJ, et al: Meta-analysis of intravenous dipyridamole-thallium-201 imaging (1985 to 1994) and dobutamine echocardiography (1991 to 1994) for risk stratification before vascular surgery. J Am Coll Cardiol 27:787-798, 1996. 277.

Wei K, Jayaweera AR, Firoozan S, et al: Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion. Circulation 97:473-483, 1998. 278.

Porter TR, Li S, Kricsfeld D, et al: Detection of myocardial perfusion in multiple echocardiographic windows with one intravenous injection of microbubbles using transient response second harmonic imaging. J Am Coll Cardiol 29:791-799, 1997. 279.

Kaul S, Senior R, Dittrich H, et al: Detection of coronary artery disease with myocardial contrast echocardiography. Circulation 96:785-792, 1997. 280.

Lindner JR, Villanueva FS, Dent JM, et al: Assessment of resting perfusion with myocardial contrast echocardiography: Theoretical and practical considerations. Am Heart J 139:231-240, 2000. 280A.

Senior R, Kaul S, Soman P, et al: Power Doppler harmonic imaging: A feasibility study of a new technique for the assessment of myocardial perfusion. Am Heart J 139:245-251, 2000. 280B.

Memmola C, Iliceto S, Rizzon P: Detection of proximal stenosis of left coronary artery by digital transesophageal echocardiography: Feasibility, sensitivity, and specificity. J Am Soc Echocardiogr 6:149-157, 1993. 281.

Faletra F, Cipriani M, Corno R, et al: Transthoracic high-frequency echocardiographic detection of atherosclerotic lesions in the descending portion of the left coronary artery. J Am Soc Echocardiogr 6:290-298, 1993. 282.

Sawada SG, Ryan T, Segar D, et al: Distinguishing ischemic cardiomyopathy from nonischemic dilated cardiomyopathy with coronary echocardiography. J Am Coll Cardiol 19:1223-1228, 1992. 283.

Tardif JC, Vannan MA, Taylor K, et al: Delineation of extended lengths of coronary arteries by multiplane transesophageal echocardiography. J Am Coll Cardiol 24:909-919, 1994. 284.

Eteedgui JA, Neches WH, Pahl E: The role of cross-sectional echocardiography in Kawasaki disease. Cardiol Young 1:221, 1991. 285.

Isaaz K, Bruntz JF, Ethevenot G, et al: Abnormal coronary flow velocity pattern in patients with left ventricular hypertrophy, angina pectoris, and normal coronary arteries: A transesophageal Doppler echocardiographic study. Am Heart J 128:500-510, 1994. 286.

Yamagishi M, Yasu T, O'Hara K, et al: Detection of coronary blood flow associated with left main coronary artery stenosis by transesophageal Doppler color flow echocardiography. J Am Coll Cardiol 17:87-93, 1991. 287.

DISEASES OF THE AORTA Cigarroa JE, Isselbacher EM, DeSanctis RW, et al: Diagnostic imaging in the evaluation of suspected aortic dissection: Old standards and new directions. N Engl J Med 328:35-43, 1993. 288.

Erbel R, Daniel W, Visser C, et al: Echocardiography in diagnosis of aortic dissection. Lancet 1:457-461, 1989. 289.

Erbel R, Oelert H, Meyer J, et al: Effect of medical and surgical therapy on aortic dissection evaluated by transesophageal echocardiography: Implications for prognosis and therapy. Circulation 87:1604-1615, 1993. 290.

Keren A, Kim CB, Hu BS, et al: Accuracy of biplane and multiplane transesophageal echocardiography in diagnosis of typical acute aortic dissection and intramural hematoma. J Am Coll Cardiol 28:627-636, 1996. 291.

Ballal RS, Nanda NC, Gatewood R, et al: Usefulness of transesophageal echocardiography in assessment of aortic dissection. Circulation 84:1903-1914, 1991. 292.

Nienaber CA, von Kodolitsch Y, Nicolas V, et al: The diagnosis of thoracic aortic dissection by noninvasive imaging procedures. N Engl J Med 328:1-9, 1993. 293.

Hashimoto S, Kumada T, Osakada G, et al: Assessment of transesophageal Doppler echography in dissecting aortic aneurysm. J Am Coll Cardiol 14:1253-1262, 1989. 294.

Mohr-Kahaly S, Erbel R, Rennollet H, et al: Ambulatory follow-up of aortic dissection by transesophageal two-dimensional and color-coded Doppler echocardiography. Circulation 80:24-33, 1989. 295.

Smith MD, Cassidy JM, Souther S, et al: Transesophageal echocardiography in the diagnosis of traumatic rupture of the aorta. N Engl J Med 332:356-362, 1995. 296.

Armstrong WF, Bach DS, Carey L, et al: Spectrum of acute dissection of the ascending aorta: A transesophageal echocardiographic study. J Am Soc Echocardiogr 9:646-656, 1996. 297.

Armstrong WF, Bach DS, Carey LM, et al: Clinical and echocardiographic findings in patients with suspected acute aortic dissection. Am Heart J 136:1051-1060, 1998. 298.

Keane MG, Wiegers SE, Yang E, et al: Structural determinants of aortic regurgitation in type A dissection and the role of valvular resuspension as determined by intraoperative transesophageal echocardiography. Am J Cardiol 85:604-610, 2000. 298A.

Nishino M, Masugata H, Yamada Y, et al: Evaluation of thoracic aortic atherosclerosis by transesophageal echocardiography. Am Heart J 127:336-344, 1994. 299.

Tunick PA, Rosenzweig BP, Katz ES, et al: High risk for vascular events in patients with protruding aortic atheromas: A prospective study. J Am Coll Cardiol 23:1085-1090, 1994. 300.

Tunick PA, Kronzon I: Atheromas of the thoracic aorta: Clinical and therapeutic update. J Am Coll Cardiol 35:545-554, 2000. 300A.

Stern A, Tunick PA, Culliford AT, et al: Protruding aortic arch atheromas: Risk of stroke during heart surgery with and without aortic arch endarterectomy. Am Heart J 138:746-752, 1999. 300B.

Di Tullio MR, Sacco RL, Savoia MR, et al: Aortic atheroma morphology and the risk of ischemic stroke in a multiethnic population. Am Heart J 139:329-336, 2000. 300C.

301.

Mohr-Kahaly S, Erbel R, Kearney P, et al: Aortic intramural hemorrhage visualized by

transesophageal echocardiography: Findings and prognostic implications. J Am Coll Cardiol 23:658-664, 1994. Villacosta I, San Roman JA, Ferreiros J, et al: Natural history and serial morphology of aortic intramural hematoma: A novel variant of aortic dissection. Am Heart J 134:495-507, 1997. 302.

El Habbal MH: Cardiovascular manifestations of Marfan's syndrome in the young: Comparison with clinical findings and with reoentgenographic estimation of aortic root size. Am Heart J 123:752-757, 1992. 303.

Rozendaal L, Groenink M, Naeff MS, et al: Marfan syndrome in children and adolescents: An adjusted nomogram for screening aortic root dilatation. Heart 79:69-72, 1998. 304.

Cabanes L, Garcia E, VanDamme C, et al: Aneurysm of the noncoronary sinus of Valsalva ruptured into the left atrium. Am Heart J 124:1659-1661, 1992. 305.

Dev V, Goswami KC, Shrivastava S, et al: Echocardiographic diagnosis of aneurysm of the sinus of Valsalva. Am Heart J 126:930-936, 1993. 306.

CARDIAC MASSES Shyu KG, Chen JJ, Cheng JJ, et al: Comparison of transthoracic and transesophageal echocardiography in the diagnosis of intracardiac tumors in adults. J Clin Ultrasound 22:381-389, 1994. 307.

Engberding R, Daniel WG, Erbel R, et al: Diagnosis of heart tumours by transesophageal echocardiography: A multicentre study in 154 patients. Eur Heart J 14:1223-1228, 1993. 308.

309.

Markel ML, Waller BF, Armstrong WF: Cardiac myxoma: A review. Medicine 66:114-125, 1997.

Grande AM, Minzioni G, Pederzolli C, et al: Cardiac lipomas: Descriptions of 3 cases. J Cardiovasc Surg 39:813-815, 1998. 310.

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Lestuzzi C, Nicolosi GL, Mimo R, et al: Usefulness of transesophageal echocardiography in evaluation of paracardiac neoplastic masses. Am J Cardiol 70:247-251, 1992. 311.

Geibel A, Kasper W, Keck A, et al: Diagnosis, localization and evaluation of malignancy of heart and mediastinal tumors by conventional and transesophageal echocardiography. Acta Cardiol 51:395-408, 1996. 312.

Rashid H, Exner DV, Mirsky I, et al: Comparison of echocardiography and radionuclide angiography as predictors of mortality in patients with left ventricular dysfunction (studies of left ventricular dysfunction). Am J Cardiol 84:299-303, 1999. 312A.

SPECIFIC CLINICAL UTILIZATION OF ECHOCARDIOGRAPHY Lee RJ, Bartzokis T, Yeoh TK, et al: Enhanced detection of intracardiac sources of cerebral emboli by transesophageal echocardiography. Stroke 22:734-739, 1991. 313.

Labovitz AJ: Transesophageal echocardiography and unexplained cerebral ischemia: A multicenter follow-up study. Am Heart J 137:1082-1087, 1999. 314.

DeRook FA, Comess KA, Albers GW, et al: Transesophageal echocardiography in the evaluation of stroke. Ann Intern Med 117:922-932, 1992. 315.

Mugge A, Kuhn H, Nikutta P, et al: Assessment of left atrial appendage function by biplane transesophageal echocardiography in patients with nonrheumatic atrial fibrillation: Identification of a subgroup of patients at increased embolic risk. J Am Coll Cardiol 23:599-607, 1994. 316.

Fatkin D, Kelly RP, Feneley MP: Relations between left atrial appendage blood flow velocity, spontaneous echocardiographic contrast and thromboembolic risk in vivo. J Am Coll Cardiol 23:961-969, 1994. 317.

Manning WJ, Silverman DI, Gordon SPF, et al: Cardioversion from atrial fibrillation without prolonged anticoagulation with use of transesophageal echocardiography to exclude the presence of atrial thrombi. N Engl J Med 328:750-755, 1993. 318.

Grimm RA, Stewart WJ, Arheart KL, et al: Left atrial appendage "stunning" after electrical cardioversion of atrial flutter: An attenuated response compared with atrial fibrillation as the mechanism for lower susceptibility to thromboembolic events. J Am Coll Cardiol 29:582-589, 1997. 319.

Silverman DI, Manning WJ: Role of echocardiography in patients undergoing elective cardioversion of atrial fibrillation. Circulation 98:479-486, 1998. 320.

Goldman ME, Pearce LA, Hart RG, et al: Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: I. Reduced flow velocity in the left atrial appendage (The Stroke Prevention in Atrial Fibrillation [SPAF-III] Study). J Am Soc Echocardiogr 12:1080-1087, 1999. 320A.

Asinger RW, Koehler J, Pearce LA, et al: Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: II. Dense spontaneous echocardiographic contrast (The Stroke Prevention in Atrial Fibrillation [SPAF-III] Study). J Am Soc Echocardiogr 12:1088-1096, 1999. 320B.

Rittoo D, Sutherland GR, Samuel L, et al: Role of transesophageal echocardiography in diagnosis and management of central pulmonary artery thromboembolism. Am J Cardiol 71:1115-1118, 1993. 321.

Cheriex EC, Steeram N, Eussen YFJM, et al: Cross-sectional Doppler echocardiography as the initial technique for the diagnosis of acute pulmonary embolism. Br Heart J 72:52-57, 1994. 322.

Rudoni RR, Jackson RE, Godrey GW, et al: Use of two-dimensional echocardiography for the diagnosis of pulmonary embolus. J Emerg Med 16:5-8, 1998. 323.

Bossone E, Duong-Wagner TH, Paciocco G, et al: Echocardiographic features of primary pulmonary hypertension. J Am Soc Echocardiogr 12:655-662, 1999. 324.

Bossone E, Rubenfire M, Bach DS, et al: Range of tricuspid regurgitation velocity at rest and during exercise in normal adult men: Implications for the diagnosis of pulmonary hypertension. J Am Coll Cardiol 33:1662-1666, 1999. 325.

Martin GR, Ruckman RN: Fetal echocardiography: A large clinical experience and follow-up. J Am Soc Echocardiogr 3:4-8, 1990. 326.

Callahan JA, Seward JB, Nishimura RA, et al: Two-dimensional echocardiography guided pericardiocentesis: Experience in 117 consecutive patients. Am J Cardiol 55:476-479, 1985. 327.

Chu E, Fitzpatrick AP, Chin MC, et al: Radiofrequency catheter ablation guided by intracardiac echocardiography. Circulation 89:1301-1305, 1994. 328.

Chu E, Kalman JM, Kwasman MA, et al: Intracardiac echocardiography during radiofrequency catheter ablation of cardiac arrhythmias in humans. J Am Coll Cardiol 24:1351-1357, 1994. 329.

Pytlewski G, Georgeson S, Burke J, et al: Endomyocardial biopsy under transesophageal echocardiographic guidance can be safely performed in the critically ill cardiac transplant recipient. Am J Cardiol 73:1019-1020, 1994. 330.

Ewert P, Berger F, Daehnert I, et al: Diagnostic catheterization and balloon sizing of atrial septal defects by echocardiographic guidance without fluoroscopy. Echocardiography 17:159-163, 2000. 330A.

Thomas MR, Monaghan MJ, Smyth DW, et al: Comparative value of transthoracic and transesophageal echocardiography before balloon dilation of the mitral valve. Br Heart J 68:493-497, 1992. 331.

Boutin C, Dyck J, Benson L, et al: Balloon atrial septostomy under transesophageal echocardiographic guidance. Pediatr Cardiol 13:176-177, 1992. 332.

VanDerVelde ME, Sanders SP, Keane JF, et al: Transesophageal echocardiographic guidance of transcatheter ventricular septal defect closure. J Am Coll Cardiol 23:1660-1665, 1994. 333.




GUIDELINES USE OF ECHOCARDIOGRAPHY Thomas H. Lee Guidelines for the use of echocardiography were published by an ACC/AHA task force in 1997.[1] These guidelines focus on transthoracic and transesophageal echocardiography (TTE and TEE, respectively), with Doppler analysis; they do not address newer technologies such as three-dimensional echocardiography, intravascular ultrasound, or contrast medium-enhanced echocardiography. In the absence of randomized trials that explictly test the impact of diagnostic tests on outcomes, these guidelines are based on expert consensus and observational studies. Additional recommendations for use of echocardiography for specific issues related to valvular heart disease were developed by a later ACC/AHA task force focusing on valvular heart disease.[2] These recommendations are summarized in the Guidelines following Chapter 46 . Recommendations for the use of echocardiography in patients with suspected endocarditis are also described in the Guidelines following Chapter 47 . The guidelines provide recommendations regarding the appropriateness of use of echocardiography in various clinical settings, using the standard three-class system of ACC/AHA guidelines. The guidelines specify situations in which echocardiography is considered unlikely to contribute information that improves the management of patients. They also address recommendations about the frequency with which Doppler echocardiography should be repeated for some clinical issues. In general, the guidelines discourage routine use of echocardiography for patients whose initial echocardiograms show minimal or mild abnormalities, unless there is a change in clinical signs or symptoms.

MURMURS AND VALVULAR HEART DISEASE Echocardiography is a critical tool for the assessment of patients with cardiac murmurs in the setting of cardiorespiratory symptoms and in patients with possible structural heart disease (Table 7-G-1) . However, the guidelines emphasize that echocardiography is not a substitute for a careful cardiovascular examination, and they specify that this test is not appropriate in patients with murmurs that an experienced observer identifies as functional or innocent. Characteristics of such murmurs as identified in the guidelines are a systolic murmur of short duration, grade 1 or 2 intensity at the left sternal border, a systolic ejection pattern, a normal S2 , no other abnormal sounds or murmurs, no evidence of ventricular hypertrophy or dilatation, no thrills, and the absence of an increase in intensity with the Valsalva maneuver. For patients with known or suspected valvular stenosis, echocardiography is an appropriate test for assessing severity of valvular stenosis and ventricular dysfunction. This test is appropriate for evaluation of changes in symptoms or signs, and also in asymptomatic patients with severe valvular stenosis or with left ventricular dysfunction or hypertrophy (see Table 7-G-1) . In contrast, the guidelines discourage routine use of echocardiography for serial re-evaluations of patients with mild aortic or mitral stenosis whose functional status and clinical examination are unchanged. Doppler echocardiography is also the test of choice to evaluate valvular regurgitation and assess the need for surgical intervention.

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TABLE 7-7-G-1 -- ACC/AHA GUIDELINES FOR USE OF ECHOCARDIOGRAPHY Indication Class I Class IIa Class IIb Class III Evaluation of heart murmurs

1. A murmur in a patient with cardiorespiratory symptoms 2. A murmur in an asymptomatic patient if the clinical features indicate at least a moderate probability that the murmur is reflective of structural heart disease

1. A murmur in an asymptomatic patient in whom there is a low probability of heart disease but in whom the diagnosis of heart disease cannot be reasonably excluded by the standard cardiovascular clinical evaluation

1. In an adult, an asymptomatic heart murmur that has been identified by an experienced observer as functional or innocent

Valvular stenosis

1. Diagnosis; assessment of hemodynamic severity 2. Assessment of LV and RV size, function, and/or hemodynamics 3. Reevaluation of patients with known valvular stenosis with changing symptoms or signs 4. Assessment of changes in hemodynamic severity and ventricular compensation in patients with known valvular stenosis during pregnancy 5. Reevaluation of asymptomatic patients with severe stenosis

1. Assessment of the hemodynamic significance of mild to moderate valvular stenosis by stress Doppler echocardiography 2. Reevaluation of patients with mild to moderate aortic stenosis with LV dysfunction or hypertrophy even without clinical symptoms

1. Reevaluation of patients with mild to moderate aortic valvular stenosis with stable signs and symptoms

1. Routine reevaluation of asymptomatic adult patients with mild aortic stenosis having stable physical signs and normal LV size and function 2. Routine reevaluation of asymptomatic patients with mild to moderate mitral stenosis and stable physical signs

Native valvular regurgitation

1. Diagnosis; assessment of hemodynamic severity 2. Initial assessment and reevaluation (when indicated) of LV and RV size, function, and/or hemodynamics 3. Reevaluation of patients with mild to moderate valvular changing symptoms 4. Reevaluation of asymptomatic patients with severe regurgitation 5. Assessment of changes in hemodynamic severity and ventricular compensation in patients with known valvular regurgitation during pregnancy 6. Reevaluation of patients with mild to moderate regurgitation with ventricular dilation without clinical symptoms 7. Assessment of the effects of medical therapy on the severity of regurgitation and ventricular compensation and function

1. Reevaluation of patients with mild to moderate mitral regurgitation without chamber dilation and without clinical symptoms 2. Reevaluation of patients with moderate aortic regurgitation without chamber dilation and without clinical symptoms

1. Routine reevaluation in asymptomatic patients with mild valvular regurgitation having stable physical signs and normal LV size and function

Mitral valve 1. Diagnosis; prolapse (MVP) assessment of hemodynamic severity, leaflet morphology, and/or ventricular compensation in patients with physical signs MVP

1. To exclude MVP in patients who have been diagnosed but without clinical evidence to support the diagnosis 2. To exclude MVP in patients with first-degree relatives with known myxomatous valve disease 3. Risk stratification in patients with physical signs of MVP or known MVP

Interventions for valvular heart disease and prosthetic valves

1. Routine reevaluation study after baseline studies of patients with valve replacements with mild to moderate ventricular dysfunction without changing clinical signs or symptoms

1. Assessment of the timing of valvular intervention based on ventricular compensation, function, and/or severity of primary and secondary lesions 2. Selection of alternative therapies for mitral valve disease (such as balloon valvuloplasty, operative valve repair, valve replacement)* 3. Use of echocardiography (especially transesophageal) in performing interventional techniques (e.g., balloon valvotomy) for valvular disease 4.

1. Exclusion of MVP in patients with ill-defined symptoms in the absence of a constellation of clinical symptoms or physical findings suggestive of MVP or a positive family history 2. Routine repetition of echocardiography in patients with MVP with no or mild regurgitation and no changes in clinical signs or symptoms 1. Routine reevaluation at the time of increased failure rate of a bioprosthesis without clinical evidence of prosthetic dysfunction

1. Routine reevaluation of patients with valve replacements without suspicion of valvular dysfunction and unchanged clinical signs and symptoms 2. Patients whose clinical status precludes therapeutic interventions

transesophageal) in performing interventional techniques (e.g., balloon valvotomy) for valvular disease 4. Postinterventional baseline studies for valve function (early) and ventricular remodeling (late) 5. Reevaluation of patients with valve replacement with changing clinical signs and symptoms; suspected prosthetic dysfunction (stenosis, regurgitation) or thrombosis* Patients with chest pain

1. Diagnosis of underlying cardiac disease in patients with chest pain and clinical evidence of valvular, pericardial, or primary myocardial disease 2. Evaluation of chest pain in patients with suspected acute myocardial ischemia, when baseline ECG is nondiagnostic and when study can be obtained during pain or soon after its abatement 3. Evaluation of chest pain in patients with suspected aortic dissection 4. Chest pain in patients with severe hemodynamic instability

1. Evaluation of chest pain for which a noncardiac etiology is apparent 2. Diagnosis of chest in a patient with ECG changes diagnostic of myocardial ischemia/infarction

dissection 4. Chest pain in patients with severe hemodynamic instability Diagnosis of acute myocardial ischemic syndromes

1. Diagnosis of suspected acute ischemia or infarction not evident by standard means 2. Measurement of baseline LV function 3. Patients with inferior myocardial infarction and bedside evidence suggesting possible RV infarction 4. Assessment of mechanical complications and mural thrombus (TEE is indicated when TTE studies are not diagnostic.)

1. Identification of location/severity of disease in patients with ongoing ischemia

Risk assessment, prognosis, and assessment of therapy in acute myocardial ischemic syndromes

1. Assessment of infarct size and/or extent of jeopardized myocardium 2. In-hospital assessment of ventricular function when the results are used to guide therapy 3. In-hospital or early postdischarge assessment of the presence/extent of inducible ischemia whenever baseline abnormalities are expected to compromise ECG interpretation

1. In-hospital or early postdischarge assessment of the presence/extent of inducible ischemia in the absence of baseline abnormalities expected to compromise ECG interpretation 2. Assessment of myocardial viability when required to define potential efficacy of revascularization 3. Reevaluation of ventricular function during recovery when results are used to guide therapy

1. Diagnosis of acute myocardial infarction already evident by standard means

1. Assessment of long term prognosis ( 2 years after acute myocardial infarction)

1. Routine reevaluation in the absence of any change in clinical status

3. Reevaluation of ventricular function during recovery when results are used to guide therapy 4. Assessment of ventricular function after revascularization Diagnosis and prognosis of chronic ischemic heart disease

1. Diagnosis of myocardial ischemia in symptomatic individuals

None

2. Assessment of global ventricular function at rest 3. Assessment of myocardial viability (hibernating myocardium) for planning revascularization 4. Assessment of functional significance of coronary lesions (if not already known) in planning percutaneous transluminal coronary angioplasty Assessment of interventions in chronic ischemic heart disease

1. Assessment of LV function when needed to guide institution and modification of drug therapy in patients with known or suspected LV dysfunction 2. Assessment for restenosis after revascularization in patients with atypical recurrent symptoms

1. Assessment of restenosis after revascularization in patients with typical recurrent symptoms

1. Diagnosis of myocardial ischemia in selected patients with an intermediate or high pretest likelihood of coronary artery disease

1. Screening of asymptomatic persons with a low likelihood of coronary artery disease 2. Routine periodic reassessment of stable patients for whom no change 2. Assessment of in therapy is an asymptomatic contemplated patient with 3. Routine positive results substitution for from a screening treadmill exercise treadmill test testing in patients 3. Assessment of for whom ECG a global ventricular analysis is function with expected to exercise suffice

1. Routine assessment of asymptomatic patients after revascularization

Patients with dyspnea, edema, or cardiomyopathy

1. Assessment of None LV size and function in patients with suspected cardiomyopathy or clinical diagnosis of heart failure* 2. Edema with clinical signs of elevated central venous pressure when a potential cardiac etiology is suspected or when central venous pressure cannot be estimated with confidence and clinical suspicion of heart disease is high * 3. Dyspnea with clinical signs of heart disease 4. Patients with unexplained hypotension, especially in the intensive care unit* 5. Patients exposed to cardiotoxic agents, to determine the advisability of additional or increased dosages 6. Reevaluation of LV function in patients with established cardiomyopathy when there has been a documented change in clinical status to guide medical therapy

1. Reevaluation of patients with established cardiomyopathy when there is no change in clinical status 2. Reevaluation of patients with edema when a potential cardiac cause has already been demonstrated

1. Evaluation of LV ejection fraction in patients with recent (contrast or radionuclide) angiographic determination of ejection fraction 2. Routine reevaluation in clinically stable patients in whom no change is contemplated 3. In patients with edema, normal venous pressure, and no evidence of heart disease

Pericardial disease

1. Patients with suspected pericardial disease, including effusion, constriction, or effusive-constrictive process 2. Patients with suspected bleeding in the pericardial space (e.g., trauma, perforation) 3. Follow-up study to evaluate recurrence of effusion or to diagnose early constriction. Repeat studies may be goal directed to answer a specific clinical question. 4. Pericardial friction rub developing in acute myocardial infarction accompanied by symptoms such as persistent pain, hypotension, and nausea

1. Follow-up studies to detect early signs of tamponade in the presence of large or rapidly accumulating effusions. A goal-directed study may be appropriate. 2. Echocardiographic guidance and monitoring of pericardiocentesis

1. Postsurgical pericardial disease, including postpericardiotomy syndrome, with potential for hemodynamic impairment 2. In the presence of a strong clinical suspicion and nondiagnostic TTE, TEE assessment of pericardial thickness to support a diagnosis of constrictive pericarditis

1. Routine follow-up of small pericardial effusion in clinically stable patients 2. Follow-up studies in patients with cancer or other terminal illness for whom management would not be influenced by echocardiographic findings 3. Assessment of pericardial thickness in patients without clinical evidence of constrictive pericarditis 4. Pericardial friction rub in early uncomplicated myocardial infarction or early postoperative period after cardiac surgery

Patients with 1. Evaluation of cardiac masses patients with and tumors clinical syndromes and events suggesting an underlying cardiac mass 2. Evaluation of patients with underlying cardiac disease known to predispose to mass formation for whom a therapeutic decision regarding surgery or anticoagulation will depend on the results of echocardiography 3. Follow-up or surveillance studies after surgical removal of masses known to have a high likelihood of recurrence (i.e., myxoma) 4. Patients with known primary malignancies when echocardiographic surveillance for cardiac involvement is part of the disease staging process

1. Screening persons with disease states likely to result in mass formation but for whom no clinical evidence for the mass exists

1. Patients for whom the results of echocardiography will have no impact on diagnosis or clinical decision making

Suspected thoracic aortic disease

TEE: 1. Aortic dissection 2. Aortic aneurysm 3. Aortic rupture 4. Degenerative or traumatic aortic disease with clinical atheroembolism 5. Follow-up of aortic dissection especially after surgical repair when complication or progression is suspected TTE: 1. Aortic aneurysm (especially for aortic root aneurysm) 2. Aortic root dilation in Marfan or other connective tissue syndromes 3. Follow-up of aortic dissection, especially after surgical repair without suspicion of complication or progression 4. First-degree relative of a patient with Marfan syndrome or other connective tissue disorder

Pulmonary disease

1. Suspected pulmonary hypertension 2. Pulmonary emboli and suspected clots in the right atrium or ventricle or main pulmonary artery branches * 3. For distinguishing cardiac vs. noncardiac etiology of dyspnea in patients in whom all clinical and laboratory clues are ambiguous* 4. Follow-up of pulmonary artery pressures in patients with pulmonary hypertension to evaluate response to treatment 5. Lung disease with clinical suspicion of cardiac involvement (suspected cor pulmonale)

1. Measurement of exercise pulmonary artery pressure 2. Patients being considered for lung transplantation or other surgical procedure for advanced lung disease *

1. Lung disease without any clinical suspicion of cardiac involvement 2. Reevaluation studies of RV function in patients with chronic obstructive lung disease without a change in clinical status

Hypertension

1. When assessment of resting LV function, hypertrophy, or concentric remodeling is important in clinical decision making 2. Detection and assessment of functional significance of concomitant coronary artery disease (stress echocardiography) 3. Follow-up assessment of LV size and function in patients with LV dysfunction when there has been a documented change in clinical status or to guide medical therapy

1. Identification of LV diastolic filling abnormalities 2. Assessment of LV hypertrophy in a patient with borderline hypertension without LV hypertrophy on ECG to guide decision making regarding initiation of therapy. A limited goal-directed echocardiogram may be indicated for this purpose

1. Risk stratification for prognosis by determination of LV performance

1. Reevaluation to guide antihypertensive therapy based on LV mass regression 2. Reevaluation in asymptomatic patients to assess LV function

Patients with neurological events or other vascular occlusive events

1. Patients of any age with abrupt occlusion of a major peripheral or visceral artery 2. Younger patients (typically < 45 years) with cerebrovascular events 3. Older patients (typically > 45 years) with neurological events without evidence of cerebrovascular disease or other obvious cause 4. Patients for whom a clinical therapeutic decision (e.g., anticoagulation) will depend on the results of echocardiography

Patients with 1. Arrhythmias with arrhythmias clinical suspicion of and palpitations structural heart disease 2. Arrhythmia in a patient with a family history of a genetically transmitted cardiac lesion associated with arrhythmia such as tuberous sclerosis, rhabdomyoma, or hypertrophic cardiomyopathy 3. Evaluation of patients as a component of the work-up before electrophysiological ablative procedures

1. Patients with suspicion of embolic disease and with cerebrovascular disease of questionable significance

1. Patients with a neurological event and intrinsic cerebrovascular disease of a nature sufficient to cause the clinical event

1. Patients for whom the results of echocardiography will not impact a decision to institute anticoagulant therapy or otherwise alter the approach to diagnosis or treatment

1. Arrhythmia requiring treatment 2. TEE guidance of transseptal catheterization and catheter placement during ablative procedures

1. Arrhythmias commonly associated with, but without clinical evidence of, heart disease 2. Evaluation of patients who have undergone radiofrequency ablation in the absence of complications. (In centers with established ablation programs, a postprocedural echocardiogram may not be necessary.)

1. Palpitation without corresponding arrhythmia or other cardiac signs or symptoms 2. Isolated premature ventricular contractions for which there is no clinical suspicion of heart disease

Before cardioversion

1. Evaluation of patient for whom a decision concerning cardioversion will be impacted by knowledge of prognostic factors (e.g., LV function, coexistent mitral valve disease) TEE only: 1. Patients requiring urgent (not emergent) cardioversion for whom extended precardioversion anticoagulation is not desirable* 2. Patients who have had prior cardioembolic events thought to be related to intraatrial thrombus* 3. Patients for whom anticoagulation is contraindicated and for whom a decision about cardioversion will be influenced by TEE results* 4. Patients for whom intraatrial thrombus has been demonstrated in previous TEE*

1. Patients with atrial fibrillation of 75 percent occlusion) coronary artery stenosis of at least one major vessel on arteriography. Of those with significant coronary disease on arteriography, 56 percent had calcification at fluoroscopy.[69] Another study was performed in asymptomatic patients with type II hyperlipidemia who were younger than 55 years. Of those with both positive exercise tests and coronary calcification on fluoroscopy, 92 percent had angiographically determined coronary artery disease. Fluoroscopy had an 82 percent accuracy in the detection of significant coronary artery disease.[70] In yet a third study, 108 asymptomatic men underwent cardiac fluoroscopy and exercise testing; 81 percent of those with a positive exercise test had coronary

calcifications, and 35 percent of these had a positive exercise test. Only 4 percent of men without calcified coronary arteries had a positive exercise test. Finally, in this same series, 92 percent had at least one stenosed coronary artery diagnosed by angiography.[71] The same authors showed that approximately 90 percent of patients with fluoroscopically detectable coronary calcifications had significant coronary disease.[71] Since exercise tests alone yield 10 to 20 percent positive results in asymptomatic middle-aged males without coronary artery disease, fluoroscopy was suggested as an effective additional screening test for the identification of patients with critical coronary artery disease.

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Figure 8-18 A, Pulmonary blood flow redistribution. Enlargement of the upper lobe vessels is seen in a patient with ischemic cardiomyopathy and elevated pulmonary venous pressure. B, Pulmonary interstitial edema. The vessels are indistinct and enlarged, and peribronchial cuffing is present. C, Pulmonary alveolar edema in a patient with congestive cardiomyopathy. The central perihilar distribution of edema, termed "bat wing" edema, is typical of pulmonary alveolar edema caused by cardiovascular or fluid overload (uremic). D, Preferential right upper lobe distribution of pulmonary edema in a 65-year-old man with mitral regurgitation. E, Right pleural effusion and residual right upper and bilateral lower lobe edema in a patient with acute mitral regurgitation.

Fluoroscopy was most valuable for assessing atypical chest pain or for screening asymptomatic patients. Although fluoroscopy can detect moderate to large calcifications, its ability to identify small calcifications is poor. For example, in a 1990 study, Agatston and colleagues found that only 52 percent of calcified deposits identified by CT were detected by fluoroscopy.[72] Other disadvantages of fluoroscopy are dependence on the skills of the fluoroscopist, the inability to objectively quantify the extent of calcification, and difficulty in diagnosis because of overlapping structures.[67] Conventional CT.

Conventional CT is clearly superior to both plain film radiography and fluoroscopy for the detection of coronary calcification. In fact, approximately 50 percent more patients will be found to have calcified coronary arteries and critical coronary artery disease with CT than with fluoroscopy.[67] Recent studies with CT have emphasized its value as a screening procedure, but it also has important limitations that reduce its sensitivity, [60] [73] including slow scanning times, breathing misregistration, and volume averaging. Since CT is performed routinely for other disease indications, it is important to make note of coronary calcifications and their distribution on CT to alert the clinician to their presence and significance.

Spiral or Helical CT.

This technique is now commonly available in most radiology departments. The advantage of helical CT for the detection of coronary artery calcification is based on scan times as fast as 0.6 second with breath-holding technique. Calcific deposits are less blurred than on conventional CT, but small calcifications may still not be seen. Double-helical CT appears to be superior to single-helical CT for the identification of coronary artery calcifications because of thinner section capability and superior resolution.[74] [75] [76] Electron Beam CT.

Electron beam or ultrafast CT (EBCT) uses an electron beam to traverse stationary tungsten targets to generate radiographic images. Three-millimeter, 100-millisecond axial slices triggered by the electrocardiogram at 80 percent of the RR interval to minimize cardiac motion are acquired during one or more breath-holds.[67] Because cardiac and respiratory motion are virtually eliminated, coronary arteries are readily identified and coronary artery wall calcification is detected. Small amounts of calcium can be detected with greater sensitivity than with either conventional or helical CT, in part because of the small pixel size (0.25 to 0.5 mm2 ) possible with this technology. [65] [77] [78] [79] [80]

By using a calcium-scoring method based on an arbitrary Hounsfield number (CT values) of +130 H for calcium multiplied by the actual area of calcification, a total score is calculated. With this method, a number of investigators have demonstrated sensitivities of 85 to 100 percent for significant coronary artery stenosis.[76] [77] [78] [79] [80] [81] A recently published multicenter EBCT calcium-scoring study reviewed data from both coronary arteriography and EBCT studies. A high calcium score was very predictive in separating patients with and without cardiac events (Fig. 10-41) . Of a number of demographic variables and coronary arteriographic

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Figure 8-19 Myocardial calcification. A, Left ventricular calcification. The thick mural calcification within the left ventricle is due to an aneurysm (arrows). B, A thin curvilinear calcification (arrow) is present in the superior and anterior wall of the left atrium in this patient with multivalvular rheumatic heart disease and atrial fibrillation. Prosthetic valves are seen in the aortic, tricuspid, and mitral areas. C, Aortic valve calcification. A fluoroscopic spot film shows that the aortic valve is densely calcified (the curved arrow indicates a calcified raphe in this patient with a biscuspid valve). D, Ultrafast CT demonstrates calcification of the aortic valve leaflets in a different patient with a congenital biscupid aortic valve (arrowheads). (Courtesy of Stephanie Flicker, M.D.)

findings, only the calcium score generated by EBCT appeared to significantly predict cardiac events.[82] However, the accumulated evidence leaves several questions

unanswered concerning the efficacy of EBCT screening in asymptomatic patients and whether the calcium screening method addresses the problem of unstable or noncalcified atherosclerotic plaque.[67] CALCIFICATION OF THE GREAT VESSELS (Fig. 8-22) .

Aortic calcification, particularly in the region of the arch, is almost ubiquitous in individuals older than 50 years. It is usually noted on chest radiographs as a thin curvilinear opacity near the lateral border of the arch. When the calcification is located deep to the aortic border, dissection may be present. Other causes of aortic calcification are syphilis (usually involving the ascending aorta), sinus of Valsalva aneurysm, calcified ductus arteriosus, and Takayasu arteritis[83] [84] The origin of the main pulmonary artery occasionally calcifies following right ventricular outflow tract surgery for total correction of tetralogy of Fallot. Calcification of the main pulmonary artery also occurs in severe longstanding pulmonary hypertension.[85] TUMOR CALCIFICATION.

The most common primary tumor of the heart is myxoma, a polypoid gelatinous mass occurring most frequently in the left atrium. About 10 percent of myxomas calcify sufficiently to be seen radiographically.[86] [87] Calcification in cardiac tumors varies from a speckled pattern to a round clump of calcium mimicking mitral annular or valve calcification. Calcification may be visible on plain film or may be seen only with fluoroscopy or CT. With fluoroscopy or CT, a calcified atrial tumor may be seen to prolapse through the atrioventricular valve during diastole and cause obstructive symptoms. Echocardiography and cine-MRI will demonstrate prolapse of a noncalcified myxoma.[86] [88] PERICARDIAL CALCIFICATION (Fig. 8-23; see also Chap. 50)

Pericardial calcification occurs most often in association with previous acute inflammation or blunt trauma.[89] The most common causes of pericardial inflammation, effusion, and later calcification are viral illness, especially Coxsackie or influenza A and B viral infection; granulomatous disease, including tuberculosis and histoplasmosis; hemopericardium following trauma; and autoimmune disease, including systemic lupus erythematosus and rheumatic heart disease. Occasionally, pericardial tumors (among them, intrapericardial teratomas and cysts) calcify. Calcification is present in up to 50 percent of patients with constrictive pericarditis.[89] The presence of calcification helps distinguish pericardial constriction from restrictive cardiomyopathy that is not associated with pericardial calcification. On the other hand, extensive calcification may be present without the signs and symptoms of pericardial constriction. Pericardial and myocardial calcifications are frequently confused with each other. However, pericardial calcification can be distinguished from myocardial calcification by differences in distribution. Pericardial calcification is most abundant along the right atrial and ventricular borders and in the area of the atrioventricular groove. The pericardium adjacent to the left ventricle is usually free of

calcification, probably because of its vigorous

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Figure 8-20 A, Calcified aortic and mitral annulus in an elderly woman. The air in a large hiatal hernia permits excellent visualization of the mitral annulus (arrowheads) in the posteroanterior (PA) projection. B, In the lateral projection, calcification is present in both the aortic (white arrow) and mitral (black arrows) annuli. C, Aortic annular calcification (arrows) in an elderly patient without signs or symptoms of aortic stenosis. D, Mitral valve calcification in the PA projection. E, Mitral valve calcification in the lateral projection. Valve calcification (black arrows) lies below the line drawn from the left main bronchus to the anterior costophrenic sulcus, which localizes it to the mitral valve. The aortic valve in this projection lies more anteriorly and above the line (white arrows).

pulsations, and calcification rarely occurs along the left atrial border because of the absence of pericardium behind the left atrium. On the other hand, myocardial calcification is usually localized to the left ventricle and is rare in the right atrium or ventricle. Pericardial calcification is often obscured on a frontal chest film because of underexposure of the mediastinal structures. Overpenetrated films or fluoroscopic examination is helpful in localizing mediastinal calcification, including pericardial calcification, and CT may demonstrate calcium not visible on plain chest films.[89] ACQUIRED HEART DISEASE Diagnosis and assessment of the severity of acquired heart disease are assisted by a combination of imaging studies, including plain chest radiography. The chest film is particularly useful for assessing overall cardiac size and pulmonary vascularity. The plain chest radiograph also offers important clues to the enlargement of individual cardiac chambers through analysis of cardiac borders. Today, echocardiography, MRI, and other cross-sectional imaging techniques have largely replaced the plain film except for its role as a useful first examination in the work-up of a cardiac patient. [90] [91] Valvular Heart Disease ( Figs. 8-24 and 8-25; see also Chap. 46) Aortic Stenosis

Isolated aortic stenosis is most frequently related to a congenital bicuspid aortic valve. Additional causes of left ventricular outflow tract narrowing resulting in left ventricular enlargement without valvular calcification are hypertrophic cardiomyopathy and supravalvular and subvalvular aortic stenoses. The typical radiographic findings of mild to moderate aortic valvular stenosis include a normal-sized heart with rounding of the left ventricular border or an elongated cardiac silhouette with downward displacement of the cardiac apex because of concentric left ventricular hypertrophy[90] (see Fig. 8-8 A). A characteristic discrete bulge located on the right side of the ascending aorta just above the sinus of Valsalva is due to poststenotic

dilatation and is best visualized in the LAO or PA projection. In pure aortic stenosis, the aortic arch and descending aorta remain normal in size and aortic valve calcification is frequent. Calcification increases with the severity of stenosis and the age of the

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Figure 8-21 Coronary artery calcification. A, Lateral projection demonstrating the "tram track" pattern of coronary artery calcification involving the left anterior descending (arrowheads) and circumflex coronary (arrow) arteries. B, A coned-down magnification view in another patient shows a "tramtrack" calcification of the left anterior descending (LAD, arrow) artery. A calcified bicuspid valve inferior in position to the LAD artery is also present. C, Calcification of the LAD and the circumflex (Cx) arteries is clearly visualized on axial CT images.

patient, so by the age of 40 years, more than 90 percent of patients with aortic stenosis have visible aortic calcification. Aortic valvular calcification has also been associated with a peak systolic gradient at the aortic valve of greater than 30 mm Hg in 97 percent of patients.[9] With severe aortic stenosis, the left atrium and ventricle will decompensate and enlarge.[92] The degree of enlargement of both chambers is correlated with the severity of aortic stenosis and with mitral regurgitation caused by left ventricular dilatation or by associated intrinsic mitral valve disease. CONGENITAL AORTIC STENOSIS.

This type of stenosis may take two forms. The more common is a bicuspid valve with congenital commissural fusion and a central or eccentric orifice. The second form is a bicuspid valve or a tricuspid valve that is initially nonobstructive but undergoes commissural fusion with time. Turbulent blood flow traumatizes the valve and causes irregular nodular scarring of both leaflets, which subsequently undergo gradual fusion and calcification.[4] [91] With time, these valves may also become insufficient because of either incomplete closure of the deformed valve leaflets or infective endocarditis.[4] DEGENERATIVE AND RHEUMATIC AORTIC VALVULAR STENOSIS.

These types of stenosis may be found in normally tricuspid aortic valves. On the chest film, linear or coarse calcifications may be found in the area of the aortic valve leaflets or annulus. In patients with rheumatic aortic stenosis, mitral calcifications are also frequently present.[93] SUBAORTIC STENOSIS.

Both the obstructive and nonobstructive forms of hypertrophic cardiomyopathy (see Chap. 48) and membranous subaortic stenosis are characterized radiographically by left

ventricular hypertrophy.[8] Although the plain film findings are suggestive, a specific diagnosis of hypertrophic cardiomyopathy can be best established with MRI, echocardiography, and/or radionuclide studies.[60] [94] [95] Since the aortic leaflets are not involved, blood flow is normal during ventricular systole, and as a result, the ascending aorta does not dilate and the aortic valve does not calcify. Left atrial enlargement, when present, is usually associated with mitral regurgitation. Aortic Regurgitation (see Figs. 8-8 B and C and 8-24 )

Aortic regurgitation may result from a stenotic bicuspid valve with incomplete closure caused by endocarditis or degeneration. Rheumatic valvulitis and infective endocarditis are other important primary causes. A secondary cause of aortic regurgitation is dilatation of the aortic annulus in diseases preferentially affecting the ascending aorta, such as

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Figure 8-22 Aortic calcification. A, Posteroanterior projection. B, Lateral projection. An abundant thin line of calcification extends from the aortic root to the distal descending thoracic aorta in a young woman. Biopsy revealed Takayasu aortitis.

ankylosing spondylitis, annuloaortic ectasia, Marfan syndrome, Reiter syndrome and psoriatic arthritis.[96] [97] [98] Aortic regurgitation caused by rheumatic heart disease is commonly associated with mitral involvement alone or may involve all four cardiac valves. Aortic regurgitation may also be due to direct trauma or may accompany dissection of the ascending aorta. In mild aortic regurgitation, the aorta is radiographically normal or mildly enlarged and the left ventricle remains normal in size. With moderate or severe regurgitation, increased dilatation of the left ventricle is seen, and the cardiothoracic ratio usually exceeds 0.55. The aorta is diffusely and often massively dilated, unlike aortic stenosis, where only the ascending aorta is involved (see Fig. 8-8 C and D). If the sinus portion of the ascending aorta is the only portion selectively dilated, Marfan syndrome (annuloaortic ectasia) is the most likely diagnosis. If the ascending aorta is also calcified, syphilis or, occasionally, Takayasu aortitis (see Chap. 40) is the likely diagnostic possibility. If the valve itself is calcified, aortic regurgitation secondary to a congenital bicuspid aortic valve or rheumatic disease should be considered. If the mitral valve is also regurgitant, the left atrium may be markedly enlarged visually and obscure the enlarged left ventricle. When aortic regurgitation occurs acutely as a result of infective endocarditis, trauma, or dissection, the left ventricle remains normal in size, but because end-diastolic pressure is dramatically increased, pulmonary venous pressure rises and pulmonary interstitial and/or alveolar edema may be observed. Pulmonary arterial hypertension has been described in longstanding aortic regurgitation.[99] In chronic compensated aortic regurgitation, progressive volume overload occurs with left ventricular dilatation and an increase in overall cardiac size but with normal-appearing

lungs.[97] As is true of aortic stenosis, aortic regurgitation is best diagnosed by Doppler echocardiography or cine-MRI.[96] [100] In selected cases, especially those with calcified aortic valves, analysis of the plain chest radiograph will often establish the diagnosis or reveal specific findings that support the diagnosis of this abnormality. Mitral Stenosis (see Fig. 8-25)

Rheumatic carditis is the most common cause of mitral stenosis. Isolated mitral valve involvement is most common, followed by a combination of mitral and aortic valve diseases. Left atrial myxoma and, rarely, congenital mitral stenosis, parachute mitral valve myxoma, and metastatic tumor are also causes of mitral valve obstruction. The early roentgenographic signs of mitral stenosis are often subtle and include mild left atrial enlargement with a discrete convex border in the area of the left atrial appendage on the PA projection. In most patients with mitral stenosis, the left ventricle or the pulmonary artery borders are normal in appearance. With more severe mitral stenosis, the left atrium usually increases further in size; however, in any given patient, poor correlation is seen between the severity of mitral stenosis and the size of the left atrial chamber. The left atrial appendage can be disproportionately enlarged, but the shape of the appendage appears to bear no relationship to the presence or absence of thrombosis.[101] The left main stem bronchus may be displaced upward by the enlarged left atrium. The right atrium is displaced to the right, and pulmonary blood flow is redistributed to the upper lobes. The main pulmonary artery is enlarged, the left ventricle and aorta are usually normal or small, and the mitral valve is often calcified. In addition, calcification of the left atrial wall is most commonly found in the posterior wall and appendage and is often associated with atrial fibrillation. Patients have evidence of pulmonary interstitial edema, characterized by "hilar haze" or central vascular indistinctness, Kerley B lines or interlobular effusions at the lung bases, and subpleural stripes as pulmonary venous pressure rises to the range of 25 mm Hg. Hemosiderosis resulting from recurrent small hemorrhages related to chronically elevated capillary pressure is often associated with chronic mitral stenosis. The radiographic appearance of hemosiderosis is that of interstitial or miliary lung disease, most prominent in the mid and lower lung zones. With chronic pulmonary interstitial edema, small punctate pulmonary opacities may be found that represent

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Figure 8-23 Pericardial calcification. A, Posteroanterior projection. B, Lateral projection. Both show extensive calcification of the pericardium in the atrioventricular groove in a patient with a history of rheumatic heart disease. C, Axial CT at the level of the atrioventricular groove demonstrates extensive

pericardial calcification (arrowheads). LA=left atrium, RA=right atrium.

small islands of bone within the alveoli and are visible as dense nodules on the chest radiograph. Mitral Regurgitation (see Fig. 8-18 D)

Acute mitral regurgitation may be related to ruptured chordae tendineae, rupture of the papillary muscles, ischemic dysfunction, or infective endocarditis. While the heart may not be enlarged in acute mitral regurgitation, severe pulmonary edema is frequently present as a result of left-sided cardiac failure (see Fig. 8-18 E). Although pulmonary edema secondary to mitral regurgitation is usually symmetrical, selective right upper lobe pulmonary edema has been described in as many as 9 percent of patients with acute or chronic mitral regurgitation. It is probably due to selective retrograde flow from the mitral valve to the right upper lobe pulmonary veins.[102] [103] Chronic mitral regurgitation may be secondary to rheumatic heart disease, mitral prolapse from myxomatous degeneration, infective endocarditis, ischemic cardiomyopathy, hypertrophic cardiomyopathy, extensive mitral annulus calcification, collagen disease, Marfan syndrome, and other causes.[92] In chronic mitral regurgitation, the left atrium as well as the left ventricular border appears enlarged radiographically and may be massive in size because of volume overload and increased pressure. When the left atrium is enlarged, it may extend toward the right side and will be observed as a double shadow along the right atrial border. In the LAO projection, the large atrium causes upward displacement of the left main stem bronchus. Coexistent pulmonary arterial hypertension or tricuspid regurgitation may cause dilatation of the right atrium and ventricle and enlargement of the pulmonary arteries.[96] MRI and echocardiography can demonstrate the abnormality of the valve apparatus and evaluate the amount of regurgitant flow.[100] [104] [105] Ischemic Heart Disease

Many imaging modalities contribute to the diagnosis of ischemic heart disease, including coronary arteriography, radionuclide scintigraphy, echocardiography, CT, and MRI.[104] [105] [106] [107] In ischemic cardiomyopathy, the chest roentgenogram may be entirely normal, even in patients with advanced disease; however, left ventricular enlargement and/or

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Figure 8-24 Aortic regurgitation with massive diffuse aortic dilation in a male with severe valvular regurgitation related to annuloaortic ectasia. A, Posteroanterior projection. B, Lateral projection.

Figure 8-25 Mitral stenosis. A, The left atrial border is prominently convex. The aorta is small in this 19-year-old patient with mitral stenosis (arrow). B, A subtle convex bulge can be noted at the level of the left atrial appendage (open arrow). A double atrial shadow is present on the right atrial border (black arrow), and the heart is not enlarged in this 54-year-old woman with mitral stenosis. C, Mitral stenosis with chronic interstitial pulmonary edema and small punctate opacities representing small islands of ossification within the alveoli. D, Mitral stenosis, right anterior oblique view. This posterior displacement of the barium column is related to the enlarged left atrium.

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aneurysm is often present. After infarction of 25 percent or more of the left ventricular muscle mass, pulmonary edema may occur, even in patients with a normal-sized heart.[107] When congestive heart failure persists in spite of treatment, complications of myocardial infarction such as aneurysm, pseudoaneurysm, ventricular wall or papillary muscle rupture, and interventricular septal defect must be excluded.[9] Complications of Myocardial Infarction (see Chap. 35)

An interventricular septal defect occurs in 0.5 to 1.0 percent of patients with recent septal infarction and is characterized by cardiomegaly, pulmonary edema, and poor myocardial contractility. On the plain film radiograph, the typical shunt pattern may not be appreciated because of pulmonary edema but can emerge months later if the patient survives. Such defects usually involve the muscular septum and occur within 7 to 12 days after myocardial infarction. The radiographic picture of post-myocardial infarction syndrome (Dressler syndrome) is that of a heart enlarged because of pericardial effusion. Unilateral or, less often, bilateral pleural effusions are common, and lower lobe consolidation, particularly on the left side, occurs in less than 20 percent of patients. It generally occurs 2 to 6 weeks after myocardial infarction and is analogous to the postpericardiotomy syndrome.[97] [108] Aneurysm of the left ventricle is an abnormal bulge or outpouching of the myocardial wall that develops in 12 to 15 percent of patients after myocardial infarction. It occurs most commonly at the cardiac apex or along the anterior free wall of the left ventricle. The chest film shows a localized bulge along the ventricular wall near the apex, with or without a thin rim of calcification. CT, MRI, and echocardiography will all demonstrate, with precision, areas of altered contractility often augmented by pharmaceutical challenge and contrast enhancement.[109] The differential diagnosis of left ventricular aneurysm includes other deformities of the left heart border caused by pericardial cysts, mediastinal or pleural tumor, thymoma, and other mediastinal masses. Cardiac rupture usually occurs in patients who have had an acute transmural infarction.[110] Most die immediately, but in a minority of patients the rupture is contained or enclosed by the surrounding extracardiac soft tissue and a pseudoaneurysm is formed. Radiographically, a paracardiac mass is present, with sharply marginated edges free of calcification. The mass is usually posterior on the lateral projection, unlike

the more anterior position of a true aneurysm. A firm diagnosis is made by echocardiography, MRI, or contrast-enhanced CT. Coronary arteriography will show complete absence of vessels in the wall of the pseudoaneurysm, unlike a true aneurysm, which may have a rim of mural vessels.[108] Papillary muscle rupture follows myocardial infarction in approximately 1 percent of patients. Plain film radiographic findings vary from a normal chest to gross cardiomegaly with left atrial and ventricular enlargement and pulmonary edema. Left ventriculography, MRI, or Doppler echocardiography will demonstrate the flail mitral valve leaflets and estimate the degree of mitral regurgitation. [102] The Cardiomyopathies (see Chap. 48)

The term cardiomyopathy describes a spectrum of myocardial disorders of varying etiology and pathophysiology. They are classified as dilated or congestive, infiltrative, restrictive, hypertrophic, and ischemic.[9] [96] In congestive, dilated, and ischemic cardiomyopathy, the left ventricular ejection fraction is reduced, often severely. Chest radiographs will exhibit a wide spectrum of findings from a normal heart to diffuse nonspecific enlargement that may resemble a large pericardial effusion. Echocardiography demonstrates decreased ventricular contraction and enlargement of the left atrium and ventricle. With time, the right atrium and ventricle also enlarge. Doppler echocardiography or MRI may reveal mitral or tricuspid regurgitation caused by dilatation of the valve annulus.[96] Left-sided and, later, biventricular failure occurs in most patients, an important predictive indicator of shortened survival time. The radiographic appearance of hypertrophic cardiomyopathy is variable. Chest roentgenograms may demonstrate a normal heart or enlargement of the left ventricle, which can be focal or diffuse. If mitral regurgitation is present, the left atrium is also enlarged. Unlike aortic stenosis, no dilatation of the ascending aorta is present unless the patient has coincidental systemic hypertension or atherosclerotic uncoiling of the aorta. The diagnosis of hypertrophic cardiomyopathy is usually established by echocardiography or MRI, and cardiac catheterization with angiography is reserved for cases in which noninvasive techniques are technically inadequate, coronary disease is suspected, or surgery is contemplated. During systole, angiography demonstrates a narrow slitlike left ventricular chamber, marked wall thickening, and hyperdynamic contractions. CT and MRI are less invasive alternatives to angiography.[111] Restrictive cardiomyopathy is characterized by marked myocardial rigidity with poor left ventricular diastolic relaxation. There are no consistent radiographic features of restrictive cardiomyopathy. The heart is normal in size or may be moderately or, more rarely, markedly enlarged. The left atrium may also be enlarged when mitral regurgitation is present. Pulmonary congestion occurs in most patients, and calcification of the right or left ventricular wall may develop.

POSTOPERATIVE AND CRITICAL CARE RADIOLOGY (Fig. 8-26) With the continued growth of coronary artery bypass graft surgery and other cardiac surgical procedures during the last three decades, the postoperative supine portable chest roentgenogram has become one of the most frequently ordered examinations. In a typical tertiary care medical center, over 50 percent of inpatient chest roentgenograms are performed at the bedside, usually in the ICU. About one-third of these studies are of postsurgical cardiac patients. To interpret the postoperative chest film properly, special attention must be given to optimization of technique. TECHNIQUES.

Appropriate film-screen combinations, as well as careful patient positioning, are needed to overcome the effects of low-capacity portable equipment producing low-kilovoltage technique and high amounts of scatter radiation and motion artifacts.[112] The use of laser beam-aligned antiscatter grids and featureless grids that require less precise alignment with the x-ray source are approaches to obtain higher quality portable chest films than are possible with nongrid systems.[113] Although conventional analog portable chest x-rays continue to be the "norm," digital images provide a variety of advantages and are becoming a popular replacement for film-screen chest radiographs as a radiation detector, image display modality, and archival medium.[114] At present, computed radiology with storage phosphor plates as the radiation detector and laser scanning of conventional film-screen radiographs are the most frequently

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Figure 8-26 The early postoperative portable chest radiograph. A, Multiple catheters and tubes are present and must be identified and their position determined. A=intraaortic balloon catheter; E=endotracheal tube; N=nasogastric tube; S=Swan-Ganz catheter. B, The Swan-Ganz catheter is in the right pulmonary artery (arrowhead). The endotracheal tube lies 2 cm above the carina (arrow). It should be repositioned proximally to prevent selective bronchial placement. C, This 60-year-old man had a massive myocardial infarction. The intraaortic balloon catheter (IABP) is located above the top of the arch near the orifice of the left subclavian artery.

used methods for producing digital chest images.[115] One major advantage of storage phosphor plates is their sensitivity over a wide range of exposures as opposed to the much narrower exposure range of conventional x-ray film. This difference results in consistent image quality over a wider range of exposures than is possible with conventional film-screen systems.[116] This advantage is particularly important in bedside x-rays, where overexposure and underexposure are ubiquitous. Consistency of technique from film to film in the same patient helps increase diagnostic accuracy and reduces the need for repeat films.[117]

POSTOPERATIVE FILMS.

When preoperative and postoperative chest films are compared, the differences in vascularity, cardiac size, and degree of inspiration between preoperative erect PA and postoperative supine AP films must be taken into account. For example, an 11 percent increase in cardiac diameter, a 9 percent increase in the cardiothoracic ratio, and a 15 percent increase in mediastinal width have been described when an inspiratory PA film is compared with an inspiratory AP chest film. For this reason, many surgeons and radiologists recommend that a preoperative supine AP film be taken to guarantee the availability of a comparable film. Following cardiac surgery, a daily morning film exposed in the ICU is a typical scenario. A number of studies suggest that daily films in subsets of postoperative patients are justified, including patients with an endotracheal (ET) tube and those with a Swan-Ganz catheter or following placement of a pacing device or intraaortic balloon catheter[118] [119] [120] [121] (see Fig. 8-26) . Most cardiac surgery is performed through an extrapleural median sternotomy with the use of cardiopulmonary bypass. Except for specific problems related to the patient's preexisting cardiac disorder or the specific surgical procedure, changes in the postoperative chest film are common to all cardiac surgical procedures. In the postoperative chest x-ray, a myriad of tubes, wires, catheters, and other devices are present in or overlie the postoperative chest,[119] [122] [123] including an ET tube, which should be positioned in the midtrachea 5 ± 2 cm above the carina to allow excursion with flexion and extension of the neck. If the ET tube is too close to the carina, flexion of the head or neck may force the distal end of the tube into the right or, less often, the left main stem bronchus and cause varying degrees of atelectasis of the opposite lung and barotrauma if assisted ventilation is used.[119] If the tube is too high, the patient may run the risk of aspiration, and dead space is increased.[123] [124] However, despite the opportunity that the bedside chest radiograph gives one to assess tube position, 12 to 15 percent of patients have significant malposition of the ET tube after cardiac surgery[118] [119] (see Fig. 8-26 B). A spherical endotracheal cuff seen in the postoperative x-ray indicates overinflation of the cuff, which may lead to tracheal injury. [122] The central venous pressure monitor is ideally placed between the most proximal valve of the subclavian vein and the right atrium within the superior vena cava. When the distal tip is found in the right atrium, pressure measurements will remain accurate, but the risk of perforation of the thin-walled cardiac chamber is increased. In addition to malposition, compression or "pinch-off" of the catheter by the clavicle and first rib may produce narrowing or chinking of the catheter. Pinch-off is seen in 1 percent of catheter placements.[125] When pinch-off occurs, the catheter should be removed and replaced with a more rigid catheter, one that is oval rather than round in cross section.

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Peripherally inserted central catheters (PICC lines) are frequently introduced after cardiac surgery. They are small-caliber tubes placed under sterile conditions. A major

advantage of PICC lines is that they may be left in place for long periods. A Swan-Ganz catheter is usually placed in either major pulmonary artery (ideally with the tip lying within a proximal pulmonary artery 2 to 3 cm distal to the bifurcation) to monitor pulmonary artery or pulmonary capillary wedge pressure and to obtain mixed venous blood samples (see Fig. 8-26 A and B). From that position, the tip can float distally to a wedged position, whereupon the balloon is inflated. If the catheter is too peripheral in position, the inflated balloon near the tip of the catheter may damage the pulmonary artery wall and produce a perforation leading to hemorrhage or pseudoaneurysm. Anterior mediastinal drainage catheters are located in the parasternal area, and posterior mediastinal drainage catheters usually lie on the left side behind the heart. When circulatory assistance is needed, a sausage-shaped intraaortic counterpulsation balloon (IACB) may be positioned just below the level of the left subclavian artery within the proximal descending aorta. Placement of the IACB is critical to avoid occluding the subclavian or renal arteries (see Fig. 8-26 A and C). Pacemaker leads, prosthetic valves, and implantable cardioverter-defibrillators[126] require careful observation for lead or component malposition, pouch infection, or fracture. [127] A nasogastric tube is also usually present. It may be inadvertently placed in a bronchus and pass into the lung or even the pleura. If malposition of a nasogastric tube is unrecognized, aspiration of fluid may occur and cause a chemical pulmonary edema or pneumonia. Early recognition of the normal and abnormal positions of the large number of catheters, wires, and tubes found on the postoperative chest radiograph requires rapid interpretation by a physician thoroughly familiar with both the appearance of the postoperative chest radiograph and the possible complications that may frequently occur. The Early Postoperative Chest Radiograph (see Fig. 8-26) .

The first postoperative chest film usually demonstrates varying degrees of left and, to a lesser extent, right lower lobe atelectasis, mediastinal widening, pulmonary edema, and pleural effusion.[128] Unilateral or bilateral lower lobe atelectasis, usually accompanied by small pleural effusions, is the source of the lower lung zone opacities found in almost all cardiac surgery patients. Lower lobe opacities representing atelectases and pleural effusion usually appear within 8 hours after surgery and clear within 5 to 7 days. Pneumonia can occur as an early postoperative complication, but it is certainly unusual. The mechanisms for preferential left lower lobe atelectasis include paralysis of the phrenic nerve caused by cardioplegic solutions or crushed ice administered for myocardial preservation or retained secretions. Decreased diaphragmatic motion may persist for many weeks after surgery but eventually resolves in most patients. Other causes of postoperative left lower lobe atelectasis include dependent pooling of secretions, preferential suctioning of the right main stem bronchi, and compression from the cardiac insulation pad used during surgery. Pleural Effusion.

Pleural effusion is manifested radiographically by blunting of the costophrenic angle, loss of sharpness of the diaphragmatic contour, and increased opacity behind the

diaphragmatic dome. It may be difficult to identify in a postoperative supine film but is more easily identified on an erect bedside radiograph. A lateral bedside film may also help identify pleural effusion if necessary.[129] Postoperative pleural effusions are probably related to pericardial fluid that leaks into the pleural space through the surgically created pericardial window or to irritation of the pleura during surgery. Postpericardiotomy syndrome and congestive heart failure are sources of pleural effusion in some patients. Increasingly larger or persistent pleural effusions may be due to hemomediastinum, which occurs when blood escapes into the pleural space through a pleural tear. Large pleural effusions are more common after left internal mammary bypass surgery because the pleural space is entered during that procedure. Patchy or occasionally diffuse consolidation in both lungs after cardiac surgery is usually caused by pulmonary edema. Pulmonary edema from increased capillary permeability or adult respiratory distress syndrome is common after cardiac surgery and is caused by release of vasoactive substances during cardiopulmonary bypass that affect capillary permeability. Pulmonary edema usually occurs within 2 days of surgery and is reversible with supportive therapy, including diuretics.[123] Postperfusion pulmonary edema occurs after cardiopulmonary bypass because of a marked increase in fluid in the extravascular space. The mechanism for postperfusion pulmonary edema is thought to be related to the contact of circulating blood with foreign surfaces during bypass.[123] Congestive heart failure following cardiac bypass surgery occurs in patients with poor cardiac output. Typically, vascular redistribution to the upper lobes, Kerley B lines, small bilateral pleural effusions, and the patchy opacities resulting from pulmonary edema are present. Other early findings of cardiac surgery identified with the AP portable chest radiograph include sternal dehiscence, pneumothorax, pneumomediastinum, mediastinal hematoma, pneumopericardium, subcutaneous emphysema, and the findings of pulmonary embolism.[130] Rib fractures occur in 2 to 4 percent of patients and are usually identified by plain films. Their importance lies in the possible misdiagnosis of chest pain of another cause, such as angina or aortic dissection. Pneumothorax is often difficult to identify in a supine patient. Unlike pneumothorax in the PA erect film, where the crisp opaque line of the visceral pleura located medial to the rib cage is diagnostic, in the supine position a pneumothorax appears as a poorly defined lucency overlying the lower lung zones.[123] Decubitus views are helpful in clearly defining the presence of a pleural air collection. Pneumomediastinum may occur when the mediastinum is entered during surgery. In most cases, the mediastinal air resolves spontaneously within several days. A radiolucency overlying the center of the sternum following median sternotomy is due to a small gap in the sternum and soft tissues at the surgical site; this finding occurs in approximately one-third of patients. No correlation between this thin radiolucency and sternal dehiscence has been proved. MEDIASTINAL HEMORRHAGE.

Widening of the mediastinum because of hematoma is common after cardiac surgery but is seldom serious enough to require reoperation. In the typical postoperative patient, the mediastinum is widened by up to 35 percent in comparison with the preoperative PA chest film. Katzberg and associates found that if the mediastinum is widened more than

70 percent in comparison with the baseline radiograph, surgery is usually required to remove the hematoma.[131] However, considerable bleeding may be present without visible mediastinal widening, especially if the patient is receiving positive end-expiratory pressure support, which may compress the mediastinum. Moreover, some patients may have a wide mediastinum but are hemodynamically stable, have no significant bloody drainage, and do not require reoperation. Both CT and echocardiography are helpful in establishing the diagnosis of intrapericardial hematoma. With echocardiography, the hematoma has an echo-free center and a refractile margin. CT, with and without contrast enhancement, is also useful to differentiate hematoma from other masses. On nonenhanced CT, the hematoma is denser than other soft tissues. Enlargement of the cardiac silhouette during the early postoperative period may be due to cardiac failure with or without myocardial infarction or to a mediastinal or pericardial fluid collection. In some patients, pericardial tamponade occurs from bleeding of small arteries in the area of the sternal incision. Equalization of diastolic pressures and elevation of the pulmonary capillary wedge pressure without pulmonary redistribution or edema, together with diffuse enlargement of the cardiac silhouette, suggest pericardial tamponade. Although the chest roentgenogram may be suggestive of tamponade, both CT and echocardiography will clearly reveal the presence of pericardial fluid or thickening and tapered narrowing of both ventricles. CT is the imaging procedure of choice to detect an extrapericardial mediastinal fluid collection.

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Late Complications of Cardiac Surgery POSTPERICARDIOTOMY SYNDROME.

This common late complication of cardiac surgery is characterized by pleuritis, pericarditis, and fever. It is believed to be the result of an immune response to necrotic epicardial tissue. It generally occurs several weeks after surgery and is self-limited. Occasionally, cardiac tamponade or constrictive pericarditis occurs as a complication of the postpericardiotomy syndrome. Unilateral or bilateral pleural effusions may obscure portions of the cardiac silhouette, and small basilar pulmonary opacities are found radiographically. Echocardiography or CT will identify pleural or pericardial fluid collections. Other late postoperative complications of cardiac surgery include sternal osteomyelitis, especially after internal mammary artery surgery, dehiscence at the surgical site, mediastinitis, pneudoaneurysm of the ascending aorta, cardiac rupture, and dissection.[123] [132] [133] PSEUDOANEURYSM OF THE THORACIC AORTA.

This rare but serious complication of cardiac surgery is associated with sternal osteomyelitis and mediastinitis following median sternotomy.[133] It may occur at the site

of an aortic cannulation or vent, the aortic clamp line, or the saphenous graft-aortic anastomosis.[133] Cardiac pseudoaneurysms can also occur at sites where full-thickness cardiac incisions were made. Although plain film radiographs will demonstrate a mass anterior to the heart or in the ascending aortic region, enhanced CT or MRI is diagnostic and should be performed before reoperation.[133] AORTIC DISSECTION.

Although aortic dissection rarely occurs in patients who have undergone cardiac surgery, it should be considered in the differential diagnosis of mediastinal widening or a postoperative mediastinal mass. Although a dissection may appear immediately after surgery, it is more likely to occur weeks to months later. Transesophageal echocardiography in unstable patients, MRI, and contrast-enhanced CT are helpful to distinguish between dissection and hematoma, abscess, tumor, or prominent mediastinal fat.[134] [135] Prosthetic Valve Surgery (see also Chap. 46)

The chest roentgenogram is helpful in monitoring patients for the potential complications of cardiac valve implantation. Identification of the site of a prosthetic valve is not as simple as identification of a calcified native cardiac valve because only an AP film may be available during the early postoperative period and prosthetic valves vary in position and often overlap each other. If the patient fails to improve clinically after valve replacement or if pulmonary edema occurs after a brief period of improvement, malfunction of the prosthetic valve may be the cause. Major malfunctions result from sewing ring dehiscence, tissue encroachment into the ring orifice, and infective endocarditis. The plain chest film may show enlargement of the adjacent cardiac chambers and/or pulmonary edema. Late calcification of the tissue components of a bioprothesis may be seen and is usually caused by tissue degeneration. Fracture and separation of radiopaque components and their distal migration have been described and may be identified by fluoroscopy or on radiographs of the chest and abdomen. [47] [55] However, these complications do not appear to be associated with currently implanted valves.[136] Fluoroscopy will document prosthetic valve motion, the integrity of the mechanical components, and the presence of calcification. Reduced or absent excursion of the valve occluder suggests thrombus, tissue intrusion, or vegetation. Doppler echocardiography will document regurgitant blood flow proximal to the valve. Contrast-enhanced cine-EBCT and cine-MRI can identify and quantify valvular regurgitation. Cardiac Transplantation (see also Chap. 20)

Most transplant candidates have a history of end-stage cardiac failure caused by ischemic cardiomyopathy. The heart is invariably enlarged, and vascular redistribution or edema is generally present. In orthotopic cardiac transplantation, the recipient heart is removed and the donor heart, with intact aorta and pulmonary arteries, is attached to

a cuff of native left atrium containing the pulmonary veins. After transplant surgery, typical radiographic changes associated with median sternotomy are found, including a widened mediastinum, pleural effusion, left lower lobe consolidation, and atelectasis. Within 2 months of transplantation, the heart becomes smaller and reaches stability 6 months after surgery. Persistent cardiomegaly is most likely caused by pericardial effusion, which may result from cyclosporine therapy or placement of a small donor heart in a large pericardial sac.[137] After transplantation, the radiograph demonstrates a double density in the vicinity of the right atrial border because of the overlapping donor and recipient atria. MRI or CT can clearly depict postoperative transplantation anatomy, as well as the presence of pericardial effusion and lymphadenopathy.[138] If graft rejection occurs, the heart enlarges, but pulmonary edema does not usually develop. Rejection is diagnosed by demonstration of lymphocytic infiltration and myocytic necrosis on endomyocardial biopsy.[139] MRI can demonstrate alterations in signal intensity caused by moderate and severe rejection.[140] CONGENITAL HEART DISEASE IN THE ADULT (see also Chap. 44) The plain film findings of adult congenital heart disease can be classified in a number of ways, such as classification based on the frequency of the disorder or a combination of the hallmarks of disease, such as the state of the pulmonary vasculature, related skeletal abnormalities, the position of the aortic arch and cardiac apex, cardiac size, and abdominal situs. Combining the radiographic findings with a history of the presence or absence of cyanosis, the time of onset of the cardiac murmur, and the clinical state of the patient should narrow the diagnostic choices.[36] [41] [142] Several of the more common congenital cardiovascular disorders found with some frequency in adults are discussed below. Coarctation of the Aorta (Fig. 8-27)

Coarctation of the aorta is a common anomaly that accounts for 8 percent of congenital heart defects in children and about 6 percent of adult congenital heart disease. Of those who escape diagnosis in early childhood, 25 percent are dead by the age of 20 and almost 50 percent by the age of 30. The clinical findings are highly variable and range from left ventricular failure in infancy to systemic hypertension in otherwise asymptomatic adult patients, depending on the site and severity of the coarctation and the presence of associated abnormalities.[143] [144] The most common associated anomaly is a bicuspid aortic valve, which occurs in as many as 85 percent of patients with coarctation of the

266

Figure 8-27 Coarctation of the aorta. A, Displacement of the barium column to the right above and below the coarctation. B, Thoracic aortography. The luminal narrowing at the isthmus and enlargement of the

left subclavian artery (LSCA) are characteristic of coarctation. It may be described as a "3" sign or "E" sign because of the precoarctation bulge of the LSCA, the coarctation itself, and postcoarctation aortic dilatation. Dilatation of the ascending aorta is due to a regurgitant bicuspid aortic valve. C, Sagittal T1-weighted MRI in the same patient shows the same findings as the aortogram but without contrast media, radiation, or catheterization.

aorta.[142] Other associated anomalies include ventricular septal defect, stenosis or atresia of the left subclavian artery, PDA, Turner syndrome PDA, and mitral valve prolapse.[145] [146] The diagnosis of coarctation of the aorta can be established from the PA chest film alone in up to 92 percent of patients.[142] Widening of the left subclavian artery border is the most common finding, but the most useful radiographic sign is an abnormal contour of the aortic arch, which may appear as a double bulge above and below the usual site of the aortic knob. This pattern has been described as a "figure 3" sign. The upper arc of the "3" is the dilated arch proximal to the coarctation and/or a dilated left subclavian artery. The lower arc or bulge represents poststenotic dilatation of the aorta immediately below the coarctation. The indentation between the two bulges is the coarctation itself. When the esophagus is filled with barium, a reverse "3" or "E" sign is often seen and represents a mirror image of the areas of prestenotic and poststenotic dilatation. The "3" sign is variable in that the upper arc may be small and the lower arc large or vice versa. Superior mediastinal widening or sternal scalloping caused by large internal mammary collateral arteries is visible in some patients. A prominent left ventricular border often occurs with coarctation, particularly when a bicuspid aortic valve is associated with aortic stenosis. Bilateral symmetrical rib notching, readily appreciated on the chest film, is diagnostic of aortic coarctation. It is due to obstructed blood flow at the narrowed aortic segment with collateral blood flow through the intercostal arteries. Rib notching is unusual in infancy, but becomes more frequent with increased age and is present in 75 percent of adults with coarctation. Rib notching occurs along the inferior margin of the third to the eighth ribs and is caused by pulsation of dilated intercostal arteries. The major pathways of collateral flow include (1) subclavian artery to the internal mammary artery to the intercostal arteries, (2) subclavian artery to the costovertebral trunk to the intercostal arteries, and (3) transverse cervical and suprascapular arteries to the intercostal arteries. Cardiac catheterization and angiography are diagnostic and demonstrate both the site of the coarctation and associated anomalies, including aortic stenosis. However, MRI and echocardiography have largely replaced these procedures. Echocardiography, for example, clearly demonstrates the presence or absence of bicuspid aortic and mitral valve deformities. MRI will not only vividly portray the anatomy of the coarctation but will also demonstrate the bicuspid valve and the state of left ventricular function, as well as restenosis following angioplasty or surgical repair.[142] [147] [148] [149] Left-to-Right Intracardiac Shunts

OSTIUM SECUNDUM ATRIAL SEPTAL DEFECT (Fig. 8-28) .

ASD, the most common left-to-right shunt diagnosed in adult life, accounts for over 40 percent of adult congenital heart defects.[150] [151] Although the chest radiograph may be normal in a patient with a small shunt, typically, the main pulmonary artery, the peripheral pulmonary branches, the right atrium, and the right ventricular borders are enlarged. Differentiation from other left-to-right shunts is often possible. Less pulmonary artery dilatation is usually seen in PDA than in ASD, and both PDA and ventricular septal defect are associated with enlarged left-sided cardiac chambers (Fig. 8-29) . In adults older than 50 years, the radiographic findings of ASD are often atypical and may include left atrial enlargement, vascular cephalization, and pulmonary edema.[142] Echocardiography demonstrating right ventricular chamber dilatation and paradoxical anterior systolic motion of the interventricular septum is diagnostic of ASD. The size and the location of the ASD can often be visualized, as well as associated abnormalities such as mitral valve prolapse. Both CT and MRI can also demonstrate the defect of the atrial septum. However, a pitfall of MRI is the normally thin atrial septum at the fossa ovalis, which may not be visualized by MRI and thus simulate an ASD. For the diagnosis of ostium secundum ASD by MRI, at least two consecutive

Figure 8-28 Atrial septal defect. A 45-year-old woman with an ostium secundum defect has an enlarged pulmonary artery with prominence of the right atrial border. Enlargement of the right ventricle displaces the left heart border upward and to the left.

267

Figure 8-29 Patent ductus arteriosus in a patient with a cardiac pacemaker. An inverted "Y" calcification representing the ductus is present above an enlarged pulmonary artery (arrow).

anatomical sections showing the defect are necessary to establish the diagnosis with confidence.[152] Pulmonary Valvular Stenosis (Fig. 8-30)

Valvular stenosis in adults is usually an isolated anomaly. Most patients are asymptomatic even with severe obstruction. Mild to moderate enlargement of the main pulmonary artery is present because of poststenotic dilatation resulting from the jet effect of blood flow through the narrowed pulmonary valve orifice. Since the jet is directed toward the left, the left pulmonary artery is often preferentially enlarged. Calcification of the pulmonary valve is rare in this condition. The differential diagnosis of pulmonary valvular stenosis includes primary and secondary pulmonary hypertension

and idiopathic pulmonary artery dilatation.[141] [142] Congenital Corrected Transposition of the Great Arteries (Fig. 8-31)

In this condition, ventricular inversion and transposition of the pulmonary artery and aorta result from formation of a left (levo or l) rather than a right (dextro or d) bulboventricular loop. Systemic venous flow is transmitted to the lungs by way of a right-sided anatomical left ventricle and the transposed pulmonary artery. Pulmonary venous flow traverses the left atrium and a left-sided anatomical right ventricle en route to the aorta. Radiographically, the ascending aorta is positioned to the left and forms a long continuous shadow along the left cardiac border from the ventricular apex to the aortic arch. The main pulmonary artery lies behind and to the right of the aorta and is not border-forming with the lung in the PA view. A left-to-right shunt may or may not be present, and left atrioventricular valve regurgitation and conduction abnormalities leading to heart block are fairly common. The heart is normal to enlarged, depending on the degree of atrioventricular valve regurgitation. Cross-sectional imaging supports the plain film diagnosis by showing an anterior left-sided aorta and a pulmonary artery lying behind and medial to the aorta. Cyanotic Congenital Heart Disease in the Adult (see also Chap. 44) TETRALOGY OF FALLOT.

This abnormality is the most common cyanotic congenital cardiac lesion in adults, as well as in children. Most adults with tetralogy of Fallot demonstrate mild to moderate pulmonary hypovascularity. Those with mild infundibular pulmonary stenosis have normal pulmonary blood flow. Small tortuous bronchial arteries are found in both lungs when severe pulmonary outflow tract stenosis or atresia is present. A right aortic arch is found in 25 percent of patients[153] (see Fig. 8-5) . The combination of a right aortic arch and cyanosis should always suggest the diagnosis of tetralogy of Fallot. Echocardiography often demonstrates a high and large ventricular septal defect, overriding of the ventricular septum by the aorta, and right ventricular hypertrophy. Both EBCT and MRI also demonstrate the septal defect and the large ascending aorta, as well a right aortic arch.[147] Plain films show a boot-shaped heart in some adult patients, but this finding is less common than in children because those who survive into adulthood are less likely to have severe right ventricular outflow tract stenosis (see Fig. 8-6 E). EBSTEIN ANOMALY

(see Fig. 8-9 B). In Ebstein anomaly, the tricuspid valve is malformed and partially fused to the walls of the right ventricle. This combination results in downward displacement of the tricuspid orifice, and regurgitation ensues. A right-to-left shunt is present at the atrial level and causes cyanosis. The right heart chambers are enlarged, often markedly, as a manifestation of the tricuspid regurgitation. The typical radiographic findings are

Figure 8-30 Asymmetrical pulmonary blood flow in a 51-year-old man with pulmonary valvular stenosis. The left pulmonary artery is larger than the right because the jet of blood is directed to the left pulmonary artery (arrow).

268

Figure 8-31 Corrected transposition of the great vessels (ventricular inversion). A, Posteroanterior chest film. The unique appearance of the left-sided ascending aorta is diagnostic (arrow). B, Aortography also shows the left-sided aorta originating from a morphological right ventricle.

those of a large rounded or triangular heart with a narrow vascular pedicle. [147] The pulmonary vasculature is reduced, depending on the degree of right-to-left shunting. The greater the shunt, the more diminished the vascularity. Echocardiography shows the abnormal placement of the tricuspid valve with downward displacement of the septal and posterior leaflets. Tricuspid regurgitation can be evaluated by two-dimensional and Doppler echocardiography. MRI and CT also demonstrate the downward displacement of the valve and enlargement of the right atrium.[147] THE PERICARDIUM (see also Chap. 50) The incidence of pericardial disease in patients with cardiac disease parallels the frequency of cardiac surgery, multisystem inflammatory disease, thoracic irradiation, and the use of an array of therapeutic agents that affect the pericardium. The presence of pericardial disease is also increasingly being recognized because cross-sectional modalities such as echocardiography and CT portray pericardial disease with great accuracy.[154] [155] [156] THE NORMAL PERICARDIUM.

The normal pericardium is frequently identified on lateral plain film projections of the chest as a thin linear opacity separating the anterior subxiphoid mediastinal fat from subepicardial fat. The pericardium may also be visualized in the frontal projection paralleling the left heart border. The extent of normal and abnormal pericardium is best appreciated with CT and MRI in most patients because of superior contrast resolution. With both CT and MRI, the anterior, lateral, and posterior portions of the pericardium are clearly separated from mediastinal fat, and subtle discontinuous areas of pericardial thickening and loculated effusions may be clearly seen. One disadvantage of MRI and CT is that while the pericardial recesses are clearly defined, they may on occasion mimic aortic dissection or mediastinal lymphadenopathy. PERICARDIAL EFFUSION (Fig. 8-32) .

Pericardial effusion may be a transudate or exudate, may be hemorrhagic, gaseous, or

chylous, and may be caused by a wide variety of disorders. When fluid accumulates in the pericardial space, the cardiac silhouette assumes a flasklike, triangular, or globular silhouette. The normal indentations and prominences along both the left and right heart borders are effaced, so the shape of the cardiac silhouette becomes smooth and featureless. Since the pericardium extends up to the pulmonary bifurcation, when a large pericardial effusion is present, the hilar structures are draped and obscured by the distended pericardial cavity. This radiographic appearance should help distinguish a large pericardial effusion from massive cardiomegaly, which will not obscure the hilar vessels. In the lateral chest radiograph in a patient with pericardial effusion, the retrosternal space is typically narrowed or obliterated by the expanding cardiac silhouette. Normally, the low-density subepicardial fat merges imperceptibly with the mediastinal fat since the two fat planes are separated by only the 2-mm-thick stripe of the pericardium. When pericardial effusion is present, the subepicardial fat is displaced posteriorly by the higher density fluid, which may be visible as a wide opaque vertical band between the anterior border of the heart and the mediastinum. This "epicardial fat pad sign" is best visualized on the lateral projection and is highly specific for pericardial effusion (Fig. 8-32 B and C). ECHOCARDIOGRAPHY (see also Fig. 7-94) .

Echocardiography is the most efficient method for the detection of simple pericardial effusion and/or thickening. A major advantage of echocardiography is that the ultrasound apparatus can be transported to the bedside to examine critically ill patients. The technique is noninvasive and is diagnostically sensitive to fluid-filled structures. When the pericardial fluid volume is small, it appears as an elliptical hypoechoic region behind the left ventricle. When the effusion is large, the pericardial hypoechoic zone expands to surround the right ventricular apex. In some cases, echocardiography may fail to identify pericardial fluid when constriction, neoplasm, or hemorrhage is present.[154] [157] If echocardiography is inconclusive, CT can be helpful in detecting pericardial thickening, diffuse or loculated effusion, calcification, and adjacent mediastinal and pulmonary disease, as well as neoplasm[154] (see Fig. 8-32 E). The nature of the fluid may be identified by analysis of CT density numbers. For example, higher CT density values are seen in hemopericardium than in serous effusions. Chylous pericardial effusions may have a lower attenuation value than normal pericardial fluid.[158] MRI (see also Fig. 10-17) .

MRI can clearly detect pericardial effusion. On T1-weighted images, the pericardial cavity is shown as a dark signal void because of motion of fluid in the pericardial sac. On the other hand, the pericardial effusion is bright on a gradient-echo sequence. Pericardial fibrosis is characterized by a medium-intensity signal on T1-weighted or dark signal on T2-weighted images. Intrapericardial masses, cysts, and diffuse thickening are well demonstrated with MRI. Furthermore, MRI can clearly define pericardial recesses, mediastinal fat, and other anatomical landmarks that may present pitfalls for the echocardiographer.[159]

PERICARDIAL CONSTRICTION.

Pericardial constriction may complicate viral or tuberculous pericarditis, hemopericardium,

269

Figure 8-32 Pericardial effusion. A, The heart assumes a globular shape after development of a pericardial effusion. The normal indentations along the heart borders are effaced, so the cardiac silhouette is smooth and featureless. B, The subepicardial radiolucent fat stripe is derived from the subxiphoid fat anterior to a thin, higher density stripe of pericardial fluid (arrowhead). C, The pericardial stripe (arrowheads) is wider than in B because of a small pericardial effusion. D, A large pericardial effusion is present (arrows). E, Contrast-enhanced CT shows a large band of nonenhanced water density surrounding the heart that represents pericardial effusion.

pericarditis associated with radiation, and postpericardiotomy syndrome. In patients with chronic pericardial constriction, the overall heart size is large when the pericardium is thickened to 2 cm or more; otherwise, the cardiac silhouette remains normal or small. The right atrial border is flattened, and pulmonary vascular redistribution may be observed. Small to large pleural effusions are found in 60 percent of patients with pericardial constriction, and enlargement of the azygos vein and left atrium occurs in 20 percent. Pericardial calcification is best appreciated along the anterior and inferior cardiac borders or in the atrioventricular groove. While it is important to appreciate that the presence of pericardial calcification indicates chronic pericarditis, it does not in itself establish a diagnosis of pericardial constriction. Pericardial constriction is often confused with restrictive cardiomyopathy, and MRI and CT are particularly helpful in differentiating between these entities (see Fig. 10-45) . The pericardium in patients with restrictive cardiomyopathy is normal in thickness, and no calcification is present. In addition, diffuse limitation of global cardiac excursion in systole and diastole is present, together with myocardial thickening in hearts with restrictive cardiomyopathy.[157] CONGENITAL ABSENCE OF THE PERICARDIUM.

This abnormality may be partial or complete. Complete absence is less common than partial absence and is usually left sided.[160] Partial absence most frequently occurs along the upper border of the pericardium on either side. If the left-sided defect is small, herniation of the left atrial appendage and/or the pulmonary trunk may occur. On the frontal chest film, herniation through a pericardial defect may resemble the appearance of pulmonary stenosis, mitral stenosis, or a mediastinal tumor. When the left

pericardium is completely absent, the aortic knob remains in its usual position, but the remainder of the cardiac silhouette shifts to the left and rotates toward the right so that the right ventricle may become border-forming and the pulmonary artery and left atrial appendage are prominent.[160] In patients with absence of the left pericardium, a plain film shows the lung interposed between the medial border of the pulmonary artery and the thoracic aorta and outlining the pulmonary artery on both its medial and lateral sides, and aerated lung may be visible between the heart and the diaphragm. CT and MRI demonstrate to best advantage absence of the left anterior pericardium between the ascending aorta and the main pulmonary artery. Displacement of the main pulmonary artery laterally and anteriorly is often a clue to the diagnosis. PERICARDIAL CYST.

A pericardial cyst generally appears as a smooth convex bulge along the middle or lower right heart border near the cardiophrenic sulcus. However, 20 percent of pericardial cysts lie along the left heart border, sometimes mimicking a prominent left atrial appendage or left ventricular aneurysm.[161] Occasionally, pericardial recess cysts are manifested as a soft tissue mass along the right superior mediastinal border in the area of the superior vena cava[161] (Fig. 8-33) . Pericardial cysts rarely calcify and do not communicate with the pericardial space. Their clinical importance lies in the need to differentiate pericardial cysts from other masses with a similar appearance, such as thymoma, lymphoma, and postoperative hematoma. Pericardial cysts are best diagnosed by echocardiography, CT, or MRI as smoothly marginated, fluid-filled structures adjacent to the right heart border. [58] [59] [60] [61]

270

Figure 8-33 Pericardial recess cyst. A, Posteroanterior chest film showing a mediastinal bulge along the right paratracheal line. B, MRI in the sagittal plane shows the cyst as a homogeneous medium-intensity structure behind the superior vena cava.

REFERENCES HISTORICAL PERSPECTIVE 1.

Williams FH: Notes on x-rays in medicine. Trans Assoc Am Physicians 11:375, 1896.

Williams FH: A method for more fully determining the outline of the heart by means of a fluoroscope together with other uses of this instrument in medicine. Boston Med Surg J 135:335, 1896. 2.

3.

Eisenberg RL: Radiology: An Illustrated History. St. Louis, Mosby-Year Book, 1992.

Steiner RM, Gross GW, Flicker S, et al: Congenital heart disease in the adult patient: The value of plain film chest radiology. J Thorac Imaging 10:1-26, 1995. 4.

Henry DA: Radiologic evaluation of the patient after cardiac surgery. Radiol Clin North Am 34:119-135, 1996. 5.

Henschke C, Yankelevitz DF, Wand A, et al: Accuracy and efficiency of chest radiography in the intensive care unit. Radiol Clin North Am 34:21-27, 1996. 6.

Goldstein DJ, Oz MC, Rose EA: Implantable left ventricular devices. N Engl J Med 339:1522-1532, 1998. 7.

8.

Wandtke JC: Bedside chest radiology. Radiology 190:1-10, 1994.

9.

Miller SW: Cardiac Radiology, the Requisites. St. Louis, Mosby-Year Book, 1996, p 4.

Graham RJ, Meziane MA, Rice TW, et al: Postoperative portable chest radiographs: Optimum use in thoracic surgery. J Thorac Cardiovasc Surg 115:45-52, 1988. 10.

NORMAL CARDIAC ANATOMY 11.

Chasen MH, Charnsangave C: Venous chest anatomy: Clinical implications. Eur J Radiol 27:2, 1998.

Takahashi K, Shinozaki T, Hyodo H, et al: Focal obliteration of the descending aortic interface on normal frontal chest radiographs: Correlation with CT findings. Radiology 191:685-690, 1994. 12.

Beigelman C, Mourey-Gerosa I, Gamsu G, Greiner P: New morphologic approach to the classification of anomalies of the aortic arch. Eur Radiol 5:425, 1995. 13.

Stanford W, Galvin JR: The radiology of right heart dysfunction: Chest roentgenogram and computed tomography. J Thorac Imaging 4:7, 1989. 14.

Padhani AR, Hale HL: Mediastinal venous anomalies: Potential pitfalls in cancer diagnosis. Br J Radiol 71:792, 1998. 15.

Caceres J, Mata JM, Andreu J: Azygos lobe: Normal variants that may simulate disease. Eur J Radiol 27:15, 1998. 16.

Murphy ML, Blue LR, Ferris EJ, et al: Sensitivity and specificity of chest roentgenogram criteria for right ventricular hypertrophy. Invest Radiol 23:853, 1988. 17.

Marzullo P, L'Abbate AL, Marcus M: Patterns of global and regional systolic and diastolic function in the normal right ventricle assessed by ultrafast computed tomography. J Am Coll Cardiol 17:1318, 1991. 18.

19.

Robinson AE: The lateral chest film: Is it doomed to extinction? Acad Radiol 5:322, 1998.

Lorenz CH, Walker ES, Morgan VL, et al: Normal human right and left ventricular mass, systolic function and gender differences by cine magnetic resonance imaging. J Cardiovasc Magn Reson 1:7-21, 1999. 20.

21.

Katz J, Whang J, Boxt LM, Barst RJ: Estimation of right ventricular mass in normal subjects and in

patients with pulmonary hypertension by magnetic resonance imaging. J Am Coll Cardiol 21:1475-1481, 1993. Hoffman RB, Rigler LG: Evaluation of left ventricular enlargement in the lateral projection of the chest. Radiology 85:93, 1965. 22.

Mandalam KR, Subramanyan R, Joseph S, et al: Natural history of aortoarteritis: Angiographic study in 26 survivors. Clin Radiol 49:38, 1994. 23.

Morgan PW, Goodman LR, Aprahamian C, et al: Evaluation of traumatic aortic injury: Does dynamic contrast enhanced CT play a role? Radiology 182:661, 1992. 24.

Keren A, Kim KB, Hu BS, et al: Accuracy of multiplane transesophageal echocardiography in diagnosis of typical acute aortic dissection and intramural hematoma. J Am Coll Cardiol 28 627, 1996. 25.

Fattori R, Nienaber CA: MRI of acute and chronic aortic pathology: Preoperative evaluation. J Magn Reson Imaging 10:741, 1999. 26.

27.

Benson JS: Patient and physician radiation during fluoroscopy. Radiology 82:286, 1992.

Bejvan SM, Ephron JH, Takasugi JE, et al: Imaging of cardiac pacemakers. AJR Am J Roentgenol 169:1371, 1997. 28.

Bordlee RP: Cardiac valve reconstruction and replacement: A brief review. Radiographics 12:659, 1992. 29.

Heussel CP, Voigtlaender T, Kavczor HU, et al: Detection of coronary calcifications predicting coronary heart disease: Comparison of fluoroscopy and spiral CT. Eur Radiol 8:1016, 1998. 30.

31.

Duerinckx AJ, Higgins CB: Valvular heart disease. Radiol Clin North Am 32:613, 1994.

32.

Van der Jagt EJ, Smits HJ: Cardiac size in the supine chest film. Eur J Radiol 14:173, 1992.

33.

Tocino I: Chest imaging in the intensive care unit. Eur J Radiol 23:46, 1996.

Kabala JE, Wilde P: Measurement of heart size in the anteroposterior chest radiograph. Br J Radiol 60:981, 1987. 34.

PULMONARY VASCULATURE 35.

Woodring JH: Pulmonary artery-bronchus ratio. Radiology 179:115, 1991.

Baron MG: Plain film diagnosis of common cardiac anomalies in the adult. Radiol Clin North Am 37:401, 1999. 36.

Chang CH: The normal roentgenographic measurement of the right descending artery in 1085 cases. AJR Am J Roentgenol 87:929, 1962. 37.

Baque-Juston MC, Wells AU, Hansell DM: Pericardial thickening or effusion in patients with pulmonary arterial hypertension: A CT study. AJR Am J Roentgenol 172:361, 1999. 38.

Cailes JB, du Bois RM, Hansell DM: Density gradient of the lung parenchyma at computed tomographic scanning in patients with pulmonary hypertension and systematic sclerosis. Acad Radiol 3:724, 1996. 39.

Sherwick AD, Swensen SJ, Hartman TE: Mosaic pattern of lung attenuation on CT scans; frequency among patients with pulmonary hypertension of different causes. AJR Am J Roentgenol 169:79, 1997. 40.

Rich S, Brundage BH: Pulmonary hypertension: A cellular basis for understanding the pathophysiology and treatment. J Am Coll Cardiol 14:545, 1989. 41.

Vogel M, Berger F, Kramer A, et al: Incidence of secondary pulmonary hypertension in adults with atrial septal or sinus venosus defects. Heart 82:30, 1999. 42.

Bergin C: Chronic thromboembolic pulmonary hypertension disease, the diagnosis and the treatment. Semin Ultrasound CT MR 18:383, 1997. 43.

Mark EJ, Patalas ED, Chang HT, et al: Fatal pulmonary hypertension associated with short-term use of fenfluramine and phentermine. N Engl J Med 337:602, 1997. 44.

Sharma S, Bhargava A, Krishnakumar R, Rajani M: Can pulmonary venous hypertension be graded by the chest radiograph? Clin Radiol 53:899, 1998. 45.

271

Herman PC, Khan A, Kallman CE, et al: Limited correlation of left ventricular end diastolic pressure with radiographic assessment of pulmonary hemodynamics. Radiology 174:721, 1990. 46.

Tanaka F, Hayakawa R, Satol Y, et al: Evaluating bronchial drainage in patients with lung disease using digital subtraction and angiography. Invest Radiol 28:434, 1993. 47.

Ketai CH, Goodwin JD: A new view of pulmonary edema and acute respiratory distress syndrome: State of the art. J Thorac Imaging 131:147-171, 1998. 48.

Milne ENC, Pistolesi M: Reading the Chest Radiograph: A Physiologic Approach. St Louis, Mosby-Year Book, 1993, pp 9-50. 49.

Gluecker T, Capasso P, Schnyder P, et al: Clinical and radiologic features of pulmonary edema. Radiographics 19:1507-1531, 1999. 50.

51.

Kerley PJ: Radiology in heart disease. BMJ 2:594, 1933.

Morgan P, Goodman L: Pulmonary edema and acute respiratory distress syndrome. Radiol Clin North Am 29:943, 1991. 52.

Stern EJ, Muller NL, Swensen SJ, Haitman TE: CT mosaic pattern of lung attenuation: Etiologies and terminology. J Thorac Imaging 10:294-297, 1995. 53.

Primack SL, Muller NL, Mayo JR, et al: Pulmonary parenchymal abnormalities of vascular origin: High-resolution CT findings. Radiographics 14:739-746, 1994. 54.

CARDIAC CALCIFICATION 55.

Lasser A: Calcification of the myocardium. Hum Pathol 14:824, 1983.

Jing J, Kawashima A, Sickler K, et al: Metastatic cardiac calcification in a patient with chronic renal failure undergoing hemodialysis: Radiographic and CT findings. AJR Am J Roentgenol 170:903, 1998. 56.

Leonard JJ, Katz S, Nelson D: Calcification of the left atrium: Its anatomic location, diagnostic significance and roentgenologic demonstration. N Engl J Med 256:629, 1957. 57.

58.

van der Geest RJ, Reiber JH: Quantification in cardiac MRI. J Magn Reson Imaging 10:602-608, 1999.

Chin BB, Bloomgarden DC, Xia W, et al: Right and left ventricular volume and ejection fraction by tomographic gated blood pool scintigraphy. J Nucl Med 38:942, 1997. 59.

Wood AM, Hoffmann KR, Lipton MJ: Cardiac function: Quantification with magnetic resonance and computed tomography. Radiol Clin North Am 32:553-579, 1994. 60.

61.

Greenberg SB, Sandhu S: Ventricular function. Radiol Clin North Am 37:341-359, 1999.

Rodan BA, Chen JTT, Halber MD, et al: Chest roentgenographic evaluation of the severity of aortic stenosis. Invest Radiol 17:453, 1962. 62.

Lippert JA, White CS, Mason AC, Plotnick GD: Calcification of aortic valve detected incidentally on CT scans: Prevalence and clinical significance. AJR Am J Roentgenol 164:73, 1995. 63.

Doherty TM, Detrano RC: Coronary arterial calcification as an active process: A new perspective on an old problem. Calcif Tissue Int 54:224-230, 1994. 64.

Stanford W, Thompson BH, Weiss RM: Coronary artery calcification: Clinical significance and current methods of detection. AJR Am J Roentgenol 161:1149, 1993. 65.

Shemesh J, Tenenbaum A, Fisman EZ, et al: Coronary calcium as a reliable tool for differentiating ischemic from nonischemic cardiomyopathy. Am J Cardiol 77:191, 1996. 66.

Stanford W, Thompson BH: Imaging of coronary artery calcification: Its importance in assessing atherosclerotic disease. Radiol Clin North Am 37:257-272, 1999. 67.

Schultz KW, Thorsen MK, Gurney JW, et al: Comparison of fluoroscopy, angiography, and CT in coronary artery calcification. Appl Radiol 19:38, 1989. 68.

Bartel AG, Chen JTT, Peter RH, et al: The significance of coronary calcification detected by fluoroscopy: A report of 360 patients. Circulation 49:1247, 1974. 69.

Aldrich RF, Brensike JF, Battaglini JW, et al: Coronary calcification in the detection of coronary artery disease and comparison with electrocardiographic exercise testing. Circulation 59:113, 1979. 70.

Kelley MJ, Huang EK, Langou RA: Correlations of fluoroscopically detected coronary artery calcification and exercise stress testing in asymptomatic men. Radiology 729:1, 1978. 71.

Agatston AS, Janowitz WH, Hildner F, et al: Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 15:827-832, 1990. 72.

Timins ME, Pinsk R, Sider L, et al: The functional significance of calcification of coronary arteries as detected on CT. J Thorac Imaging 7:79-82, 1991. 73.

Shemesh J, Apter S, Rozenman J, et al: Calcification of coronary arteries: Detection and quantification with double-helix CT. Radiology 197:779-783, 1995. 74.

Woodhouse CE, Janowitz WR, Viamonte M Jr: Coronary arteries: Retrospective cardiac gating technique to reduce cardiac motion artifact at spinal CT. Radiology 204:566, 1997. 75.

Broderick LS, Shemesh J, Wilensky RL, et al: measurement of coronary artery calcium with dual slice helical CT compared with coronary angiography, evaluation of CT scoring methods, interobserver variations and reproducibility. AJR Am J Roentgenol 167:439, 1996. 76.

Stanford W, Thompson, BH, Weiss RM: Coronary artery calcification: Clinical significance and current methods of detection. AJR Am J Roentgenol 161:1139-1146, 1993. 77.

Breen JF, Sheedy PF II, Schwartz RS, et al: Coronary artery calcification detected with ultrafast CT as an indication of coronary artery disease. Radiology 185:435-439, 1992. 78.

Mautner GC, Mautner SL, Froehlich J, et al: Coronary artery calcification: Assessment with electron beam CT and histomorphometric correlation. Radiology 192:619-623, 1994. 79.

Mautner SL, Mautner GC, Froehlich J, et al: Coronary artery disease: Prediction with in vitro electron beam CT. Radiology 192:625-630, 1994. 80.

Fallavollita JA, Brody AS, Bunnell IL, et al: Fast computed tomography detection of coronary calcification in the diagnosis of coronary artery disease: Comparison with angiography in patients 25 mm Hg) or depressed cardiac function. In calculating ventricular volumes or dimensions from angiograms, it is essential to take into account and apply appropriate correction factors for magnification as well as for distortion resulting from nonparallel x-ray beams (pincushion distortion). To apply these correction factors, care must be exercised to determine with accuracy the tube-to-patient and tube-to-film distances. THE CONDUCTANCE CATHETER.

The conductance technique provides a method to measure left ventricular volume on line in the cardiac catheterization laboratory avoiding the problems associated with multiple injections of contrast medium.[13] In this technique, a multielectrode catheter is passed across the aortic valve and the tip is advanced to the apex of the left ventricle.

An electrical field is generated (20 kHz, 0.03 mA RMS current) in the left ventricle between electrodes positioned at the top of the catheter in the apex and just above the aortic valve. Sensing electrodes that are evenly distributed along the catheter are used to measure the potential produced by the current. From these measurements, the resistance (and its inverse--conductance) between electrode pairs spanning the long axis of the left ventricle are calculated. The conductances from the electrode pairs are summed and converted to volume using a signal conditioner, assuming that all the current flows through blood in the left ventricular chamber.[13] Recently, the conductance catheter has been miniaturized for use in experimental studies of transgenic mice.[14] NONINVASIVE METHODS.

Cardiac catheterization and quantitative selective angiography are the standard tools for evaluating the function of the heart, but these invasive procedures have some risk and are not suitable for repeated application in the same patient. Therefore, a continuing search has been made for reliable noninvasive methods of assessing cardiac volume. Such methods are needed particularly for detecting serial changes in cardiac function and in evaluating both acute and chronic effects of interventions such as drug therapy and cardiac operations. Discussed elsewhere in this book are the four principal noninvasive methods for assessing cardiac performance: echocardiography (see p. 162), radionuclide angiography (see Chap. 9) , ultrafast computed tomography (see Chap. 10) , and magnetic resonance imaging[14A] (see Chap. 10) . All of these are alternatives to contrast angiography for measurement of ventricular volumes and/or dimensions and, therefore, permit the noninvasive estimation of ejection phase indices (see later). All four noninvasive imaging methods allow estimation of ventricular systolic and diastolic volumes and both global and regional ejection fraction. LEFT VENTRICULAR VOLUME.

The normal left ventricular end-diastolic volume averages 70 ± 20 (SD) ml/m2 (Table 15-1) .[15] Left ventricular performance ordinarily is considered to be depressed when ventricular end-diastolic volume is clearly elevated (i.e., > 110 ml/m2 , or > 2 SDs above the normal mean) and total stroke volume and/or cardiac index and work are either reduced or within normal limits, while heart rate and arterial pressure are normal. Left ventricular stroke volume is the quantity of blood ejected with each beat and is the difference between end-diastolic volume and end-systolic volume. The normal stroke volume is 45 ± 13 ml/m2 (see Table 15-1) . The cardiac output is equal to the stroke volume multiplied by the heart rate. In the absence of valvular regurgitation or intracardiac shunt, the angiographic stroke volume should correlate closely with an independent measurement of stroke volume (cardiac output/heart rate) using the Fick or thermodilution methods. In the presence of valvular regurgitation or a shunt lesion, the total stroke volume, determined by angiocardiography, is greater than the effective forward stroke volume, determined by the Fick or indicator dilution method. The difference between the two represents the regurgitant (or shunt) flow per cardiac cycle.

TABLE 15-1 -- LEFT VENTRICULAR VOLUME DATA IN PATIENTS GROUP NO. OF END-DIASTOLIC STROKE MASS EJECTION PATIENTS VOLUME (ml/m2 ) VOLUME (gm/m2 ) FRACTION (ml/m2 ) Normal*

70±20.0

45±13.0

92±16.0

0.67±0.08

AS

14

84±22.9

44±10.1

172±32.7 0.56±0.17

AR

22

193±55.4

92±30.9

223±73.0 0.56±0.13

AS and AR

13

138±36.5

75±19.1

231±56.9 0.53±0.10

MS

37

83±21.2

43±11.9

98±24.1

MR

29

160±53.1

87±21.3

166±49.9 0.47±0.10

MS and MR 29

106±34.4

58±14.7

119±27.8 0.57±0.12

A and M combined

45

130±55.8

69±25.5

156±55.9 0.55±0.12

Myocardial disease

15

199±75.7

44±14.5

145±27.6 0.25±0.09

0.57±0.14

AS=aortic valve stenosis with peak systolic pressure gradient >30 mm Hg; AR=aortic valve insufficiency with regurgitant flow >30 ml per beat; MS=mitral valve area 20 ml per beat; A and M combined=combined aortic and mitral valve disease; myocardial disease=primary cardiomyopathy or myocardial disease secondary to coronary atherosclerosis. From Dodge HT, Baxley WA: Left ventricular volume and mass and their significance in heart disease. Am J Cardiol 23:528, 1969. *Normal values from Kennedy JW, et al: Quantitative angiocardiography: The normal left ventricle in man. Circulation 34:272, 1966.

483

Ejection Fraction.

The ejection fraction (EF) is the ratio between stroke volume (SV) and end-diastolic volume (EDV). In the presence of valvular regurgitation, the total stroke volume ejected by the ventricle (i.e., the sum of forward and regurgitant volumes) is used in this calculation. The regurgitant fraction (RF) is the ratio of regurgitant flow per beat to the total left ventricular stroke volume:

where SV total is determined by angiography and SV forward by the Fick or indicator

dilution method. When mitral and aortic regurgitation coexist, the regurgitant fraction reflects the sum of the two regurgitant volumes and does not distinguish between them. It is important to recognize that there are errors in measuring both total SV and forward SV. These errors summate in the calculation of the regurgitant volume and the regurgitant fraction. Thus, it is difficult to determine regurgitant volume. LEFT VENTRICULAR MASS.

Left ventricular mass can be determined by M-mode or two-dimensional echocardiography using several techniques (see Chap. 7) .[16] In one of these methods, left ventricular mass is calculated as the difference between total ventricular volume (estimated from the product of the epicardial left ventricular length and the area of the left ventricle in the short axis) and the volume of the left ventricular cavity. Echocardiographically determined left ventricular mass is an important prognostic factor in patients with left ventricular hypertrophy. [17] [18] [19] Computed tomography and magnetic resonance imaging are also useful methods to accurately measure left ventricular mass (see Chap. 10) .[16] [16A] Left ventricular wall thickness normally averages 10.9 ± 2.0 (SD) mm and left ventricular mass averages 92 ± 16 gm/m2 (see Table 15-1) . Chronic cardiac dilatation secondary to volume overload or primary myocardial disease increases left ventricular mass, as does chronic pressure overload. Hypertrophy caused by pressure overload (such as aortic stenosis) is characterized by an increased muscle mass resulting from an augmentation of wall thickness with little change in ventricular chamber volume (concentric hypertrophy) (see Table 15-1) . In contrast, hypertrophy caused by volume overload or by primary myocardial disease is characterized by an increased muscle mass resulting from ventricular dilatation, with only a slight increase in wall thickness (eccentric hypertrophy) (see Table 15-1) . LEFT VENTRICULAR FORCES.

The forces acting on the myocardial fibers within the ventricular wall can be calculated from the dimensions of the left ventricular cavity, wall thickness, and intraventricular pressure. Left ventricular tension (force/cm) is the force acting on a hypothetical slit in the ventricular wall that would pull its edges apart. According to Laplace's law, tension is the product of the intraventricular pressure and radius. Wall stress (sigma) is the force or tension per unit of cross-sectional area of the ventricular wall. Wall stress may be considered to act in three directions--circumferential, meridional, and radial (Fig. 15-5) . The calculation of stress requires assumptions concerning the shape and configuration of the ventricle.[20] [21] Circumferential wall stress, the strongest force generated within the ventricular wall, can be approximated as:

where CWS=circumferential wall stress in dynes per square centimeter×103 ; P=left ventricular pressure in dynes per square centimeter; a and b are major and minor

semiaxes (i.e., half the longest lengths), respectively, in cen

Figure 15-5 Circumferential (sigmac ), meridional (sigma m ), and radial (sigma r ) components of left ventricular wall stress from an ellipsoid model. The three components of wall stress are mutually perpendicular. (From Fifer MA, Grossman W: Measurement of ventricular volumes, ejection fraction, mass, and wall stress. In Grossman W [ed]: Cardiac Catheterization and Angiography. 5th ed. Philadelphia, Lea & Febiger, 1996, p 324.)

timeters; and h=left ventricular wall thickness in square centimeters.[22] Meridional wall stress (MWS) can be approximated as:

where r is the internal radius of the ventricle in centimeters. Simultaneous recording of left ventricular dimensions and intraventricular pressure recorded with a high-fidelity micromanometer allows calculation of left ventricular tension and stress throughout the cardiac cycle. A simple method of analyzing the instantaneous left ventricular tension throughout the cardiac cycle consists of recording left ventricular pressure simultaneously with left ventricular diameter across the minor axis of the left ventricle determined by echocardiography. This combination of measurements provides the data necessary to calculate ventricular circumferential fiber shortening (at either the endocardium or the midwall) and midwall circumferential stress, using minor modifications of the equations presented earlier. However, the use of echocardiography, especially M mode, for these calculations is based on the assumption of uniform wall motion. This assumption is reasonable only in conditions that affect left ventricular function relatively uniformly, such as dilated cardiomyopathy or aortic or mitral regurgitation. These assumptions are not correct when there is regional left ventricular dysfunction. During isovolumetric contraction, left ventricular wall tension and stress rise rapidly as the ventricle contracts without decreasing the chamber volume. During ejection, as the left ventricular cavity decreases in size and wall thickness increases, the stress and tension decline even though pressure is maintained. REGIONAL VENTRICULAR WALL MOTION.

Ischemic heart disease typically produces regional abnormalities of contraction. Hyperkinesis of normal areas may compensate for impaired function of an abnormal region, leaving global left ventricular function normal or only minimally depressed. Thus, assessment of regional wall motion is more sensitive

484

Figure 15-6 Left ventricular angiograms in the 30-degree right anterior oblique (RAO) and 60-degree left anterior oblique (LAO) projections. End-diastolic (ED) and end-systolic (ES) frames are shown. Tracing of ED and ES images are superimposed on the far right. The images on top are from a patient with normal left ventricular contraction. The patient on the bottom has anterior-apical and septal akinesis (arrows).

in detecting ventricular dysfunction in such patients than analysis of global ventricular function. Regional wall motion can be assessed with a variety of methods, including contrast angiography.[23] Marked focal abnormalities of contraction can be appreciated by visual inspection of ventriculograms; segments of abnormal ventricular contraction can be localized by superimposing end-diastolic and end-systolic outlines of the left ventricular cavity (Fig. 15-6). Akinesis is present when a portion of each of the two silhouettes shares a common line; dyskinesis is present when the end-systolic silhouette extends outside the end-diastolic silhouette. The abnormally contracting segments (both akinetic and dyskinetic) may be expressed simply as percentages of the total enddiastolic circumference. Hypokinesis (focal decreases in the extent of contraction) as well as asynchrony (abnormalities of timing of contraction) are less severe disturbances of contraction. Analysis of wall motion from multiple cine frames and automated border detection may be necessary for the detection of these more subtle abnormalities (Fig. 15-7) .[24] RIGHT VENTRICULAR AND ATRIAL VOLUME.

The shape of the right ventricle is much more complex than the shape of the left ventricle. Thus, the prolate ellipsoid that is a useful model to calculate left ventricular volume is not appropriate for the right ventricle.[25] One method is to consider the right ventricle as a pyramid with a triangular base. An alternate approach is to calculate right ventricular volume using Simpson's rule. The shape of each atria is less complex than that of the right ventricle. Thus, the atrial volumes can be calculated assuming an ellipsoidal geometry.[26]

485

Figure 15-7 Automated border recognition tracing of the left ventricular endocardial borders from two-dimensional echocardiograms obtained in the four-chamber (A) and short-axis (B) views. ROI=region of interest; MV=mitral valve; PM=papillary muscle. (From Hashimoto I, Ichida F, Miura M, et al: Automatic border detection identifies subclinical anthracycline cardiotoxicity in children with malignancy. Circulation

99:2369, 1999. Copyright 1999, American Heart Association.)

ASSESSMENT OF LEFT VENTRICULAR FUNCTION The factors that determine myocardial function (preload, afterload, contractility, heart rate, and rhythm; see Chap. 14) can be estimated from left ventricular pressure and volume. Preload (See also p. 464)

Left ventricular preload can be assessed from the left ventricular filling pressure, left ventricular end-diastolic volume, or left ventricular end-diastolic stress.[27] [28] The pressure distending the ventricle immediately before contraction is the end-diastolic pressure. In the absence of disease of the mitral valve this is equivalent to the pressure in the left atrium at this time (the post a wave or Z point pressure). When there is a vigorous atrial contraction, the end-diastolic pressure is substantially higher than the mean left atrial pressure. It is important to recognize that the amount of pulmonary congestion is related to the mean pulmonary capillary (or left atrial) pressure, whereas the end-diastolic volume is determined by the left ventricular end-diastolic pressure.[27] In the absence of pulmonary vascular disease, mean pulmonary capillary wedge pressure approximates the pulmonary artery diastolic pressure. In the presence of a tall v wave, the mean atrial pressure (and mean pulmonary capillary edge pressure) may exceed the ventricular end-diastolic pressure.[29] The left ventricular preload depends on the end-diastolic volume produced by the distending pressure of the ventricle. Because interventions that alter end-diastolic pressure may also alter the relation between end-diastolic volume and pressure, changes in end-diastolic pressure do not always represent changes in end-diastolic volume or changes in end-diastolic fiber stretch. Afterload

After aortic valve opening the ventricle ejects into the arterial circulation. Thus, the systolic pressure in the simplest sense represents the afterload opposing left ventricular ejection. However, arterial systolic pressure is not a pure measure of left ventricular afterload. The tension in the ventricular wall that the sarcomeres must overcome to shorten is related not only to the systolic pressure but also to the cavity size through the Laplace relation. Thus, at similar systolic pressures a larger ventricle will have greater wall tension than a smaller ventricle. Furthermore, the arterial systolic pressure depends not only on the characteristics of the arterial circulation but also on the pumping performance of the left ventricle. The more vigorous the left ventricular contraction, the larger the volume ejected and the higher the systolic pressure. Thus, left ventricular systolic function and left ventricular afterload are interrelated. The steady-state arterial load opposing left ventricular ejection can be quantified as the peripheral vascular resistance.[3] ° This is calculated as the cardiac output divided by the mean arterial pressure minus the mean venous pressure (see Chap. 11) . Because

venous pressure is very low relative to mean arterial pressure, it is frequently neglected in this calculation. The peripheral vascular resistance provides only steady-state information concerning the relation between flow and pressure in the arterial system. However, the left ventricular ejection is pulsatile, and there are pulsatile elements to the arterial load that increase in importance with tachycardia, aging, and peripheral vascular disease.[31] [32] The full relation between flow and arterial pressure can be evaluated in the frequency domain as the arterial input impedance.[33] [34] Calculation of the input impedance spectrum requires the high-fidelity measurement of aortic pressure and flow at the same point. The impedance spectrum consists of a magnitude and phase at each frequency. The magnitude of the impedance at a given frequency is the ratio of a sinusoidally varying pressure and related flow at that frequency. Because arterial pressure and flow do not vary sinusoidally, the Fourier transformation is used to mathematically describe the aortic pressure and flow as a combination of a fundamental sine wave (at the heart rate)

486

Figure 15-8 Recordings of ascending aortic pressure and flow (A) and the resulting aortic input impedance spectra (B) from a 56-year-old normotensive subject ( -) and a 61-year-old subject with isolated systolic hypertension ( --), with an impedance spectrum from a young (28 years) normotensive subject ( --), shown for comparison. Peripheral vascular resistance (R), impedance moduli of the first harmonic (Z i ) and characteristic impedance (Z 0 ) were all higher in the subject with isolated systolic hypertension. Also, the impedance moduli minimum was shifted to a higher frequency in the subject with isolated systolic hypertension. Yrs=years; Freq=frequency. (From Nichols WW, Nicolini FA, Pepine CJ: Determinants of isolated systolic hypertension in the elderly. J Hypertension 10[Suppl 6]:S73, 1992.)

Figure 15-9 Left ventricular arterial coupling assessed in the pressure-volume plane. The left ventricular end-systolic pressure-volume relation (ESPVR) is used to describe left ventricular systolic performance. Top left, Pressure-volume loops for variably loaded beats are shown with the upper left corner of each beat falling on the ESPVR (dotted line). Top right, The arterial circulation is described as a relation between stroke volume and end-systolic pressure (solid line). The slope of this relation represents the effective end-systolic arterial elastance (E A ). Bottom left, The left ventricular ESPVR and the aortic ESPVR (A O PES -VES ) are plotted on the same axis. End systole occurs at the intersection of the two relations. Thus, description of the arterial circulation in terms of the aortic P ES -SV relation allows understanding of the coupling between the left ventricle and arterial circulation. (Redrawn from Little WC, Cheng CP: Left ventricular-arterial coupling in conscious dogs. Am J Physiol 261:H70, 1991. Reproduced by permission of the American Physiological Society.) Bottom right, Pressure-volume loops in the same format recorded in an elderly patient without cardiac disease. (Reproduced from Chen CH, Nakayama M, Nevo E, et al: Coupled systolic-ventricular and vascular stiffening with age: Implications for pressure

regulation and cardiac reserve in the elderly. J Am Coll Cardiol 32:1225, 1998.)

487

and a series of harmonic waves. The impedance spectrum is then calculated as the ratio of the pressure to flow at each frequency. Figure 15-8 provides an example of such an impedance spectrum. Although the impedance spectrum contains all the information concerning the linear relation between pulsatile flow and pressure in the arterial circulation, its clinical usefulness is limited by the difficulty in obtaining the appropriate measurement and the calculations. Evaluation of the interaction of the left ventricle and the arterial system requires that they be described in similar terms. Description of the arterial system in the frequency domain does not easily allow this coupling to be assessed because the left ventricle is difficult to describe in these terms. Because the left ventricle can be evaluated in the pressure-volume plane, Sunagawa and colleagues[35] proposed that the arterial system be evaluated in an analogous manner. In this analysis, the arterial system is described by the relation between the stroke volume and end-systolic pressure (Fig. 15-9) . The higher the stroke volume, the greater the end-systolic pressure. The slope of this relation represents the effective arterial end-systolic elastance (EA ). If it is assumed that this relation passes through the origin, then EA can be calculated as the ratio of end-systolic pressure to stroke volume. As shown in Figure 15-9 , this can be plotted on the left ventricular pressure-volume loop. End systole occurs at the intersection of the arterial and ventricular relations. The production of SW is maximum when the EES and EA are approximately equal.[36] Under usual conditions, EA , the slope of the arterial end-systolic pressure stroke volume relation, can be approximated by the peripheral vascular resistance multiplied by the heart rate.[37] In older hypertensive patients, EA may exceed the product of peripheral vascular resistance and heart rate. However, EA can be accurately estimated over a wide range of conditions from arterial systolic (PSYS ) and diastolic pressures (Pdiast ) as: (2×PSYS +Pdias )/3 divided by the stroke volume.[37] Contractile State (See also p. 464)

In experimental cardiac muscle or isolated heart preparations, loading can be readily controlled and the effects of an intervention on the strength, extent, and velocity of muscle shortening indicate its effect on the contractile

Figure 15-10 A, Recording of left ventricular pressure (LVP), the rate of change of left ventricular pressure (dP/dt) and left ventricular volume (LVV). The maximum value of dP/dt, (dP/dt max ) increases in response to dobutamine; however, dP/dt max also increases when left ventricular end-diastolic volume is

increased by infusing dextran. This demonstrates the sensitivity of dP/dtmax to both contractility and left ventricular end-diastolic volume (preload). (Data from Little WC: The left ventricular dP/dt max -end-diastolic volume relation in closed chest dogs. Circ Res 56:808, 1985. Copyright 1985, American Heart Association.) B, Recordings in a normal subject demonstrating increase in dP/dt max during increases in contractility produced by pacing tachycardia, isoproterenol, and exercise. (Modified from Inagaki M, Yokota M, Izawa H, et al: Impaired force-frequency relations in patients with hypertensive left ventricular hypertrophy. Circulation 99:1826, 1999. Copyright 1999, American Heart Association.)

488

TABLE 15-2 -- EVALUATION OF LEFT VENTRICULAR SYSTOLIC PERFORMANCE: NORMAL VALUES FOR SOME ISOVOLUMIC AND EJECTION PHASE INDICES CONTRACTILITY INDICES NORMAL VALUES (MEAN±SD) Isovolumic Indices Maximum dP/dt

1650±300 mm Hg/sec

Maximum (dP/dt)/P

44±8.4 sec-1

VPM or peak [dP/dt 28P]

1.47±0.19 ML/sec

dP/dt/DP at DP=40 mm Hg

37.6±12.2 sec-1

Ejection Phase Indices LVSW

81±23 gm-m

LVSWI

50±20 gm-m/M2

EF: angio:

0.72±0.08

MNSER angio:

3.32±0.84 EDV/sec

MNSER echo:

2.29±0.30 EDV/sec

Mean VCF angio:

1.83±0.56 ED circ/sec

echo:

1.09±0.12 ED circ/sec

dP/dt=rate of rise of left ventricular (LV) pressure; DP=developed LV pressure; ML=muscle lengths; LVSW=left ventricular stroke work; LVSWI=left ventricular stroke work index; MNSER=mean normalized systolic ejection rate; ED=end-diastolic; V=volume; circ=circumference; EF=ejection fraction.From Grossman W: Evaluation of systolic and diastolic function of the myocardium. In Grossman W, Baim DS (eds): Cardiac Catheterization, Angiography, and Intervention, 5th ed. Philadelphia, Lea & Febiger, 1996, p 339.

state. It is more difficult to make analogous measurements in patients in whom preload and afterload are interrelated and cannot be readily controlled. Many drugs that affect myocardial contractility also act on the arterial and/or venous beds, thereby altering

cardiac loading. Furthermore, in patients with valvular heart disease, it is necessary to evaluate the level of myocardial contractility despite the marked alterations in loading conditions. These considerations have led to the search for methods of evaluating cardiac function that go beyond analysis of the pumping function of the ventricle and provide an assessment of contractility. A number of indices of contractility have been proposed and investigated empirically. Unfortunately, there is no absolute measure of myocardial contractility; that is, there is no gold standard with which these indices can be compared. Furthermore, at the sarcomere level, contractility and load are interrelated and, thus, not independent variables.[1] Many indices have been proposed as measures of left ventricular contractile function [38] (Table 15-2) . These can be divided into isovolumetric phase indices, ejection phase indices, and measures derived from left ventricular pressure-volume relations. ISOVOLUMETRIC INDICES OF CONTRACTILITY. Ventricular dP/dt.

The maximum rate of rise of ventricular pressure (dP/dt max ) is highly sensitive to acute changes in contractility (Fig. 15-10) .[39] Under normal conditions dP/dtmax occurs before aortic valve opening; thus it is not affected by steady-state alterations in aortic pressure. However, dP/dtmax may be delayed until after aortic valve opening in patients with severe left ventricular depression or marked arterial vasodilation with very low aortic diastolic pressures. In the absence of these conditions, dP/dtmax can be considered to be relatively independent of afterload. However, dP/dtmax is very sensitive to changes in preload. This preload sensitivity is greater in ventricles with enhanced contractility but is reduced in depressed ventricles.[39] However, a change in dP/dtmax without a change in preload or with an opposite change in preload indicates an alteration in contractility. Although dP/dtmax correlates with basal contractility, the wide variation between individuals and the marked preload dependence decreases its usefulness for assessing basal contractility. Instead, dP/dtmax is more useful in assessing directional changes in contractility during acute interventions when used in combination with a measure of left ventricular preload. Vmax .

This is the maximum velocity of shortening of the unloaded contractile elements (CE). It was originally proposed as a measure of myocardial contractility that is independent of preload or afterload. However, there are theoretical and practical limitations to the calculation of CE Vmax in isolated muscle, and even more so in the intact heart. Because of the theoretical problems and practical difficulties in calculating Vmax , it is no longer used as a clinical measure of contractility. Relation Between dP/dt and Developed Pressure.

Some of the difficulties involving the calculation of Vmax can be partially avoided by the selection of certain points on the curve relating dP/dt to DP, the developed left ventricular pressure (i.e., left ventricular pressure minus end-diastolic pressure). The dP/dt at a DP of 40 mm Hg, a level of pressure that almost always occurs before the opening of the aortic valve, is commonly used. dP/dt at a DP of 40 mm Hg and the maximum dP/dt/DP are useful for assessing directional changes in contractility, because it is unaffected by changes in afterload and less sensitive to changes in preload than dP/dtmax . EJECTION PHASE INDICES.

The extent of left ventricular ejection can be measured as the stroke volume, ejection fraction, or fractional shortening, and the rate of ejection can be quantified as the mean and peak velocity of shortening (VCF ).[40A] All of these measurements are influenced by both contractility and load.[40] The marked preload dependence of the stroke volume is minimized by dividing by the end-diastolic volume producing the ejection fraction. However, the ejection fraction is sensitive to changes in afterload; so it is best to consider it a measure of systolic performance, because it is not a pure measure of contractility (see later). The afterload dependence of the ejection fraction or measures of the left ventricular shortening can be minimized using concepts derived from the myocardial force-velocity relation of isolated cardiac muscle (Fig. 15-11) . For example, the relation between ejection fraction or frac

Figure 15-11 The relation between left ventricular ejection fraction (EF) and arterial load (E a ) in patients with aortic regurgitation. EF falls with increasing arterial load, both in patients with normal contractile function (solid circles) and those with impaired contractile performance (open circles). The fall in ejection performance (EF) with load is more marked in the patients with reduced contractile performance. (From Devlin WH, Petrusha J, Briesmiester K, et al: Impact of vascular adaptation to chronic aortic regurgitation on left ventricular performance. Circulation 99:1027, 1999. Copyright 1999, American Heart Association.)

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myocardial fiber shortening and left ventricular end-systolic stress, obtained in the basal state and during pharmacologically altered afterload, provides a useful framework for assessing the basal level of left ventricular contractility.[41] [42] [43] [44] Augmentation of VCF at a constant wall stress signifies an improvement of contractility. These relations are particularly useful in patients who have a reduced ejection fraction, because it distinguishes between reduced myocardial shortening due to excessive afterload and that due to depressed myocardial contractility.[45] The VCF -sigmaES relation during a

single beat is not defined by parallel straight lines; thus, it may not be accurately defined from measurements made from a single loading condition.[46] PRESSURE-VOLUME RELATIONS.

As discussed earlier, consideration of the left ventricle in the pressure-volume plane provides a powerful method to understand left ventricular performance.[2] [47] [48] The generation of variably loaded beats allows determination of several relations that provide information concerning left ventricular contractility and systolic performance. The variably loaded beats can be produced by transient balloon occlusion of the inferior vena cava.[49] [50] An alternate approach is to generate a range of loading conditions using graded infusions of vasoactive agents, such as methoxamine and nitroprusside.[50] [51]

Left Ventricular ESPVR.

The upper left-hand corner of variably loaded pressure-volume loops defines the left ventricular ESPVR (Fig. 15-12) . In the physiological range, this relation can be approximated as a straight line. Thus, it can be described with a slope (EES ) and volume axis intercept (V0 ),[52] [53] that is,

The slope, which has dimensions of pressure/volume (units of mm Hg/ml), has been called the end-systolic elastance (EES ). This represents the end-systolic stiffness of the left ventricle and indicates how sensitive ejection will be to increases in afterload (as reflected in the end-systolic pressure). With enhanced contractility, EES increases. The volume axis intercept (V0 ) of the ESPVR has been referred to as the "dead volume" of the ventricle. This is the volume at which the left ventricle would generate no pressure. This volume intercept cannot be directly measured clinically. Instead, it must be determined by extrapolation and thus is subject to large errors.[52] [53] [54] In many clinical studies the extrapolated V0 is negative, which is a physiological impossibility. This indicates the difficulties involved in accurately determining V0 in clinical studies. [54] The position of the ESPVR on the volume axis at the operating pressure (e.g., the end-systolic volume associated with an end-systolic pressure of 100 mm Hg) indicates the extent of ejection. Global increases in contractility, such as the infusion of dobutamine, both increase EES and shift the ESPVR to the left in the physiological range.[53] [54] Thus, at a constant afterload (i.e., constant left ventricular end-systolic pressure) the left ventricle with enhanced contractility ejects to a lower volume and is less sensitive to changes in systolic pressure. Global decreases in contractility produce the opposite effect. Thus, EES and the position of the ESPVR in the physiological range provide load-insensitive measures of the contractile state.[53] [54] Regional left ventricular dysfunction resulting from coronary artery occlusion produces a parallel rightward shift of the left ventricular ESPVR in the physiological range with little

change in the EES .[55] [56] A similar parallel shift of the ESPVR occurs during dysynchronous activation of the left ventricle (Fig. 15-13) . [57] [58] An echocardiographically determined left ventricular end-systolic dimension or cross-sectional area can be used as a surrogate for left ventricular volume in the left ventricular ESPVR provided there is not a segmental wall motion abnormality.[59] Automated echocardiographic border detection makes it possible to determine pressure-area relations on-line.[60] There are practical and theoretical difficulties in using the ESPVR as a clinical measure of left ventricular contractility. First, to accurately define the ESPVR, a wide range of loading conditions must be obtained. Such alterations in

Figure 15-12 A, Variably loaded pressure-volume loops produced by caval occlusion in a conscious experimental animal. End systole occurs at the upper left corner of the pressure-volume loops. The end-systolic points of the variably loaded beats fall along a single relation, the left ventricular end-systolic pressure-volume relation (LV ESPVR). Within the physiological range, this relation is approximated by a straight line. The line can be described in terms of its slope (EES ) and volume axis intercept (V0 ). Note that the volume axis intercept results from extrapolation of the line outside the range of end-systolic pressures in which data can be acquired. An increase in contractile state, produced by infusing dobutamine, shifts the LV ESPVR toward the left while increasing the slope. (Data from Little WC, Cheng CP, Mumma M, et al: Comparison of measures of left ventricular contractile performance derived from pressure-volume loops in conscious dogs. Circulation 80:1378, 1989. Copyright 1989, American Heart Association.) B and C, Recordings of right atrial pressure (RAP), left ventricular volume (LVV) measured with the conductance catheter, and left ventricular pressure (LVP) in a patient during transient balloon occlusion of the inferior vena cava. These variably loaded beats are shown in the pressure-volume plane on the right. The upper left corner of these loops defines the LV ESPVR (dotted line). (From Kass DA: Clinical ventricular pathophysiology: A pressure-volume view. In Warltier DC [ed]: Ventricular Function. Baltimore, Williams & Wilkins, 1995.)

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Figure 15-13 Top, Left ventricular (LV) pressure-volume loops in an experimental animal during transient caval occlusions. The upper left corners of the loops define the left ventricular end-systolic pressure-volume relation (ESPVR). During atrial pacing producing normal LV activation the ESPVR is shifted leftward in a parallel fashion, compared with ventricular pacing that produces dysynchronous LV activation and contraction. (From Park RC, Little WC, O'Rourke RA: Effect of alteration of left ventricular activation sequence on the left ventricular end-systolic pressure-volume relation in closed-chest dogs. Circ Res 57:711, 1985.) Bottom, Steady-state left ventricular pressure-volume loop recorded using the conductance catheter in a patient with dilated cardiomyopathy and dysynchronous left ventricular activation due to left bundle branch block (LBBB). A decrease in dysynchronous contraction produced by left ventricular free wall pacing (LVFW) produced loops with greater width (stroke volume) as the end-systolic pressure-volume point shifted toward the left. (From Kass DA, Chen DH, Curry C, et al: Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation 99:1570, 1999. Copyright 1999, American Heart Association.)

load may induce reflexly mediated changes in heart rate and left ventricular contractility. In addition, arterial vasoconstriction and vasodilation produce parallel shifts of the left ventricular ESPVR.[61] [62] Thus, the interventions required to accurately define the ESPVR may themselves alter the relation, thus confounding the ability to define the ESPVR with precision in clinical studies.[63] A second difficulty in evaluating the ESPVR is the determination of the timing of end systole. End systole is defined as the upper-left-hand corner of the pressure-volume loop. This may not exactly correspond to aortic valve closure or the time of maximum ventricular elastance. This difference may be accentuated when there is reduced impedance to left ventricular ejection, as occurs in mitral regurgitation. [64] A third difficulty is that the slope of the ESPVR depends on the size of the ventricle; thus it is not possible to define a normal range for E ES . Attempts to correct for ventricular size have not been uniformly successful. However, this does not prevent E ES from differentiating patients with normal from abnormal left ventricular contractile function. [65] One method of correcting for differences in left ventricular size is to evaluate the left ventricle in the stress-strain plane.[66] In this analysis the left ventricular end-systolic stress-strain relation is analogous to the ESPVR, except that which has been normalized for wall thickness and chamber size and configuration. If V0 is assumed to be small, then EES can be approximated by the ratio of left ventricular systolic pressure to end-systolic volume (PES /VES ).[53] [67] This approach has the advantage of avoiding the need to evaluate multiply loaded beats. However, the PES /VES ratio is subject to large errors in estimating EES when V0 is large and is not a sensitive measure of contractile performance. E ES can also be estimated from a single cardiac cycle using the time varying elastance model to predict V0 .[68] Despite the theoretical and practical limitations to the clinical evaluation of contractility using the ESPVR, left ventricular pressure-volume analysis provides a powerful tool to help understand the interaction of contractile state and load to produce ventricular performance (Fig. 15-14) . Other Pressure-Volume Relations.

Two other relations can be derived from variably loaded pressure-volume loops: the dP/dtmax -end-diastolic volume (VED ) relation and SW-VED relation (Fig. 15-15) . During caval occlusion, dP/dtmax and VED are linearly related.[39] The slope of the relation (dE/dtmax ) represents the maximum rate of change of left ventricular elastance during contraction and is very sensitive to contractile state. Thus, this resting dP/dtmax -VED relation accounts for the preload-dependence of dP/dtmax , which increases when the contractile state is augmented. Although it is very sensitive to changes in contractile state, the dP/dtmax -VED relation has several limitations. First, dP/dtmax is more variable

than PES , and this relation is less stable than the ESPVR.[69] Second, the dP/dtmax -VED relation saturates at volumes only slightly above the operating point.[70] Thus, this relation can be defined only by preload reduction and not by pharmacologically produced increases in load. SW is the external work performed by the left ventricle and is calculated as the area of the pressure-volume loop. It can be approximated as the product of the stroke volume and the mean arterial pressure. Thus, SW integrates the two determinants of tissue perfusion: flow and pressure. During caval occlusions, SW and VED are linearly related. SW is insensitive to arterial load in the physiological range; thus, the SW-VED relation is afterload independent under these conditions.[36] [71] [72] In response to increase in contractile state, the slope of this relation, termed preload recruitable stroke work (PRSW), increases. Thus, PRSW has been proposed as a load-independent measure of contractile state.[73] However, the SW-VED relation is not only determined by contractile state, but it also can be altered by changes in the diastolic left ventricular pressure-volume relation.[69] For example, the diastolic pressure-volume relation can be altered under some circumstances without a change in the ESPVR.[74] This alters the LV SW-VED relation and PRSW. Although importantly influenced by contractility, the SW-VED relation is best considered as a measure of integrated pump function (see later). The SW-VED relation has several important advantages.[69] First, since SW integrates pressure and volume throughout the cardiac cycle it is free of noise and is remarkably stable. Second, during reductions in preload as produced by caval occlusion, both determinants of SW (stroke volume and end-systolic pressure) decline, producing a wide range of SW values. This wide range of data increases the statistical precision with which the SW-VED relation can be defined. Finally, the slope (PRSW) has dimensions of pressure; thus, it is independent of left ventricle cavity size.

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Figure 15-14 Examples of variably loaded pressure-volume loops used to define the left ventricular end-systolic pressure-volume relations in four patients: normal ventricle, hypertrophic cardiomyopathy (HCM), left ventricular hypertrophy (LVH) due to hypertension (HTN), dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy (HCM). (From Pak PH, Maughan WL, Baughman KL, Kass DA: Marked discordance between dynamic and passive diastolic pressure-volume relations in idiopathic hypertrophic cardiomyopathy. Circulation 94:57, 1996. Copyright 1996, American Heart Association.) MAXIMUM POWER.

The power generated by the left ventricle can be calculated as the product of aortic flow and pressure. The maximum power (PWRmax ) responds to changes in contractile state, is insensitive to changes in the arterial circulation, and is linearly related to the square of

VED (VED 2 ) in the physiological range. [75] [76] Thus, PWRmax /VED 2 may provide a preload independent measure of contractility. PWRmax /VED 2 can be determined noninvasively using nuclear techniques or Doppler echocardiography to determine aortic flow and by measuring arterial pressure using indirect means.[77] Clinical Evaluation of Determinants of Left Ventricular Function

Many of the complex measures just discussed are not appropriate for routine clinical use. Although left ventricular preload is most accurately determined by its end-diastolic volume, preload is usually assessed clinically by measurements of the pulmonary capillary wedge pressure (see earlier discussion). The level of left ventricular afterload can be estimated by the systolic arterial pressure (in the absence of aortic stenosis). When the systolic pressure is low, calculation of the vascular resistance can determine whether it is due to a low arterial tone (low vascular resistance) or inadequate cardiac output. Although, the left ventricular ejection fraction is a measure of left ventricular systolic performance (see later) in the absence of abnormal afterload or valvular disease, it reflects myocardial contractility. Similarly, left ventricular end-systolic volume (or dimension) when arterial systolic pressure is normal (100-140 mm Hg) indicates the operating position of the left ventricular ESPVR, reflecting systolic (and contractile) performance. Thus, echocardiographic measurements of left ventricular end-systolic dimension can be used to follow the contractile performance of patients with mitral or aortic regurgitation.[78] [79] [79A] [80]

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Figure 15-15 Three relations describing left ventricular systolic performance derived from variably loaded pressure-volume loops: the left ventricular end-systolic pressure-volume relation, the relation between dP/dtmax and end-diastolic volume (VED ), and the relation between stroke work and VED . All three relations can be approximated by a straight line within the range of data generated by transient caval occlusion. Each relation is shifted toward the left with an increase in slope in response to increase in contractile state produced by dobutamine. (From Little WC, Cheng CP, Mumma M, et al: Comparison of measures of left ventricular contractile performance derived from pressure-volume loops in conscious dogs. Circulation 80:1378, 1989. Copyright 1989, American Heart Association.)

LEFT VENTRICULAR PUMP FUNCTION (See also p. 462 ) The contraction of individual sarcomeres is integrated into the myocardial shortening, which ultimately is expressed as the pumping function of the left ventricle. The left heart can be analyzed as a pump with an input (the pulmonary venous or mean left atrial pressure) and an output (which in simplest terms is the cardiac output=stroke volume×heart rate). The relationship between the input and output is the ventricular function curve or the Frank-Starling relationship (Fig. 15-16) . In this relationship, the output can be considered to be the stroke volume, cardiac output, or the SW.

A family of Frank-Starling curves reflects the response of the pump performance of the ventricle to a spectrum of contractile states, and the position of a given curve provides a description of ventricular contractility. Movement along a single curve represents the operation of the Frank-Starling principle, which indicates that stroke volume, cardiac output, or SW varies with preload. By contrast, upward or downward displacement of the curve represents a positive or negative inotropic effect, that is, an augmentation or depression of contractility, respectively (see Fig. 15-16) . However, it is important to recognize that this ventricular function curve represents a complex interaction of preload, afterload, and contractility. The pump performance of the left ventricle depends on its ability to fill (diastolic performance) and to empty (systolic performance) (Fig. 15-17) . The forward stroke volume is equal to the end-diastolic volume multiplied by the effective ejection fraction (see later). Thus, the generation of stroke volume depends on the conversion of the filling pressure to end-diastolic volume (diastolic performance) and the generational stroke volume from the end-diastolic volume (systolic performance). [28] Systolic Performance

Left ventricular systolic performance is reflected in the ability of the left ventricle to empty. Because myocardial contractility is an important determinant of the left ventricle's systolic performance, systolic performance and contractility are frequently considered to be interchangeable. However, they are not the same because the systolic performance of the left ventricle is also importantly influenced by load and ventricular configuration. Thus, it is possible to have abnormal systolic performance despite normal contractility when left ventricular afterload is excessive. Alternatively, left ventricular systolic performance may be nearly normal despite decreased myocardial contractility if left ventricular

Figure 15-16 Depiction of the Frank-Starling relationship. With increasing left ventricular filling pressure measured by the pulmonary capillary wedge pressure (reflecting the pulmonary venous pressure), there is an increase in cardiac output and stroke work. The positions of the curves are influenced by the contractile state of the left ventricle. An enhancement of contractile state shifts the curves upward, whereas a depression produces a downward shift.

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Figure 15-17 Block diagram of left ventricular pump performance. The input is the pulmonary venous pressure, and the output is the cardiac output. These are related by the Frank-Starling relations (see Fig. 15-16) . The stroke volume depends on the end-diastolic volume (ED) and the effective left ventricular ejection fraction (EF). See text for discussion.

afterload is low, as occurs in some patients with mitral regurgitation. Left ventricular systolic performance can be quantified as the left ventricular emptying fraction or ejection fraction. In the presence of a left-sided valvular regurgitant lesion (mitral regurgitation or aortic regurgitation) or a shunt (ventricular septal defect or patent ductus arteriosus), the left ventricular stroke volume may be high, whereas the forward stroke volume (stroke volume minus regurgitant volume or shunt volume), which contributes to useful cardiac output, is lower. Accordingly, the effective ejection fraction is the forward stroke volume divided by end-diastolic volume.[38] [81] The effective ejection fraction is a useful means to quantitate systolic function because it represents the functional emptying of the left ventricle that contributes to cardiac output and is relatively independent of left ventricular end-diastolic volume over the clinically relevant range. An operational definition of systolic dysfunction is an effective ejection fraction of less than 50 percent.[81] [82] When defined in this manner, systolic left ventricular dysfunction may result from impaired myocardial function, increased left ventricular afterload, and/or structural abnormalities of the left side of the heart. If left ventricular contractile state and arterial properties remain constant as end-diastolic volume increases, the ejection fraction stays constant or increases slightly.[40] Thus, an increase in the end-diastolic volume will allow for a normal forward stroke volume despite a reduced effective ejection fraction. Diastolic Performance

For the left ventricle to function as a pump, it must not only empty but also fill. The left atrial (and pulmonary venous) pressure is the source pressure for left ventricular filling. Thus, normal left ventricular diastolic function can be defined as filling of the left ventricle sufficient to produce a cardiac output commensurate with the body's needs with a normal pulmonary venous pressure (less than 12 mm Hg).[27] In some instances this definition of normal integrated diastolic performance can be met despite clear abnormalities of left ventricular diastolic properties. For example, a compensated patient with a dilated cardiomyopathy may have an adequate cardiac output at rest without an elevated pulmonary venous pressure despite impaired relaxation and a very abnormal left ventricular diastolic pressure-volume curve. A patient with systolic dysfunction (reduced effective ejection fraction) requires a larger end-diastolic volume to produce an adequate stroke volume and cardiac output. If the larger left ventricular end-diastolic volume can be achieved without an abnormally high pulmonary venous pressure, this can compensate for impaired systolic performance. However, if the larger end-diastolic volume requires an elevation of pulmonary venous pressure, the systolic dysfunction (i.e., reduced effective ejection fraction) will result in diastolic dysfunction. Thus, when defined in this manner, systolic dysfunction in symptomatic patients is usually associated with diastolic dysfunction. However, diastolic dysfunction frequently occurs in the absence of systolic dysfunction. As defined, diastolic dysfunction may be due to an obstruction to left ventricular filling or an external compression of the left ventricle, but it is usually considered to result from left ventricular abnormalities. Such left ventricular diastolic dysfunction may result from

increased myocardial stiffness or impaired relaxation. Relaxation can be slowed, decreasing early diastolic filling, or incomplete, which impairs filling throughout diastole and decreases end-diastolic distensibility. In the pressure-volume plane, reduced distensibility is represented by a leftward and upward shift of the end-diastolic pressure-volume relation (EDPVR) (Fig. 15-18) . When this occurs, significantly higher pressures are required to distend the left ventricle to achieve the same end-diastolic volume. If the shift in the EDPVR is severe enough, filling of the left ventricle to the level sufficient to produce a normal stroke volume can only be achieved with an elevated pulmonary venous pressure that will be associated with pulmonary congestion. Thus, an alteration in diastolic distensibility may produce pulmonary congestion and congestive heart failure in the absence of systolic dysfunction.[83] [84] [85] Evaluation of Diastolic Performance

The indices of diastolic function can be organized into three groups: (1) measures of isovolumetric relaxation, (2) indices of passive left ventricular characteristics derived from the diastolic left ventricular pressure-volume relations, and (3) measurements of the pattern of left ventricular diastolic filling obtained from Doppler echocardiography or radionuclide angiography.[27] [86] [87] ISOVOLUMETRIC RELAXATION.

Isovolumetric relaxation can be quantified by measuring its duration or by describing the time-course of the fall in left ventricular pressure. The duration of isovolumetric relaxation, or the time from aortic valve closure to mitral valve opening, can be measured by M-mode echocardiography. A similar interval, the time from aortic valve closure to the onset of mitral valve flow, can be measured by combining phonocardiography and Doppler echocardiography. The duration of isovolumetric relaxation depends not only on the rate of left ventricular relaxation but also on the difference in pressures between the aorta at the time of aortic valve closure and the left atrium at mitral valve opening.[88] Thus, the duration of isovolumetric relaxation can be increased by an elevation of aortic pressure or decreased by an increase in left atrial pressure. The time interval from minimal left ventricular volume to peak left ventricular filling rate can be measured using radionuclear angiography.[87] Because this time interval spans both isovolumetric relaxation and part of early filling, the interpretation is even more complicated than the duration of isovolumetric relaxation alone. The time course of isovolumetric pressure decline has been quantitatively described by the peak rate of pressure fall (dP/dt min ) and the time constant of an exponential fit of the time course of isovolumetric pressure decline. Each of

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Figure 15-18 A, Left ventricular end-diastolic pressure-volume relation (LV EDPVR) in a patient with

normal left ventricular function. The open triangles (delta) connected by the red line indicate the exponential end-diastole pressure-volume relation. The solid circles ( ) show the viscoelastic effects during the filling of a single beat. (Modified from Pak PH, Maughan L, Baughman KL, Kass DA: Marked discordance between dynamic and passive diastolic pressure-volume relations in idiopathic hypertrophic cardiomyopathy. Circulation 94:57, 1996. Copyright 1996, American Heart Association.) B, The slope of the LV EDPVR indicates the passive chamber stiffness. Because the relation is exponential in shape, the slope increases as the end-diastolic pressure increases (curve A). A shift of the curve from A to B indicates that a higher LV pressure will be required to distend the LV to a similar volume; thus the ventricle is less distensible. (From Little WC, Downes TR: Clinical evaluation of left ventricular diastolic performance. Prog Cardiovasc Dis 32[4]:273, 1990.)

these requires the measurement of left ventricular pressure using a micromanometer. dP/dtmin is strongly influenced by the pressure at the time of aortic valve closure and is not a good measure of the rate of isovolumetric relaxation. After aortic valve closure, left ventricular pressure declines in an exponential fashion during isovolumetric relaxation (Fig. 5-19) . The rate of pressure decline can be quantified by the time-constant of the exponential decline. The time-constant (tau) is increased by processes such as ischemia or other causes of myocardial depression that slow ventricular relaxation.[89] [90] It is shortened by an acceleration of the rate of active relaxation, as caused by an increase in heart rate or sympathetic stimulation. The time-constant of isovolumetric pressure decline can also be altered by changes in loading conditions. An increase in arterial pressure or end-diastolic volume can increase the time-constant, although changes in the preload at a constant arterial pressure may have less effect.[90] Calculation of the time constant of left ventricular isovolumetric pressure decline has several technical limitations. Data are analyzed from the time of minimum dP/dt to a pressure 5 or 10 mm Hg above end-diastolic pressure. Even if pressure is measured every 2 milliseconds, there are only a limited number of data points. This contributes to a large beat-to-beat variability of tau.[91] If mitral inflow is prevented, left ventricular pressure will decay to subatmospheric levels. Thus it has been suggested that the data should be fit to an exponential function with an asymptote (PB ):

This is usually done by differentiating both sides and then using the linear least squares technique to fit the equation:

The normal range of values of tau calculated using this method is 37 to 67 milliseconds.[92] The use of an asymptote to calculate tau is particularly important when the external pressure of the left ventricle may be changing. [93] However, tau calculated from a nonfilling beat in an experimental animal in which the full time course of left ventricular

relaxation is available correlates most closely with tau calculated from a normal beat without the use of an asymptote.[94] To avoid the computational properties of nonlinear fitting in the calculation on tau without an asymptote, the relation is linearized using a natural

Figure 15-19 Left ventricular (LV) pressure measured at 2-millisecond intervals using a micromanometer. The LV pressure from the time of minimum dP/dt (dP/dt min ) to mitral valve opening is described by an exponential relation (solid line). After mitral valve opening, LV pressure deviates from the exponential line. P o +Pb =pressure (P) at dP/dtmax ; t=time; T=time constant of relaxation; PB =baseline pressure. (From Little WC, Downes TR: Clinical evaluation of left ventricular diastolic performance. Prog Cardiovasc Dis 32[4]:273, 1990.)

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logarithm transformation to result in:

The data are then fit to this equation using the linear least squares technique to determine tau. When calculated using this method the normal range of values for tau is 28 to 45 milliseconds.[92] The time course of LV pressure during isovolumetric relaxation can also be characterized using noninvasive Doppler measurement of the velocity of a regurgitant jet across the mitral valve.[10] [11] In this method, the modified Bernoulli equation is used to approximate LV pressure during isovolumetric relaxation allowing calculation of the maximum rate of left ventricular pressure decline and the exponential time constant. PASSIVE DIASTOLIC CHARACTERISTICS OF THE LEFT VENTRICLE.

The passive characteristics of the left ventricle can be described as the passive diastolic pressure-volume relation.[83] [90] Optimally, the passive left ventricular diastolic pressure-volume relation should be constructed from points that are obtained after relaxation is complete and at slow filling rates so that viscous effects are not present. [90] [95] Practically, this can be approximated using points obtained late in diastole, when relaxation is assumed to be complete, or from variously loaded beats at end diastole. However, it is important to correct for the effect of respiratory changes in intrathoracic pressure. The effective chamber stiffness can be calculated from the noninvasively measured time for early filling deceleration (see later).[96] The slope of the EDPVR is the chamber stiffness. Because the pressure-volume relation is nonlinear, the chamber stiffness depends on the point on the curve in which it is measured; thus, stiffness increases with increasing volume (see Fig. 15-19) . Several

techniques have been proposed to correct for this effect by normalizing chamber stiffness. One approach is to approximate the pressurevolume relation by an exponential function. Another technique is to compare the chamber stiffness at a common pressure or volume. However, the analysis of chamber stiffness does not account for shifts in the pressure-volume relation that can occur from the alteration of load, diseases, or pharmacological agents.[90] The position of the diastolic pressure-volume relation indicates the distensibility of the left ventricle. For example, an upward shift indicates a less distensible ventricle.[97] The diastolic pressure-volume relation represents the net passive characteristics of the left ventricular chamber. To derive information concerning the properties of the myocardium alone, the effects of wall thickness, ventricular configuration, size, and external pressure must be removed.[98] This can be accomplished by calculating the myocardial stress-strain relation from the chamber pressure-volume relation. In contrast to the slope of the pressure-volume relation, which assesses the amount of ventricular chamber distention under pressure, the stress-strain relation represents the resistance of the myocardium to stretch when subjected to stress. Thus, it should not be influenced by the configuration of the left ventricle. However, the calculation of stress requires the use of a geometric model of the left ventricle and the calculation of strain requires assumption of the unstressed left ventricular volume, which cannot be directly measured in the intact circulation. In addition to these potential theoretical limitations, these calculations require accurate measurements over a wide range of left ventricular pressures and volumes. Measurements made during rapid filling may be inappropriately influenced by active myocardial relaxation and viscoelastic effects. Observations during diastasis and atrial systole minimize this problem, but they may not supply a wide enough range of data points. The theoretical problems and the technical difficulties in determining myocardial stress-strain relations have limited their clinical application. PATTERNS OF LEFT VENTRICULAR DIASTOLIC FILLING.

Analysis of the pattern of left ventricular filling can provide useful information about diastolic left ventricular performance. Such information can be obtained by determining the left ventricular volume or dimension throughout the cardiac cycle, using contrast or radionuclide angiography[87] or M-mode or two-dimensional echocardiography, or by measuring the left ventricular inflow velocity using a Doppler determination of mitral valve flow velocities. The most widely used method is Doppler measurement of mitral valve flow velocity.[99] [100] [101] [102] [103] The pattern of left ventricular filling can also be assessed using tissue Doppler measurements and color M-mode imaging.[100] Mechanisms of Diastolic Filling.

To understand the significance of the patterns of left ventricular filling, it is important to consider the mechanisms of normal left ventricular filling.[99] [104] The events surrounding normal left ventricular filling are shown in Figure 15-20 (Figure Not Available) . From the time of aortic valve closure until mitral valve opening, the left ventricle is normally a closed chamber with a constant volume. Myocardial relaxation begins in the latter part of systole and causes a steep, exponential fall in intraventricular pressure as elastic elements of the left ventricle that were compressed and twisted during ejection are

allowed to recoil. Although no filling occurs during isovolumetric Figure 15-20 (Figure Not Available) Recording of left ventricular (LV) pressure (P LV ), left atrial pressure (PLA ), left ventricular volume (LVV), and the rate of change of LV volume (dV/dt), which indicates the rate of LV filling. LV filling occurs early in diastole and during atrial systole in response to pressure gradient from the left atrium to the left ventricle. The early diastolic pressure gradient is generated as LV pressure falls below left atrial pressure and the late diastolic gradient is generated as atrial contraction increases left atrial pressure above LV pressure. (Data recorded in a conscious animal from Cheng CP, Freeman GL, Santamore WP, et al: Effect of loading conditions, contractile state and heart rate on early diastolic left ventricular filling in conscious dogs. Circ Res 66:814, 1990. Copyright 1990, American Heart Association.)

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relaxation, the processes that determine the rate of decline of the isovolumetric pressure influence ventricular filling after opening of the mitral valve.[94] [105] For the first 30 to 40 milliseconds after mitral valve opening, relaxation of left ventricular wall tension is normally rapid enough to cause left ventricular pressure to fall, despite a substantial increase in left ventricular volume.[104] This fall in left ventricular pressure produces a pressure gradient that accelerates blood from the left atrium into the left ventricle, resulting in rapid early diastolic filling. The rate of early left ventricular filling is determined by the mitral valve pressure gradient (left atrial pressure-left ventricle pressure).[104] [106] Although peak filling occurs after the peak pressure gradient, the two are closely related. Two major factors (myocardial relaxation and left atrial pressure) determine the early diastolic mitral valve pressure gradient and the rate of left ventricular filling. Under normal circumstances more than two thirds of the stroke volume enters the left ventricle during early diastole. After filling of the left ventricle begins, the mitral valve pressure gradient decreases and then transiently reverses. This occurs because left ventricular relaxation is nearing completion and the flow of blood from the left atrium fills the left ventricle, raising the left ventricular pressure while lowering the left atrial pressure. This reversed mitral valve pressure gradient decelerates and then stops the rapid flow of blood into the left ventricle early in diastole.[96] The pressures in the left atrial and left ventricle equilibrate as mitral flow nearly ceases; thus, little left ventricular filling occurs during the midportion of diastole, termed diastasis. Atrial contraction increases atrial pressure late in diastole producing a left atrial-to-left ventricular pressure gradient that again propels blood into the left ventricle. After atrial systole, as the left atrium relaxes, its pressure decreases below left ventricular pressure, causing the mitral valve to begin closing.[107] The onset of ventricular systole produces a rapid increase in left ventricular pressure that seals the mitral valve and ends diastole. Normal Pattern of Left Ventricular Filling.

The normal pattern of left ventricular filling is characterized by rapid filling early in

diastole with some additional filling during atrial contraction (see Figs. 7-34, p. 175, and Figure 15-21 (Figure Not Available) Patterns of left ventricular (LV) filling as recorded by diastolic Doppler mitral flow velocities. In the normal pattern there is a large E wave and a small A wave. There are three abnormal patterns of mitral filling representing progressively worsening LV diastolic performance. With "impaired relaxation" the E wave is less than the A wave. The LV deceleration time (t dec ) is prolonged. In the "pseudonormalized" pattern the E wave is larger than A wave, however, t dec is shortened. In the restricted filling pattern, E is much larger than A with a very short t dec . (See also Table 15-4.) (Modified from Little WC, Warner JG Jr, Rankin KM, et al: Evaluation of left ventricular diastolic function from the pattern of left ventricular filling. Clin Cardiol 21:5, 1998.)

TABLE 15-3 -- NORMAL VALUES OF PARAMETERS OF LEFT VENTRICULAR DIASTOLIC FILLING MEASURED BY DOPPLER ECHOCARDIOGRAPHY ADULTS 16 cm H2 O Circulation time 25 sec Hepatojugular reflux Pulmonary edema, visceral congestion, or cardiomegaly at autopsy Weight loss 4.5 kg in 5 days in response to treatment of congestive heart failure Minor Criteria

Bilateral ankle edema Nocturnal cough Dyspnea on ordinary exertion Hepatomegaly Pleural effusion Decrease in vital capacity by one third from maximal value recorded Tachycardia (rate 120 beats/min) The diagnosis of congestive heart failure in this study required that two major or one major and two minor criteria be present concurrently. Minor criteria were acceptable only if they could not be attributed to another medical condition. From Ho KL, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: The Framingham Study. J Am Coll Cardiol 22(Suppl A):6A, 1993.

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Incidence and Prevalence

Heart failure is a relatively common disorder. It is estimated that 4.6 million persons in the United States are being treated for heart failure, with 550,000 new cases diagnosed each year.[4] [5] The prevalence of heart failure increases dramatically with age, occurring in 1 to 2 percent of persons aged 50 to 59 and up to 10 percent of individuals older than the age of 75 (Fig. 17-1) .[3] [5] Approximately 80 percent of all heart failure admissions occur in patients older than 65; as a result, heart failure is the leading discharge diagnosis in persons aged 65 years or older in the United States.[6] Despite a steady decline in the incidence of coronary artery disease and stroke, both the incidence and prevalence of heart failure continue to rise. Between 1985 and 1995 the number of heart failure hospitalizations increased by 51 percent,[7] and 870,000 hospital discharges for heart failure occurred in 1996.[4] In the United States, approximately 45,000 deaths each year are primarily caused by heart failure and heart failure is listed as a contributing cause in 260,000 deaths.[8] [9] This trend may be due in part to the aging of the population and in part to the improved survival of patients with cardiovascular disease. Heart failure has an enormous economic impact on the U.S. health care system, owing to direct medical costs, disability, and loss of employment. Estimated treatment costs in 1994 were $38 billion, of which $23 billion were spent on hospitalizations.[10] The cost of hospitalizations for heart failure is twice that for all forms of cancer and myocardial infarctions combined.[10]

Forms and Causes of Heart Failure Forward Versus Backward Heart Failure

The clinical manifestations of heart failure arise as a consequence of inadequate cardiac output and/or damming up of blood behind one or both ventricles. These two

principal mechanisms are the basis of the so-called forward and backward pressure theories of heart failure. The backward failure hypothesis, first proposed in 1832 by James Hope, contends that when the ventricle fails to discharge its contents, blood accumulates and pressure rises in the atrium and the venous system emptying into it.[11] There is substantial physiological evidence in favor of this theory. As discussed in Chapters 14 and 15 , the inability of cardiac muscle to shorten against a load alters the relationship between ventricular end-systolic pressure and volume so that end-systolic volume rises. The following sequence then occurs, which at first maintains cardiac output at a normal level: (1) ventricular end-diastolic volume and pressure increase; (2) the volume and pressure rise in the atrium behind the failing ventricle; (3) the atrium contracts more vigorously (a manifestation of Starling's law, operating on the atrium) [12] ; (4) the pressure in the venous and capillary beds behind (upstream to) the failing ventricle rises; and (5) transudation of fluid from the capillary bed into the interstitial space (pulmonary or systemic) increases. Many of the symptoms characteristic of heart failure can be traced to this sequence of events and the resultant increase in fluid in the interstitial spaces of the lungs, liver, subcutaneous tissues, and serous cavities. In many patients, the entire sequence of events just outlined may transpire while cardiac output at rest is still within normal limits. Indeed, the backward failure hypothesis invokes one of the principal compensatory mechanisms in heart failure, that is, Starling's law of the heart, in which distention of the ventricle helps to maintain cardiac output. The failing ventricle operates on an ascending, albeit depressed and flattened, function curve,[13] and the augmented ventricular

Figure 17-1 Prevalence rates of congestive heart failure (CHF) among Framingham Heart Study subjects, by gender and age. Among men (open bars), the prevalence increased from 8 cases/1000 in those aged 50-59 years to 66 cases/1000 in those aged 80-89 years. Among women (solid bars), the prevalence increased from 8 cases/1000 in those aged 50-59 years to 79 cases/1000 in those aged 80-89 years. (From Ho KK, et al: The epidemiology of heart failure: The Framingham Study. J Am Coll Cardiol 22:6A, 1993.)

end-diastolic volume and pressure characteristic of heart failure may aid in the maintenance of cardiac output. An important extension of the backward failure theory is the development of right ventricular failure as a consequence of left ventricular failure. According to this concept, the elevation of left ventricular diastolic, left atrial, and pulmonary venous pressures results in backward transmission of pressure into the pulmonary arterial circulation and leads to pulmonary hypertension, which ultimately causes right ventricular failure. Often, pulmonary vasoconstriction plays a part in this form of pulmonary hypertension as well. Eighty years after publication of Hope's work, Mackenzie proposed the forward failure hypothesis, which relates clinical manifestations of heart failure to inadequate delivery of blood into the arterial system.[14] According to this hypothesis, the principal clinical manifestations of heart failure are due to reduced cardiac output, which results in diminished perfusion of vital organs, including the brain, leading to mental confusion; skeletal muscles, leading to weakness; and kidneys, leading to sodium and water

retention through a series of complex neurohormonal mechanisms.[15] This retention of sodium and water, in turn, augments extracellular fluid volume and ultimately leads to symptoms of heart failure due to congestion of organs and tissues. Although these two seemingly opposing views concerning the pathogenesis of heart failure led to lively controversy during the first half of the 20th century, it no longer seems fruitful to make a rigid distinction between backward and forward heart failure, because both mechanisms appear to operate in the majority of patients with chronic heart failure. Exceptions may occur, however, and some patients, particularly those with acute decompensation, develop relatively pure forms of forward or backward failure. For instance, a massive myocardial infarction may result in either (1) forward failure with a marked reduction of left ventricular output and cardiogenic shock and clinical manifestations secondary to impaired perfusion (e.g., hypotension,

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mental confusion, oliguria) or (2) backward failure with a small transient inequality of output between the two ventricles, resulting in acute pulmonary edema. More commonly, patients with large myocardial infarctions develop a combination of forward and backward failure, with symptoms resulting from both inadequate cardiac output and pulmonary congestion. RIGHT-SIDED VERSUS LEFT-SIDED HEART FAILURE

Implicit in the backward failure theory is the idea that fluid localizes behind the specific cardiac chamber that is initially affected. Thus, symptoms secondary to pulmonary congestion initially predominate in patients with left ventricular infarction, hypertension, or aortic or mitral valve disease; that is, they manifest left-sided heart failure. With time, however, fluid accumulation becomes generalized, and ankle edema, congestive hepatomegaly, ascites, and pleural effusion occur; thus, the patients subsequently exhibit right-sided heart failure as well. FLUID RETENTION IN HEART FAILURE.

Fluid retention in heart failure is caused in part by reduction in glomerular filtration rate and in part by activation of the renin-angiotensin-aldosterone system. Reduced cardiac output is associated with a lowered glomerular filtration rate and an increased elaboration of renin, which, through the activation of angiotensin, results in the release of aldosterone (see Chap. 16 ). The combination of impaired hepatic function, owing to hepatic venous congestion, and reduced hepatic blood flow, interferes with the metabolism of aldosterone, further raising its plasma concentration and augmenting the retention of sodium and water. Cardiac output (and glomerular filtration rate) may be normal in many patients with heart failure, particularly when they are at rest. However, during stress, such as physical exercise or fever, the cardiac output fails to rise normally, the glomerular filtration rate

declines, and the renal mechanisms for salt and water retention described earlier come into play. In addition, ventricular filling pressure and therefore pressures in the atrium and systemic veins behind (upstream to) the ventricle may be normal at rest, only to rise abnormally during stress. This, in turn, may cause transudation and symptoms of tissue congestion (pulmonary in the case of the left ventricle and systemic in the case of the right) during exercise. For this reason, simple rest may induce diuresis and relieve symptoms in many patients with mild-to-moderate heart failure. ACUTE VERSUS CHRONIC HEART FAILURE

The clinical manifestations of heart failure depend importantly on the rate at which the syndrome develops and specifically on whether sufficient time has elapsed for compensatory mechanisms to become operative and for fluid to accumulate in the interstitial space (Table 17-2) . For example, when a previously normal individual suddenly develops a serious anatomical or functional abnormality of the heart, such as massive myocardial infarction, tachyarrhythmia with a very rapid rate, or rupture of a valve secondary to infective endocarditis, a marked reduction in cardiac output will occur, associated with symptoms due to inadequate organ perfusion and/or acute congestion of the venous bed behind the affected ventricle. If the same anatomical abnormality develops gradually, or if the patient survives the acute insult, a number of adaptive mechanisms become operational, especially cardiac remodeling and neurohormonal activation, and these allow the patient to adjust to and tolerate not only the anatomical abnormality but also a reduction in cardiac output with less difficulty. LOW-OUTPUT VERSUS HIGH-OUTPUT HEART FAILURE

Low cardiac output at rest, or in milder cases during exertion and other stresses, characterizes heart failure occurring in most forms of cardiovascular disease (i.e., congenital, valvular, rheumatic, hypertensive, coronary, and cardiomyopathic). A variety of high cardiac output states, including thyrotoxicosis, arteriovenous fistulas, beriberi, Paget's disease of bone, and anemia (discussed later in this chapter), may lead to heart failure as well. Low-output heart failure is characterized by clinical evidence of systemic vasoconstriction with cold, pale, and sometimes cyanotic extremities. In advanced forms of low-output failure, marked reduction in the stroke volume is reflected by a narrowing of the pulse pressure.[16] In contrast, in high-output heart failure, the extremities are usually warm and flushed and the pulse pressure is widened or at least normal. The ability of the heart to deliver the oxygen required by the metabolizing tissues is reflected in the arterial-mixed venous oxygen difference, which is abnormally widened (i.e., >50 ml/liter in the resting state) in patients with low-output heart failure. This difference may be normal or even reduced in high-output states, owing to elevation of the mixed venous oxygen saturation by the admixture of blood that has been shunted away from metabolizing tissues. Systolic Versus Diastolic Heart Failure

Implicit in the physiological definition of heart failure (inability to pump an adequate

volume of blood and/or to do so only from an abnormally elevated filling pressure) is that heart failure can be caused by an abnormality in systolic function leading to a defect in the expulsion of blood (i.e., systolic heart failure) or by an abnormality in diastolic function leading to a defect in ventricular filling (i.e., diastolic heart failure) (Fig. 17-2) . The former is the more familiar, classic heart failure associated with an impaired inotropic state. Less familiar, but perhaps just as important, is diastolic heart failure, in which the ability of the ventricle(s) to accept blood is impaired.[17] [18] [18A] (See also pp. 456, 493, and 517.) This may be due to slowed or incomplete ventricular relaxation, which may be transient, as occurs in acute ischemia, or sustained, as in concentric myocardial hypertrophy or restrictive cardiomyopathy secondary to infiltrative conditions such as amyloidosis. The principal clinical manifestations of systolic failure result from an inadequate cardiac output and secondary salt and water retention (forward heart failure), whereas the major consequences of diastolic failure relate to elevation of the ventricular filling pressure, and the high venous pressure upstream to the ventricle, causing pulmonary and/or systemic congestion (backward heart failure).

TABLE 17-2 -- ACUTE VS. CHRONIC HEART FAILURE FEATURE ACUTE HEART DECOMPENSATED FAILURE CHRONIC HEART FAILURE

CHRONIC HEART FAILURE

Symptom severity

Marked

Marked

Mild to moderate

Pulmonary edema

Frequent

Frequent

Rare

Peripheral edema

Rare

Frequent

Frequent

Weight gain

None to mild

Frequent

Frequent

Whole-body fluid volume load

No change or mild increase

Moderate to marked increase

Mild to marked increase

Cardiomegaly

Uncommon

Usual*

Common*

Ventricular systolic function

Reduced, normal, or hypercontractile

Reduced*

Reduced*

Wall stress

Elevated

Markedly elevated

Elevated

Activation of sympathetic nervous system

Marked

Marked

Mild to marked

Activation of renin-angiotensin-aldosterone system

Often increased

Marked

Mild to marked

Reparable, reversible causative lesion(s)

Common

Occasional

Occasional

Clinical and pathophysiological characteristics of the two major categories of unstable heart failure (acute heart failure and decompensated chronic heart failure) are compared with those of chronic heart failure. Adapted from Leier CV: Unstable heart failure. In Colucci WS (ed): Heart Failure: Cardiac Function and Dysfunction. 2nd ed. In Braunwald E (series ed): Atlas of Heart Diseases, vol 4. Philadelphia, Current Medicine, 1999, pp 9.1-9.17. *Patients with diastolic heart failure may have little to no cardiomegaly and normal systolic function.

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Figure 17-2 A, Schematic of a pressure-volume loop from a normal subject (dotted line) and a patient with diastolic dysfunction (solid line). Dashed lines represent the diastolic pressure-volume relation. Isolated diastolic dysfunction is characterized by a shift in the pressure-volume loop to the left. Contractile performance is normal (normal or increased ejection fraction, normal or slightly decreased stroke volume). However, left ventricular (LV) pressures throughout diastole are increased: at a common diastolic volume=70 ml/m [ 2] , LV diastolic pressure is 25 mm Hg in the patient with diastolic failure compared with a diastolic pressure of 5 mm Hg in the normal subject. B, Schematic of pressure-volume loop from a normal subject (dotted line) and a patient with systolic dysfunction (solid line). Dashed line represents the diastolic pressure-volume relation. Systolic dysfunction is characterized by displacement of the pressure-volume loop to the right. Despite compensatory dilation, stroke volume or ejection fraction remains low. LV diastolic pressures are increased as a result of large LV volume. (From Zile MR: Diastolic dysfunction: Detection, consequences, and treatment: II. Diagnosis and treatment of diastolic dysfunction. Mod Concepts Cardiovasc Dis 59:1, 1990.)

There are many examples of pure systolic or diastolic heart failure. Examples of the former are patients with acute massive myocardial infarction or pulmonary embolism, whereas examples of the latter are patients with hypertrophic or restrictive cardiomyopathy. Community-based, epidemiological studies have demonstrated that diastolic heart failure is more common than was previously thought and is particularly prevalent in elderly women with hypertension.[19] [20] However, in many patients, systolic and diastolic heart failure coexist. The most common form of heart failure, that caused by chronic coronary artery disease, is an example of combined systolic and diastolic failure. In this condition, systolic failure is caused by both the chronic loss of contracting myocardium secondary to prior myocardial infarction and the acute loss of myocardial contractility induced by transient ischemia. Diastolic failure is due to the ventricle's reduced compliance caused by replacement of normal, distensible myocardium with nondistensible fibrous scar tissue and by the acute reduction of diastolic distensibility during ischemia. A number of clinical features and laboratory findings characterize these two forms of heart failure (Table 17-3) . However, it is important to recognize that the clinical features of heart failure may be similar whether left ventricular systolic function is normal or depressed,[20] [21] underscoring the need for evaluation of ventricular function in all patients with heart failure.

CAUSES OF HEART FAILURE From a clinical viewpoint, it is useful to classify the causes of heart failure into three broad categories: (1) underlying causes, comprising the structural abnormalities--congenital or acquired--that affect the peripheral and coronary vessels, pericardium, myocardium, or cardiac valves and lead to the increased hemodynamic burden or myocardial or coronary insufficiency responsible for heart failure; (2) fundamental causes, comprising the biochemical and physiological mechanisms through which either an increased hemodynamic burden or a reduction in oxygen delivery to the myocardium results in impairment of myocardial contraction (see Chap. 16 ;) and (3) precipitating causes, including the specific causes or incidents that precipitate heart failure in 50 to 90 percent of episodes of clinical heart failure.[22] It is helpful for the clinician to identify both the underlying and the precipitating causes of heart failure. Appropriate management of the underlying heart disease (e.g., surgical correction of a congenital defect or an acquired valvular abnormality or pharmacological management of hypertension) may prevent the development or recurrence of heart failure. Similarly, treatment of a precipitating cause such as an infection will often terminate an episode of heart failure and may be lifesaving. More important, avoidance of a precipitating cause can prevent heart failure.

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TABLE 17-3 -- SYSTOLIC VS. DIASTOLIC HEART FAILURE PARAMETERS SYSTOLIC DIASTOLIC History Coronary artery disease

+++

++

Hypertension

++

++++

Diabetes

++

++


++++

-

Paroxysmal dyspnea

++

+++

Cardiomegaly

+++

+

Soft heart sounds

++++

+

S3 gallop

+++

+

S4 gallop

+

+++

Hypertension

++

++++

Physical Examination


+++

+

Rales

++

++

Edema

+++

+

Jugular venous distention

+++

+

Cardiomegaly

+++

+

Pulmonary congestion

+++

+++


++

++++

Q waves

++

+

Low voltage

+++

-


++

++++

Left ventricular dilation

++

-

Left atrial enlargement

++

++

Reduced ejection fraction

++++

-

Chest Roentgenogram

Electrocardiogram

Echocardiogram

Certain aspects of the history and physical examination, along with clinical measurements, may help to distinguish diastolic dysfunction from systolic heart failure. For example, patients with hypertensive heart disease, and particularly severe left ventricular hypertrophy, often experience heart failure because of diastolic dysfunction. Plus signs indicate "suggestive" (the number reflects relative weight). Minus signs indicate "not very suggestive."Adapted from Young JB: Assessment of heart failure. In Colucci WS (ed): Heart Failure: Cardiac Function and Dysfunction. 2nd ed. In Braunwald E (series ed): Atlas of Heart Diseases, vol 4. Philadelphia, Current Medicine, 1999, pp 7.1-7.19.

Overt heart failure may also be precipitated by the progression of the underlying heart disease. A previously stable, compensated patient may develop heart failure that is apparent clinically for the first time when the intrinsic process has advanced to a critical point, such as with further narrowing of a stenotic aortic valve or progressive obliteration of the pulmonary vascular bed in a patient with cor pulmonale. Alternatively, decompensation may occur as a result of failure or exhaustion of the compensatory mechanisms, but without any change in the load on the heart, in patients with chronic severe pressure or volume overload. Precipitating Causes of Heart Failure

In one study of 101 patients admitted to an inner city municipal hospital with the

diagnosis of heart failure, precipitating factors could be identified in 93 percent.[23] INAPPROPRIATE REDUCTION OF THERAPY.

Perhaps the most common cause of decompensation in a previously compensated patient with heart failure is inappropriate reduction in the intensity of treatment, be it dietary sodium and fluid restriction, pharmacological therapy, or both. Many patients with serious underlying heart disease, regardless of whether they have previously experienced heart failure, may be relatively asymptomatic for as long as they carefully adhere to their treatment regimen. Dietary excesses of sodium, incurred frequently on vacations or holidays or during an illness of the spouse responsible for preparing the patient's meals, are frequent causes of rapid cardiac decompensation. Education of the patient and family is a simple and effective measure to prevent this common clinical problem. Self-discontinuation or physician withdrawal of effective pharmacotherapy such as angiotensin-converting enzyme (ACE) inhibitors or digoxin can precipitate heart failure.[24] ARRHYTHMIAS.

Cardiac arrhythmias are common in patients with underlying structural heart disease and commonly precipitate or intensify heart failure. The development of arrhythmias may precipitate heart failure through several mechanisms: 1. Tachyarrhythmias, most commonly atrial fibrillation, reduce the time available for ventricular filling. When there is already an impairment of ventricular filling, as in mitral stenosis, or reduced ventricular compliance, as in left ventricular hypertrophy, tachycardia will raise atrial pressure and reduce cardiac output further. In addition, tachyarrhythmias increase myocardial oxygen demands and, in a patient with obstructive coronary artery disease, may induce or intensify myocardial ischemia. This, in turn, impairs both diastolic and systolic function, thereby raising left atrial and pulmonary capillary pressure further and causing pulmonary congestion. Tachycardia may also directly impair contractility in failing human myocardium, owing in part to a negative force-frequency relationship [25] (see Chap. 14 ), and, if persistent, may cause a reversible dilated cardiomyopathy.[26] 2. Marked bradycardia in a patient with underlying heart disease usually depresses cardiac output, because stroke volume may already be maximal and cannot rise farther to maintain cardiac output. 3. Dissociation between atrial and ventricular contraction, which occurs in many arrhythmias, results in loss of the atrial booster pump mechanism, which impairs ventricular filling, lowers cardiac output, and raises atrial pressure.[12] This loss is particularly deleterious in patients with impaired ventricular filling due to concentric cardiac hypertrophy (e.g., in systemic hypertension, aortic stenosis, and hypertrophic cardiomyopathy). 4. Abnormal intraventricular conduction, which occurs in many arrhythmias such as ventricular tachycardia, impairs myocardial performance because of loss of the normal synchronicity of ventricular contraction. In addition to precipitating heart

failure, arrhythmias (sometimes fatal) may be caused by heart failure.[27] MYOCARDIAL ISCHEMIA OR INFARCTION.

In patients with obstructive coronary artery disease, acute myocardial infarction (see Chap. 35 ), unstable angina (see Chap. 36 ), or silent ischemia (see Chap. 37 ) can precipitate heart failure. Reduced myocardial oxygen delivery may be exacerbated by the increase in myocardial oxygen demand resulting from tachycardia and hypertension. Mitral regurgitation due to ischemic papillary muscle dysfunction may contribute to heart failure and lead to acute pulmonary edema. SYSTEMIC INFECTION.

Any serious infection may precipitate cardiac failure. The mechanisms include increased total body metabolism as a consequence of fever, discomfort, and cough, which increase the hemodynamic burden on the heart; the accompanying sinus tachycardia plays an additional adverse role. Patients with congestive heart failure are particularly susceptible to pulmonary infections, presumably because of the diminished ability of congested lungs to expel respiratory secretions. Furthermore, it is postulated that increased circulating levels of proinflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-1beta, which impair myocardial function in sepsis,[28] may precipitate heart failure in the setting of non-life-threatening bacterial or viral infections.[29] [29A] PULMONARY EMBOLISM (see also Chap. 52 ).

Patients with heart failure, particularly when obese or confined to bed, are at high risk of developing pulmonary emboli. Such emboli may increase the hemodynamic burden on the right ventricle by elevating pulmonary artery pressure and pulmonary vascular resistance further and may cause fever, tachypnea, hypoxemia, and tachycardia, the deleterious effects of which have already been discussed. Congestive heart failure, when present in patients with acute pulmonary embolism, is a strong independent predictor of both short-term[30] and long-term[31] mortality. PHYSICAL, EMOTIONAL, AND ENVIRONMENTAL STRESS.

Intense, prolonged exertion or severe fatigue, such as may result from prolonged travel or emotional crises, and a severe climatic change (e.g., to a hot, humid environment) are relatively common precipitants of cardiac decompensation. CARDIAC INFECTION AND INFLAMMATION.

Myocarditis as a consequence of a variety of inflammatory, allergic, or infectious processes, including viral myocarditis (see Chap. 48 ), or of infective endocarditis (see Chap. 47 ) may impair myocardial function directly and exacerbate existing heart disease. The anemia, fever, and tachycardia that frequently accompany these

processes are also deleterious. In patients with infective endocarditis, additional valvular damage resulting, for example, in marked aortic or mitral regurgitation may also precipitate cardiac decompensation. DEVELOPMENT OF AN UNRELATED ILLNESS.

Heart failure may be precipitated in patients with compensated cardiovascular disease when an unrelated illness develops. For example, the development of acute or acute-on-chronic renal failure[31A] may further impair the ability of patients with heart failure to excrete sodium and thus may exacerbate fluid retention (see Chap. 72 ). Similarly, blood transfusion or the administration of sodium-containing fluid during and after a noncardiac operation may result in sudden heart failure in patients with underlying heart disease.

539

ADMINISTRATION OF CARDIAC DEPRESSANTS OR SALT-RETAINING DRUGS.

A number of drugs depress myocardial function; among these are beta-adrenergic antagonists, nondihydropyridine calcium antagonists (verapamil and diltiazem), many antiarrhythmic agents, inhalation and intravenous anesthetics (see Chap. 61 ), and antineoplastic drugs such as doxorubicin and cyclophosphamide (see Chap. 69 ). Others, such as estrogens, corticosteroids, and nonsteroidal antiinflammatory agents,[31B] may cause salt and water retention. Any of these drugs, when administered to a patient with already impaired cardiac function, can precipitate or aggravate heart failure. CARDIAC TOXINS.

Alcohol is a potent myocardial depressant and may be responsible for the development of cardiomyopathy (see Chap. 48 ), arrhythmias, and sudden death.[32] In patients with asymptomatic or mildly symptomatic left ventricular dysfunction, excessive alcohol consumption may precipitate heart failure, either directly by an acute depression of myocardial contractility[33] or indirectly through the development of tachyarrhythmias, most commonly atrial fibrillation,[34] or thiamine deficiency. Illicit use of cocaine may precipitate acute heart failure by a number of mechanisms, including myocardial ischemia or infarction,[35] severe hypertension, arrhythmias, myocarditis, or, in the case of injection drug users, acute infective endocarditis (see Chap. 47 ). HIGH-OUTPUT STATES.

Acute heart failure may be precipitated in patients with underlying heart disease, such as valvular heart disease, by the development of one of the hyperkinetic circulatory states, such as pregnancy or anemia (see later in this chapter).

DEVELOPMENT OF A SECOND FORM OF HEART DISEASE.

Patients with one form of heart disease often remain compensated until they develop a second form. For example, a patient with chronic hypertension and left ventricular hypertrophy but without left ventricular failure may be asymptomatic until a myocardial infarction (which may be silent) develops and precipitates heart failure. Alternatively, a patient with chronic, well-compensated mitral regurgitation may develop heart failure secondary to uncontrolled hypertension or superimposed infective endocarditis. It is essential to search for these precipitating causes systematically in all patients with congestive heart failure, because lack of recognition or treatment or both may be responsible for refractory or recurrent heart failure. In most instances, the precipitant can be treated effectively, after which appropriate measures should be instituted to avoid recurrence. When a precipitating cause of heart failure can be identified, it generally signifies a better prognosis than when a similar degree of heart failure is due simply to progression of the underlying cardiac disease. SYMPTOMS OF HEART FAILURE Respiratory Distress

Breathlessness, a cardinal manifestation of left ventricular failure, may present with progressively increasing severity as (1) exertional dyspnea, (2) orthopnea, (3) paroxysmal nocturnal dyspnea, (4) dyspnea at rest, and (5) acute pulmonary edema. EXERTIONAL DYSPNEA (see Chap. 3 ).

The principal difference between exertional dyspnea in normal subjects and in patients with heart failure is the degree of activity necessary to induce the symptom. [36] Indeed, as heart failure first develops, exertional dyspnea may simply appear to be an aggravation of the breathlessness that occurs in normal subjects during activity. An effort should be made to ascertain whether a change in the extent of exertion that causes dyspnea has actually occurred. As left ventricular failure advances, the intensity of exercise resulting in breathlessness declines progressively. However, there is no close correlation between subjective exercise capacity and objective measures of left ventricular performance at rest in patients with heart failure. [37] [38] Also, exertional dyspnea may be absent in patients with heart failure who are sedentary for a variety of reasons, such as habit, severe angina, intermittent claudication, or a noncardiovascular condition (e.g., osteoarthritis). ORTHOPNEA.

This symptom may be defined as dyspnea that develops in the recumbent position and is relieved by elevation of the head with pillows. As in the case of exertional dyspnea, it is a change in the number of pillows required that is important. In the recumbent position

there is reduced pooling of fluid in the lower extremities and abdomen; blood is displaced from the extrathoracic to the thoracic compartment. The failing left ventricle cannot accept and pump out the extra blood volume delivered to it by the competent right ventricle without dilating. Pulmonary venous and capillary pressures rise further, causing interstitial pulmonary edema, reduced pulmonary compliance, increased airway resistance, and dyspnea. In contrast to paroxysmal nocturnal dyspnea (see later), orthopnea occurs rapidly, often within a minute or two of assuming recumbency and develops when the patient is awake. It is a nonspecific symptom and may occur in any condition in which vital capacity is low. Marked ascites, for example, whatever its cause, may cause orthopnea. Likewise, a large pleural effusion of any etiology may cause a sensation of breathlessness on lying down. Patients with severe chronic obstructive lung disease sometimes complain of orthopnea. Trepopnea is a rare form of orthopnea limited to one lateral decubitus position. It has been attributed to distortions of the great vessels in one position but not in the other. The patient with orthopnea generally elevates his or her head and chest on several pillows to prevent nocturnal breathlessness and subsequently the development of paroxysmal nocturnal dyspnea. In advanced left ventricular failure, orthopnea may be so severe that the patient cannot lie down and must spend the night in the sitting position. Often such patients are observed sitting at the side of the bed, slumped over a bedside table, or sleeping upright in a chair. COUGH.

This may be caused by pulmonary congestion, occurs under the same circumstances as dyspnea (i.e., during exertion or recumbency), and is relieved by treatment of heart failure. Thus a nonproductive cough in patients with heart failure is often a "dyspnea equivalent," whereas a cough on recumbency may be considered an "orthopnea equivalent." If cough does not improve with diuresis, other common causes to consider in patients with heart failure include cough due to concomitant pulmonary disease (see later) and cough related to angiotensin-converting enzyme inhibitors.[39] PAROXYSMAL NOCTURNAL DYSPNEA.

Attacks of paroxysmal dyspnea usually occur at night. The patient awakens, often quite suddenly, and with a feeling of severe anxiety and suffocation, sits bolt upright and gasps for breath. Bronchospasm, which may be caused by congestion of the bronchial mucosa and by interstitial pulmonary edema compressing the small airways, increases ventilatory difficulty and the work of breathing and is a common complicating factor. The associated wheezing is responsible for the alternate name of this condition, cardiac asthma. In contrast to orthopnea, which may be relieved immediately by sitting upright at the side of the bed with the legs dependent, attacks of paroxysmal nocturnal dyspnea may require 30 minutes or longer in this position for relief. Episodes of paroxysmal nocturnal dyspnea may be so frightening that the patient may be afraid to go back to sleep, even after the symptoms have abated. The reason for the common occurrence of these episodes at night is not clear, but it seems likely that the combination of (1) the slow resorption of interstitial fluid from the

dependent portion of the body and the resultant expansion of thoracic blood volume, (2) elevation of thoracic blood volume and of the diaphragm that occurs immediately on assuming recumbency (as described earlier for orthopnea), (3) reduced adrenergic support of left ventricular function during sleep, and (4) normal nocturnal depression of the respiratory center all play major roles. Paroxysmal nocturnal dyspnea is a common clinical feature associated with Cheyne-Stokes respiration in patients with heart failure (see later).[40]

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TABLE 17-4 -- MECHANISMS OF DYSPNEA IN HEART FAILURE Decreased Pulmonary Function Decreased compliance Increased airway resistance Increased Ventilatory Drive Hypoxemia: PCW dot(V)/dot(Q) mismatch: PCW, CO Increased CO2 production: CO, lactic acidosis Respiratory Muscle Dysfunction Decreased strength Decreased endurance Ischemia PCW=mean pulmonary capillary wedge pressure;dot(V)/dot(Q) Q=ventilation/perfusion; CO=cardiac output; CO2 =carbon dioxide. Adapted from Mancini DM: Pulmonary factors limiting exercise capacity in patients with heart failure. Prog Cardiovasc Dis 37:347, 1995.

MECHANISMS OF DYSPNEA (Table 17-4)

Increased awareness of respiration or difficulty in breathing is commonly associated with pulmonary capillary hypertension caused by an elevation of left atrial or left ventricular filling pressure.[36] Patients with left ventricular failure typically exhibit a restrictive ventilatory defect, characterized by a reduction of vital capacity as a consequence of the replacement of the air in the lungs with blood or interstitial fluid or both. Consequently, the lungs become stiffer, air trapping occurs because of earlier than normal closure of dependent airways, and the work of breathing is increased because

higher intrapleural pressures are needed to distend the stiff lungs.[41] Tidal volume is reduced, and respiratory frequency rises in a compensatory fashion. Engorgement of blood vessels may reduce the caliber of the peripheral airways, increasing airway resistance. In addition, there are alterations in the distribution of ventilation and perfusion, resulting in widened alveolar-arterial differences for oxygen, hypoxemia, and an increased ratio of dead space to tidal volume. Thus, dyspnea and orthopnea in heart failure are clinical expressions of pulmonary venous and capillary congestion. Paroxysmal nocturnal dyspnea reflects the presence primarily of interstitial edema, whereas pulmonary edema, in which there is transudation and expectoration of blood-tinged fluid (see p. 553), is often a manifestation of alveolar edema. Whatever abnormalities in mechanics and gas exchange function of the lung exist at rest, they are aggravated during exercise (and sometimes during recumbency) when pulmonary venous and capillary pressures rise further. Transudation of fluid from the intravascular to the extravascular space results in greater stiffening of the lungs, an augmentation in the work of breathing, and increased resistance to air flow.[41] There is an increased ventilatory drive, as a consequence of the stimulation of stretch receptors in the pulmonary vessels and interstitium, as well as of hypoxemia and metabolic acidosis. The increased work of breathing, combined with a low cardiac output and resulting impaired perfusion of the respiratory muscles, causes fatigue and ultimately the sensation of dyspnea.[42] [43] Dyspnea occurs whenever the work of respiration is excessive. Increased force generation is required for the respiratory muscles to move a given volume of air if the compliance of the lungs is reduced or the resistance to air flow is increased[44] [45] ; both of these changes occur in left-sided heart failure. Dyspnea at rest also may occur in the late stages of heart failure when very low cardiac output, hypoxemia, and acidosis combine to reduce the delivery of oxygen to the respiratory muscle.[42] [45] Dyspnea may occur without pulmonary congestion in patients with right ventricular failure, a fixed low cardiac output, and/or a right-to-left shunt. Differentiation Between Cardiac and Pulmonary Dyspnea

In most patients with dyspnea there is obvious clinical evidence of disease of either the heart or the lungs, but in some the differentiation between cardiac and pulmonary dyspnea may be difficult.[36] Like patients with heart failure, those with chronic obstructive pulmonary disease also may awaken at night with dyspnea, but this is usually associated with sputum production; the dyspnea is relieved after patients rid themselves of secretions by coughing rather than specifically by sitting up. When the dyspnea arises after a history of intensified cough and expectoration, it is usually primarily pulmonary in origin. Acute cardiac asthma (paroxysmal nocturnal dyspnea with prominent wheezing) usually occurs in patients who have obvious clinical evidence of heart disease and may be further differentiated from acute bronchial asthma by diaphoresis and bubblier airway sounds and the more common occurrence of cyanosis. The difficulty in distinguishing between cardiac and pulmonary dyspnea may be compounded by the coexistence of diseases involving both organ systems. Thus, patients with a history of chronic bronchitis or asthma who develop left ventricular failure

tend to develop particularly severe bronchoconstriction and wheezing in association with bouts of paroxysmal nocturnal dyspnea and pulmonary edema. Airway obstruction and dyspnea that respond to bronchodilators or smoking cessation favor a pulmonary origin of the dyspnea, whereas symptomatic improvement with diuretics and/or nitrates supports heart failure as the cause of dyspnea. Dyspnea that persists despite appropriate cardiovascular or respiratory pharmacotherapy may be related to psychosocial factors (e.g., anxiety, emotional stress). [46] PULMONARY FUNCTION TESTING.

This should be carried out in patients in whom the etiology of dyspnea is unclear despite detailed clinical evaluation. The major alterations in pulmonary function tests in heart failure are reductions of vital capacity, total lung capacity, pulmonary diffusion capacity, and pulmonary compliance; resistance to air flow is moderately increased; residual volume and functional residual volume are normal. Often there is hyperventilation at rest and during exercise, an increase in dead space, and some abnormalities of ventilation-perfusion relations with slight reductions in arterial Pco2 and Po2 . With pulmonary capillary hypertension, pulmonary compliance decreases and there is air trapping because of earlier than normal closure of dependent airways. The airway resistance rises,[47] as does the work of breathing. Rarely, it may be difficult, on clinical examination, to differentiate among cardiac dyspnea, dyspnea based on malingering, and dyspnea caused by anxiety.[46] Careful observation for the appearance of effortless or irregular respiration during exercise testing often helps to identify the patient in whom dyspnea is related to the latter two noncardiac causes. Patients whose anxiety focuses on the heart may exhibit sighing respiration and difficulty in taking a deep breath as well as dyspnea at rest. Their breathing patterns are not rapid and shallow, as in cardiac dyspnea. Rarely a "therapeutic test" is helpful, and amelioration of dyspnea, accompanied by a weight loss exceeding 2 kg induced by administration of a diuretic, supports a cardiac origin for the dyspnea. Conversely, failure of these measures to achieve such weight reduction and to diminish dyspnea weighs heavily against a cardiac origin. Reduced Exercise Capacity MECHANISMS OF EXERCISE INTOLERANCE.

A nearly universal manifestation of heart failure is a reduction in exercise capacity.[48] Although exercise capacity may be limited for a variety of reasons in patients with heart failure, the most common causes are the development of dyspnea due to pulmonary vascular congestion and the failure of the cardiovascular system to provide sufficient blood flow to exercising muscles. The latter reflects primarily an inadequate cardiac output response to exercise due to reductions in stroke volume and heart rate.[49] [50] [51] In addition to the impaired central hemodynamic response to exercise, a number of other factors may contribute to reduced exercise capacity in patients with heart failure, including an attenuated peripheral vascular response,[52] [53] [54] abnormal skeletal muscle metabolism,[55] deconditioning of skeletal and respiratory muscles,[41] [55] [56] and patient

anxiety related to the development of exertional symptoms. A recent study demonstrated a rapid improvement in the peripheral vascular response to exercise after intensive, hemodynamically guided therapy.[54] There is evidence that the judicious use

541

of cardiac rehabilitation can improve functional capacity, quality of life, and outcomes in patients with heart failure,[57] [58] possibly by improving autonomic control of the circulation and peripheral muscle blood flow,[58A] reversing abnormalities of skeletal muscle metabolism, and improving patients' perceptions of their quality of life and symptom severity[59] (see also Chap. 39 ). Exercise Testing (See also Chap. 6. )

MAXIMAL EXERCISE CAPACITY.

Exercise stress testing may be an exceedingly useful adjunct in the clinical assessment of patients with suspected or known heart failure.[48] [60] With use of a bicycle ergometer or treadmill and a progressively increasing load, the maximum level of exercise that can be achieved can be determined; the latter correlates closely with the total oxygen uptake (dot(V)o2 ). Close observation of the patient during an exercise test may disclose obvious difficulty in breathing at a low level of exercise (or the opposite). Thus, this simple test may be considered to be an extension of the clinical examination. A more formal assessment, in which dot(V)o 2 is measured at each stage of exercise, or preferably in which dot(V)o2 and dot(V)co2 are measured continuously, allows determination of maximum dot(V)o2 . It also permits measurement of the anaerobic threshold (i.e., the point during the exercise test at which the respiratory quotient rises as a consequence of the production of excess lactate). A progressive exercise test is carried out until (1) dot(V)o2 fails to rise with further increases in activity or (2) the patient is limited by severe dyspnea and/or fatigue. When the dot(V)O2 is less than 25 ml/kg/min and the reduction is caused by a cardiac abnormality (rather than by pulmonary disease, anemia, peripheral vascular disease, an orthopedic disability, marked obesity, severe deconditioning, or malingering), it may be used to classify the severity of heart failure. It may also be used to follow the progress of the patient, assess the efficacy of therapeutic maneuvers, and assess prognosis. [60] [61] [62] SUBMAXIMAL EXERCISE CAPACITY.

Because usual daily activities generally require much less than maximal exercise capacity, the measurement of submaximal exercise capacity may provide information that is complementary to that provided by maximal exercise testing.[63] [64] In contrast to maximal exercise capacity, which reflects the adequacy of the central hemodynamic response, the ability to sustain a submaximal exercise effort may reflect regulation of

blood flow to the skeletal musculature. Submaximal exercise capacity can be assessed by measuring the duration of exercise at a constant workload that is generally chosen to be at or below the patient's anaerobic threshold.[65] A rough approximation of the submaximal exercise capacity can be obtained by measuring the distance walked in a fixed period of time.[66] The "6-minute walk test," most common of the fixed-time tests, measures the distance walked on level ground in 6 minutes.[67] [68] In this test, the patient is asked to walk along a level corridor as far as he or she can in 6 minutes. The patient can slow down or even stop, may be given a carefully controlled level of encouragement, and is told when 3 and 5 minutes have elapsed. The 6-minute walk test and other similar submaximal tests[69] are being evaluated in clinical trials to determine if they are capable of detecting a therapeutic response. They are moderately predictive of maximal oxygen consumption (Fig. 17-3) , and as noted later, the 6-minute walk test independently predicts morbidity and mortality.[68] [70] Another form of submaximal exercise test measures the distance walked on a self-powered treadmill.[71] OTHER SYMPTOMS

FATIGUE AND WEAKNESS.

These symptoms, often accompanied by a feeling of heaviness in the limbs, are generally related to poor perfusion of the skeletal muscles in patients with a lowered cardiac output. They may be associated with impaired vasodilation and altered metabolism in skeletal muscle.[52] [55] However, fatigue and weakness

Figure 17-3 Relationship between the distance walked in 6 minutes and the peak oxygen consumption in 45 patients with advanced heart failure (age 49 ± 8 years; New York Heart Association Class 3.3 ± 0.6; left ventricular ejection fraction 0.20 ± 0.06) (r=0.64, p=0.0001). In this study, distance walked less than 300 meters predicted an increased likelihood of death or hospital admission for inotropic or mechanical support. Because the 6-minute walk test involves only a submaximal exercise effort, it may be sensitive to changes in exercise function in the work range that is relevant to normal daily activities. (From Cahalin LP, et al: The six-minute walk test predicts peak oxygen uptake and survival in patients with advanced heart failure. Chest 110:325, 1996.)

are nonspecific symptoms and may be caused by a variety of noncardiopulmonary diseases, as well as by neurasthenia and depression. In heart failure, fatigue and weakness may also be caused by sodium depletion, hypovolemia, or both, usually resulting from excessive treatment with diuretics and restriction of dietary sodium and oral fluid intake. Beta-adrenergic antagonists also may cause fatigue. URINARY SYMPTOMS.

Nocturia may occur relatively early in the course of heart failure. Urine formation is suppressed during the day when the patient is upright and active; this is due, at least in part, to a redistribution of blood flow away from the kidneys during activity. When the patient rests in the recumbent position at night, the deficit in cardiac output in relation to oxygen demand is reduced, renal vasoconstriction diminishes, and urine formation increases. Nocturia may be troublesome in that it prevents the patient with heart failure

from obtaining much-needed rest. The diurnal pattern of urine flow characteristic of heart failure contrasts sharply to that existing in renal failure, in which urine formation occurs at a reasonably constant rate, both day and night. Oliguria is a sign of late cardiac failure and is related to the suppression of urine formation as a consequence of severely reduced cardiac output. CEREBRAL SYMPTOMS.

Confusion, impairment of memory, anxiety, headache, insomnia, bad dreams or nightmares, and, rarely, psychosis with disorientation, delirium, and even hallucinations may occur in elderly patients with advanced heart failure,[72] particularly in those with accompanying cerebral arteriosclerosis. SYMPTOMS OF PREDOMINANT RIGHT-SIDED HEART FAILURE.

Breathlessness is not as prominent in isolated right ventricular failure as it is in left-sided heart failure because pulmonary congestion is usually absent. Indeed, when a patient with mitral stenosis or left ventricular failure develops right ventricular failure, the more severe forms of dyspnea (i.e., paroxysmal nocturnal dyspnea and episodic pulmonary edema) tend to diminish in frequency and intensity. Congestive hepatomegaly may produce discomfort, generally described as a dull ache or heaviness, in the right upper quadrant or epigastrium. This discomfort, which is caused by stretching of the hepatic capsule, may be severe when the liver enlarges rapidly, as in acute right-sided heart failure. In contrast, chronic, slowly developing hepatic enlargement is generally painless. Other gastrointestinal symptoms, including anorexia, nausea, bloating, a sense of fullness after meals, and constipation, are due to congestion of the liver and gastrointestinal tract. In severe, preterminal heart failure, inadequate bowel perfusion can cause abdominal pain, distention, and bloody stools. Functional Classification

A classification of patients with heart disease based on the relation between symptoms and the amount of effort required

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to provoke them was developed by the New York Heart Association (NYHA).[73] Although there are obvious limitations to assigning numerical values to subjective findings, this classification is nonetheless useful in comparing groups of patients as well as the same patient at different times. In addition, NYHA Class has proven to be a strong, independent predictor of survival in patients with chronic heart failure.[74] Class I--No limitation: Ordinary physical activity does not cause undue fatigue, dyspnea, or palpitation.

Class II--Slight limitation of physical activity: Such patients are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or angina. Class III--Marked limitation of physical activity: Although patients are comfortable at rest, less than ordinary activity will lead to symptoms. Class IV--Inability to carry on any physical activity without discomfort: Symptoms of congestive failure are present even at rest. With any physical activity, increased discomfort is experienced. As discussed in Chapter 3 , the accuracy and reproducibility of this classification are limited. To overcome these limitations, Goldman and associates[75] have developed a useful classification based on the estimated metabolic cost of various activities (see Table 3-11 ).

QUALITY OF LIFE.

The three main goals of treatment for heart failure are to reduce symptoms, prolong survival, and improve quality of life. A good "quality of life" implies the ability to live as one wants, free of physical, social, emotional, and economic limitations. Heart failure can have an enormous deleterious impact on the quality of life. Although a number of generic instruments are available to assess health-related quality of life,[76] the Minnesota Living with Heart Failure (MLHF) questionnaire was designed specifically for use in these patients.[77] It consists of 21 brief questions, each of which is answered on a scale of 0 to 5. Eight questions have a strong relationship to the symptoms of dyspnea and fatigue and are referred to as physical dimension measures. Five other questions that are strongly related to emotional issues are referred to as emotional dimension measures. The test is self-administered and takes only 5 to 10 minutes to complete. For each question, the patient selects a number from 0 to 5. Zero indicates that heart failure had no effect, and 5 indicates a very large effect. Although such questionnaires have little role in routine clinical management of patients, they have provided valuable information in clinical research settings by allowing the response to various pharmacological therapies to be quantified.[77] [78] [78A] Quality of life instruments have also been used to assess response to cardiac rehabilitation (Fig. 17-4) [58] and multidisciplinary, disease management programs.[79] Physical Findings (See also Chap. 4 ) GENERAL APPEARANCE.

Patients with mild or moderate heart failure appear to be in no distress after a few minutes of rest. However, they may be obviously dyspneic during and immediately after moderate activity. Patients with left ventricular failure may become uncomfortable if they lie flat without elevation of the head for more than a few minutes. Those with severe heart failure appear anxious and may exhibit signs of air hunger in this position. Patients with heart failure of recent onset appear acutely ill but are usually well nourished, whereas those with chronic heart failure often appear malnourished and sometimes

even cachectic. Chronic, marked elevation of systemic venous pressure may produce exophthalmos and severe tricuspid regurgitation and may lead to visible systolic pulsation of the eyes[80] and of the neck veins. Cyanosis, icterus,

Figure 17-4 Changes in the Minnesota Living with Heart Failure (MHL) questionnaire scores for stable heart failure patients enrolled in a 12-month exercise training program (open circles) compared with untrained controls (closed circles) at baseline (test 1) and after 2, 14, and 24 months (tests 2, 3, and 4). MHL scores improved significantly in trained patients after 2 months and remained stable after the subsequent 12-month exercise training program and during follow-up (*p24 hours) use of organic nitrates and molsidomine is the development of tolerance (see Chap. 37) . Rapid development of tolerance to the venous and arteriolar dilating effects of organic nitrates has been known for over a century.[97] While well documented, the mechanism(s) responsible for nitrate tolerance are not clearly understood. It is likely that several mechanisms contribute to decreased responsiveness to nitrovasodilators with time and that the importance of the relative contribution of each potential mechanism differs with the specific drug used, the underlying disease (HF vs. angina), and the specific vascular bed.[97] Most of the data on the efficacy of intermittent versus continuous nitroglycerin dosing protocols have been obtained in patients with angina rather than chronic congestive HF symptoms.[98] Indeed, it is somewhat controversial whether HF patients should be exposed to a long nitrate-free period. Nevertheless, it seems prudent to recommend nitrate-free intervals in patients receiving chronic doses of isosorbide dinitrate, which can usually be achieved by providing the last dose of isosorbide dinitrate in the early

evening. "DIRECTLY ACTING" AND OTHER VASODILATORS (see also Chap. 29) Hydralazine

Hydralazine, an effective afterload-reducing agent whose cellular mechanism of action remains poorly understood, is best used in chronic HF when combined with isosorbide dinitrate to provide more effective venodilation.[77] This combination produces a more balanced form of vasodilation, and in addition, some evidence indicates that hydralazine can attenuate nitrate tolerance.[99] In HF, hydralazine reduces right and left ventricular afterload by reducing systemic as well as pulmonary artery input impedance and vascular resistance.[100] Unlike the use of hydralazine to treat hypertension, this reduction in afterload is usually accompanied by only minor reflex increases in sympathetic nervous system activity unless symptomatic hypotension occurs. These hemodynamic changes result in an increase in forward stroke volume and reductions in ventricular systolic wall stress and the regurgitant fraction in mitral or aortic regurgitation. Hydralazine's effects on regional blood flow consist of an increase in renal and skeletal muscle blood flow.[101] One of the problems with the use of hydralazine is its short half-life, which necessitates dosing four times daily. In addition, side effects that may necessitate dose adjustment or withdrawal of hydralazine therapy are common. For example, in the V-HeFT-I Trial, 20 percent of patients complained of symptoms that could have been related to hydralazine. The most common complaints--headache and dizziness--could also have been due to the concomitantly administered nitrates. However, with time, the symptoms diminish or respond to a reduction in dose. Hydralazine metabolism is primarily via hepatic acetylation, although many additional potential metabolic pathways

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have been described.[102] Therefore, patients with a "slow-acetylater" phenotype will have a prolonged elimination half-life of the drug. At the usual doses and dosing intervals of hydralazine, these patients are at greater risk of arthritis or other components of a lupus-like syndrome. Because of the somewhat equivocal results of hydralazine-isosorbide dinitrate in V-HeFT-I[100] and the superiority of the ACE inhibitor enalapril to this combination in V-HeFT-II,[103] hydralazine-isosorbide dinitrate is reserved for subjects who cannot tolerate ACE inhibitors or who have need for additional afterload reduction (blood pressure remaining high normal or greater in the face of full-dose ACE inhibition). Another potential use for hydralazine-isosorbide dinitrate is in American blacks, who in V-HeFT-II had better clinical responses to the combination than to enalapril.[104]

Flosequinan

Flosequinan is a powerful balanced vasodilator with an unknown mechanism of action that was FDA approved briefly for the treatment of HF and then withdrawn from the market by the sponsor because of a substantial increase in mortality [79] in a study that was not completed at the time of approval. Although flosequinan has weak positive inotropic effects in isolated human heart preparations,[105] the major pharmacological property of this compound is vasodilation. The flosequinan "story" is described here because of its multiple important lessons in HF therapy and drug development. The hemodynamic effects of flosequinan are sustained[106] and associated with a consistent and impressive increase in maximum exercise tolerance.[81] [82] Although flosequinan produced an excess of deaths when compared with placebo in medium-sized phase III trials,[81] [82] this result was initially disregarded because it was not statistically significant and the agent's vasodilator class was not thought to confer high risk for increasing mortality. However, the Prospective Randomized Flosequinan Longevity Evaluation (PROFILE) mortality trial[79] confirmed the increased mortality, with a nearly identical percent increase in death in comparison to placebo as occurred in the exercise trials.[81] [82] In retrospect, one clue to the mortality-enhancing potential of flosequinan was its positive chronotropic effects in that the drug increased the resting heart rate by an average of 7 beats/min in earlier phase II and III trials. In general, compounds that increase the heart rate increase mortality and vice versa.[107] The clinical trial results with flosequinan demonstrated that sustained vasodilation without concomitant neurohormonal antagonism has an adverse, rather than favorable effect on the natural history of HF. This observation, coupled with the results of V-HeFT-II,[103] spelled the end of the "vasodilator era" of therapy for chronic HF. Moreover, the flosequinan results, combined with the adverse survival results seen with higher doses of inotropic agents, ended the pure hemodynamic approach to the treatment of HF or the notion that simple pharmacological correction of hemodynamic abnormalities would improve the natural history.[108] Calcium Channel Antagonists

Although all three classes of calcium channel antagonists (i.e., phenylalkylamines such as verapamil; benzothiazepines such as diltiazem; and dihydropyridines such as nifedipine, nitrendipine, felodipine, nicardipine, isradipine, or amlodipine) are effective arteriolar vasodilators, none has been shown to produce sustained improvement in symptoms or natural history in HF patients with predominant systolic ventricular dysfunction. Indeed, some of these agents appear to worsen symptoms and may increase mortality in patients with systolic dysfunction.[109] The reason for these adverse effects or lack of efficacy of calcium channel blockers in HF is unclear. It may be related to the known negative inotropic effects of these drugs, to reflex neurohumoral activation, or a combination of these and other effects. Second-generation calcium channel antagonists of the dihydropyridine class, such as

amlodipine, nicardipine, and felodipine, have fewer negatively inotropic effects than do earlier drugs of this class as a result of their higher degrees of vasoselectivity. All three have recently been evaluated in medium or large-scale randomized trials.[110] [111] [112] In V-HeFT-III,[110] felodipine and, in the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) Study,[111] amlodipine did not increase mortality, thus indicating that these agents and probably nicardipine[112] are safe for use in treating angina in subjects with HF. K+ CHANNEL ACTIVATORS

K+ channels are composed of diverse families of integral plasma membrane proteins, the K+ conductance of which is specific to each family. [113] K+ channels are regulated by a number of mechanisms, including changes in transmembrane voltage, intracellular Ca2+ activity, intracellular adenosine triphosphate (ATP) levels, and other mechanisms.[114] [115] The distribution of K+ channel isoforms is tissue and cell type specific, [116] which permits the possibility of relatively selective tissue pharmacological activity of drugs acting on a specific family of K+ channels. In vascular smooth muscle, increased outward K+ conductance causes cellular hyperpolarization and decreased Ca2+ entry, thereby resulting in vasorelaxation. Diazoxide and minoxidil, classic "directly" acting vasodilators, are now known to act at ATP-regulated K+ channels. Nicorandil*, pinacidil,* and cromakalim* are representatives of a new class of ATP-regulated K+ channel activators that exhibit a unique spectrum of activity among vasodilator drugs. Like minoxidil, nicorandil is primarily an arteriolar vasodilator, but it is also effective in dilating epicardial coronary arteries and in reducing preload in experimental animals and patients with HF.[117] Nicorandil, pinacidil, and cromakalim have been tested in humans, primarily for hypertension and angina, and are effective and relatively well tolerated with fewer adverse effects than seen with the older vasodilators of this class. In addition, ATP-regulated K+ channel activators may have cardioprotective effects in terms of preventing ischemic damage.[118] More recently, the calcium-sensitizing inotrope-vasodilator levosimendan, which is in phase III HF clinical trials in both intravenous and oral form, has been shown to be an activator of ATP-regulated K+ channels at higher doses (see below). The experience to date with these agents in patients with HF has not been extensive. Unlike nitrovasodilators, tolerance to nicorandil has not been observed in angina studies.[119] As with any novel class of vasodilator, the utility of nicorandil and other ATP-regulated K+ channel activators must await the design and completion of large controlled efficacy and survival trials. Vasodilator Prostaglandins

Prostaglandins are biologically active eicosanoids that produce either vasodilation (e.g., prostaglandin E1 , prostacyclin) or vasoconstriction (e.g., thromboxane). One of them, prostacyclin (epoprostenol), has been developed as an intravenous vasodilator and has been used in clinical trials in right ventricular failure from primary pulmonary

hypertension (PPH)[120] (see Chap. 53) and in advanced chronic biventricular failure.[80] In both trials, prostacyclin was given intravenously by continuous infusion. The remarkable finding in these two clinical trials was that prostacyclin decreased mortality in PPH[120] but increased it in biventricular failure.[80] These findings initially seem paradoxical until the underlying pathophysiology of the two disorders is examined. In PPH, the pathophysiology is dominated by a marked increase in right ventricular afterload to levels that are severalfold above normal. The natural history of PPH is dependent on the ability of the right ventricle to withstand this insult, and any measure that can reduce afterload, such as prostacyclin, can improve the natural history of PPH. In contrast, in biventricular failure from a dilated cardiomyopathy phenotype, elevated left or right ventricular afterload is not usually the dominant pathophysiology. Rather, the natural history is related to the vicious cycle of contractile dysfunction and remodeling described in Chapter 16 . When a powerful vasodilator such as prostacyclin is administered, neurohormonal signaling pathways are probably progressively activated, thereby leading to an increase in mortality and generally worsening the natural history of HF. Indeed, results of the prostacyclin chronic HF ("Flolan International Randomized Survival Trial" [FIRST]) trial are part of the evidence that vasodilation per se is not a beneficial approach to the treatment of chronic HF. [108] Natriuretic Peptides

As discussed above in the section on diuretics, the natriuretic peptides are hormones that are produced by the heart in response to increased wall stress and are secreted into the circulation as a marker of hypertrophy or failure. In fact, one of them, BNP, has promise as a blood test for HF or left ventricular dysfunction.[121] [122] Natriuretic peptides are not simply markers of myocardial hypertrophy and failure; they are also vasodilators and are natriuretic and diuretic in some patients.[45] [46] The vasodilator properties are both venous and arteriolar.[45] [46] Because of these favorable vascular and renal effects, recombinant natriuretic peptides have been evaluated as intravenous therapy in decompensated HF, and one of them, hBNP, is in phase III clinical development. In subjects with HF, intravenous BNP increases cardiac output and lowers pulmonary wedge mean and mean pulmonary

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artery pressure without increasing the heart rate.[45] [46] The latter is probably due to the sympathoinhibitory properties of BNP[123] because systemic norepinephrine levels actually decrease[46] despite the vasodilator effects of the compound. The unique combination of vasodilation and diuresis/natriuresis creates a potentially useful acute HF treatment for certain subjects. Another approach to the use of natriuretic peptides is to deliver them subcutaneously, where they could then be used to treat chronic HF.[124] Thus far, proof of concept for the route of administration[124] has been accomplished, but no controlled trial data are

available. Neurohormonal/Cyokine Inhibitors

Although initially investigated within the vasodilator paradigm, inhibitors of vasoconstrictor neurohormones or cytokines do far more than produce vasodilation. That is, inhibitors of the renin-angiotensin, adrenergic, and endothelin systems probably exert their primary action on the heart in that they attenuate or even reverse the dysfunction/remodeling process, as discussed in Chapter 16 . However, their vasodilator properties are also useful because they tend to improve rather than worsen hemodynamics. Inhibitors of neurohormonal or cytokine systems are discussed in detail in a later section.




Positive Inotropic Agents CARDIAC GLYCOSIDES Cardiac glycosides are used to treat chronic HF in patients in sinus rhythm and to control the response of the ventricular rate to supraventricular arrhythmias, including atrial fibrillation.[124A] The first drug used to treat chronic HF was digitalis, an extract of the common foxglove plant Digitalis purpurea. Digoxin is now the most commonly prescribed cardiac glycoside because of its convenient pharmacokinetics, alternative routes of administration, and the widespread availability of serum drug level measurements. Both deslanoside, a rapidly acting agent available only for parenteral use, and digitoxin continue to be marketed in the United States. The discussion is confined to digoxin since it is the cardiac glycoside of choice worldwide. MOLECULAR MECHANISM OF ACTION.

Digoxin is an extremely complex agent in that its mode of action, inhibition of Na+ ,K+ -ATPase, affects multiple cellular processes, including several critical to cardiac myocyte function (see Chap. 14) . Digoxin is also extremely toxic, not surprising in view of its role in nature. Cardiac glycosides bind to a specific high-affinity site on the extracytoplasmic face of the alpha subunit of Na+ ,K+ -ATPase, the enzymatic equivalent of the cellular "sodium pump." [125] The affinity of the subunit for cardiac glycosides varies among species and among the three known mammalian subunit isoforms, each of which is encoded by a separate gene.[125] Cardiac glycoside binding to and inhibition of the Na+ ,K+ -ATPase sodium pump are reversible and entropically driven. Under physiological conditions, these drugs preferentially bind to the enzyme after phosphorylation of a beta-aspartate on the

cytoplasmic face of the alpha subunit, thus stabilizing this "E2 P" conformation.[125] [126] Extracellular K+ promotes dephosphorylation at this site, resulting in a decrease in the cardiac glycoside binding affinity for the enzyme.[126] This action presumably explains why increased extracellular K+ tends to reverse some manifestations of digitalis toxicity. POSITIVE INOTROPIC EFFECT.

Cardiac glycosides increase the velocity and extent of shortening of cardiac muscle, thereby resulting in an upward and left shift of the ventricular function curve (Frank-Starling) relating cardiac performance to filling volume or pressure (see Fig. 18-2) . This process occurs in normal as well as failing myocardium and in atrial as well as ventricular muscle. The effect appears to be sustained for periods of weeks or months without evidence of desensitization or tolerance.[127] The positive inotropic effect is due to an increase in the availability of cytosolic Ca2+ during systole, thus increasing the velocity and extent of sarcomere shortening. The increase in intracellular Ca2+ is a consequence of cardiac glycoside-induced inhibition of sarcolemmal Na+ ,K+ -ATPase.[125] [126] Inhibition of Na+ ,K+ -ATPase causes intracellular Na+ to increase, which is then exchanged for extracellular Ca2+ via the Na+ -Ca2+ exchanger.[128] The net effect of these adjustments is to increase intracellular Ca2+ during systole, which increases systolic function. In part because cardiac glycosides produce an increase in contractile function without increasing the heart rate, the positive inotropic effects are more energetically efficient than are the effects of beta-adrenergic agonists and higher doses of PDEIs.[129] This difference may be one of the reasons why low-dose digoxin does not increase mortality in patients with HF.[130] ANTIADRENERGIC PROPERTIES.

Na+ ,K+ -ATPase is involved in baroreflex afferent signaling and may be upregulated in the carotid sinus in HF.[131] Decreased baroreflex control[132] is one of the mechanisms responsible for an increase in generalized and cardiac[133] adrenergic activity in HF. Inhibition of Na+ ,K+ -ATPase by ouabain modulates baroreflex function toward normal in HF animal models,[131] which is likely to be the mechanism by which cardiac glycosides inhibit adrenergic activity in HF. Ferguson and colleagues demonstrated in patients with moderate to severe HF that infusion of the cardiac glycoside deslanoside increases forearm blood flow and the cardiac index and decreases the heart rate, concomitant with a marked decrease in skeletal muscle sympathetic nerve activity measured as an indicator of centrally mediated sympathetic nervous system activity.[134] In addition, controlled clinical trial data have indicated that digoxin reduces systemic[135] and cardiac[136] norepinephrine levels in subjects with chronic HF. This reduction in adrenergic activity may be another reason why digoxin does not increase mortality when used in low doses in patients with chronic HF. ELECTROPHYSIOLOGICAL ACTIONS.

Cardiac glycosides have complex electrophysiological effects that are a combination of indirect, parasympathetic, and direct effects of specialized cardiac pacemaker and conduction tissue.[137] At low to moderate therapeutic serum concentrations (0.5 to 1.9 ng/ml), digoxin usually decreases automaticity and increases maximal diastolic resting membrane potential in atrial and atrioventricular (AV) nodal cells as a result of augmented vagal tone and decreased sympathetic nervous system activity. These effects are accompanied by prolongation of the effective refractory period and decreased AV nodal conduction velocity. At higher, toxic digoxin levels or in the presence of underlying disease, patients are susceptible to sinus bradycardia or arrest, prolongation of AV conduction, or heart block. At toxic levels, cardiac glycosides can also increase sympathetic nervous system activity, potentially contributing to the generation of arrhythmias. Increased intracellular Ca2+ loading and increased sympathetic tone both contribute to an increased rate of spontaneous (phase 4) diastolic depolarization and also to delayed afterdepolarizations that may reach threshold and generate propagated action potentials. The combination of increased automaticity and depressed conduction in the His-Purkinje network predisposes to arrhythmias, including ventricular tachycardia and fibrillation. Recent data from the Digitalis Investigation Group (DIG) Trial[138] suggest that the increase in ventricular arrhythmia manifested in chronic HF as an increase in sudden death extends down to digoxin serum levels of 1.0 ng/ml, inasmuch as higher concentrations were associated with an increase in mortality. Clinical Trial Results

Despite its use for over 200 years in the treatment of HF, the debate over the use of cardiac glycosides in chronic HF continues. Small and medium-size trials conducted in the 1970s and 1980s yielded equivocal results, with some apparently

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demonstrating efficacy[139] [140] [141] and some not.[142] [143] [144] In the early 1990s, two relatively large digoxin withdrawal studies, the Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme (RADIANCE)[145] [146] and the Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED),[146] [147] provided strong support for clinical benefit from digoxin in that worsening HF developed in more patients and they had to be hospitalized if digoxin therapy was withdrawn than in patients who had placebo withdrawn and were maintained on a regimen of digoxin. However, withdrawal studies are difficult to interpret, so a large placebo-controlled mortality trial, the DIG Trial, was conducted.[130] The DIG Trial had all-cause mortality as its primary endpoint and had secondary endpoints of hospitalization and worsening HF.[130] This trial enrolled 6800 Class I to III HF patients with an average left ventricular ejection fraction of 28 percent and monitored them for an average of 37 months. Remarkably, the DIG Trial finished with a relative risk ratio of 1.00 (confidence intervals of 0.91 and 1.07, p=0.80), which indicates that at

the doses (0.125 to 0.375 mg/d, with 70 percent receiving 0.25 mg/d) and serum levels of digoxin studied, this positive inotrope does not increase mortality in chronic HF. The data indicated a strong trend (p=0.06) toward a decrease in deaths assigned to a progressive pump failure etiology, balanced by an increase in sudden and other non-pump failure cardiac deaths (p=0.04). [130] The number of patients hospitalized was statistically significantly reduced (by 4 percent) by digoxin therapy, and the total number of hospitalizations per subject was significantly reduced by 6 percent.[130] Therefore, evidence of efficacy was seen in the DIG Trial, but in view of its large size and power, this evidence is modest. One of the most important findings to emerge from the DIG Trial was that mortality was directly related to the digoxin serum level.[138] In addition, data from other studies have demonstrated that the beneficial effects of digoxin on ventricular function[148] and neurohormonal activation[148] [149] occur at the "safe" lower serum levels of 0.5 to 1.0 ng/ml. This information means that if digoxin is used in subjects with HF, trough levels should be kept between 0.5 and 1.0 ng/ml. Overall, these clinical trial results support the routine use of digoxin in patients in sinus rhythm who have mild to moderate HF, which is why most HF practice guidelines recommend the use of digoxin. Because the DIG Trial,[130] as well as RADIANCE[145] and PROVED,[147] were conducted in patients with Class II to III HF, no firm recommendation is possible for more advanced HF patients in sinus rhythm. In addition, digoxin is indicated in all HF patients with atrial fibrillation in whom ventricular response slowing is required. However, in both the sinus rhythm and atrial fibrillation settings, digoxin must be used in such a way to avoid overt toxicity or an increase in sudden death without obvious toxicity. PHARMACOKINETICS AND DOSING

Orally administered digoxin is variably absorbed, depending on the preparation, but Lanoxin is 60 to 80 percent absorbed. Digoxin is approximately 25 percent protein bound in plasma, has a large volume of distribution (4 to 7 liter/kg), and crosses both the blood-brain barrier and the placenta. Digoxin is eliminated primarily by renal mechanisms, both glomerular filtration and tubular secretion. Tubular excretion is via the energy-dependent membrane-bound efflux pump/transport enzyme P-glycoprotein, which is modulated by many other drugs. Digoxin is largely excreted in the urine unchanged with a clearance rate proportional to the GFR, which results in the excretion of approximately one-third of body stores daily. The half-life for digoxin elimination of 36 to 48 hours in patients with normal or near-normal renal function permits once-daily or every-other-day dosing.[150] In the presence of an elevated blood urea nitrogen-to-creatinine ratio (i.e., "prerenal azotemia"), digoxin clearance more closely parallels urea clearance, thus indicating that under these circumstances some drug filtered at the glomerulus undergoes tubular reabsorption.[150] In patients with HF, increased cardiac output and renal blood flow in response to treatment with vasodilators or sympathomimetic agents may increase renal digoxin clearance and necessitate dosage adjustment. Digoxin is not removed effectively by peritoneal dialysis or hemodialysis because of its large volume of

distribution.[150] The principal body reservoir is skeletal muscle and not adipose tissue. Accordingly, dosing should be based on estimated lean body mass. Although neonates and infants tolerate and may require higher doses of digoxin (e.g., 0.01 mg/kg/d) for a therapeutic effect equivalent to that of older children or adults, once-daily dosing appears to be as effective as twice-daily dosing in this population.[151] Digoxin can be loaded at a dose of 0.75 to 1.25 mg orally (or intravenously at doses 25 percent lower) over a 24-hour period in three to four divided doses and then given at a maintenance dose, or a daily maintenance dose of 0.0625 to 0.25 mg/d orally can be started, depending on renal function, body size, and the presence or absence of coadministered drugs causing pharmacokinetic interactions. In the absence of loading doses, nearly steady-state blood levels are achieved in four to five half-lives, or about 1 week after initiation of maintenance therapy if normal renal function is present. If given intravenously, administration should be carried out over at least 15 minutes to avoid vasoconstrictor responses to more rapid injection. Intramuscular digoxin is absorbed unpredictably, causes local pain, and is not recommended. Patients with HF usually have a reduced volume of distribution and reduced renal function, and both may be influenced by other treatment and by the ebb and flow of the HF. Although nomograms on digoxin dosing have been published, these nomograms should not be used in patients with HF because of the narrow therapeutic index and the unpredictability of the numerous factors that can alter digoxin pharmacokinetics. Instead, patients should be started on a dose as described above and trough levels (see below) measured 1 to 2 weeks later and at frequent intervals (every 1 to 3 months) thereafter. DRUG INTERACTIONS WITH DIGOXIN.

Multiple drugs interact with digoxin at multiple levels, including reduced renal tubular excretion by drugs inhibiting P-glycoprotein renal tubular transport,[152] induction of gut P-glycoprotein,[153] alterations in gut flora by antibiotics causing less gut metabolism of digoxin before absorption, displacement from plasma protein-binding sites, or reduction in renal function. A partial list of these interactions is given in Table 18-4 . THERAPEUTIC DRUG MONITORING

Digoxin has an extremely low therapeutic index, and its use should be carefully monitored by serum blood levels. The various clinical conditions and drug interactions that can alter digoxin's pharmacokinetics are also reflected in the serum digoxin level. Reduced thyroid function and renal function both decrease the volume of distribution of digoxin and thus necessitate downward adjustments in loading and maintenance doses. Hypochlorhydria (i.e., gastric pH >7), which is common in elderly patients and patients receiving histamine H2 receptor antagonists or gastric H+ ,K+ -ATPase inhibitors, reduces gastric metabolism of digoxin and nonrenal clearance of the drug.[154] This abnormality may lead to higher steady-state blood levels in these patients with reduced renal function, particularly in the elderly. Both hypokalemia and hypercalcemia can independently increase ventricular automaticity and lower the threshold for

digoxin-induced cardiac arrhythmias. Hypomagnesemia may also contribute to arrhythmias with digoxin. Hyperkalemia may exacerbate digoxin-induced conduction disorders and cause high-grade AV nodal block. Studies using noninvasive indices of ventricular function suggest a nonlinear relationship between the serum digoxin concentration and observed inotropic or neurohormonal antagonism, with the majority of the increase in contractility [148] or neurohormonal effects[148] [149] occurring by the time that steady-state levels around 1.4 ng/ml are reached. This information, plus DIG Trial mortality data, indicates that the optimal trough digoxin serum level is 0.5 to 1.0 ng/ml. This concentration range is also the one that should be used to control the ventricular rate response to atrial fibrillation in HF patients, particularly since digoxin is not a very effective agent in this regard in the setting of high amounts of adrenergic activity.[155] Blood samples for measurement of serum digoxin levels should be taken at least 6 to 8 hours following the last digoxin dose. Digitalis Toxicity

In patients with HF, overt clinical toxicity tends to emerge at serum concentrations greater than 2.0 ng/ml, but it must always be remembered that substantial overlap in serum levels exists among patients exhibiting symptoms and signs of toxicity and those with no clinical evidence of intoxication.[156] Disturbances in cardiac impulse formation, conduction, or both are the hallmarks of digitalis toxicity.[157] Among the common electrocardiographic manifestations are ectopic beats of AV junctional or ventricular origin, first-degree AV block, an excessively slow ventricular rate response to atrial fibrillation, or an accelerated AV junctional pacemaker. These manifestations may require only dosage adjustment and monitoring as clinically appropriate. Sinus bradycardia, sinoatrial arrest or exit block, and second- or third-degree AV conduction delay often respond to atropine, but temporary ventricular pacing is sometimes necessary and should be available.

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TABLE 18-4 -- PARTIAL LIST OF DRUG INTERACTIONS WITH DIGOXIN DRUG EFFECT ON MECHANISM SERUM DIGOXIN LEVEL Amiodarone

Increases

Verapamil

Increases

? Renal clearance Renal clearance

Nifedipine

Increases Renal clearance

Diltiazem


Quinidine

Increases

Propafenone

Increases

Displacement of protein binding, renal clearance Renal clearance

Captopril

? Increases

Carvedilol

Increases

? Renal clearance Oral bioavailability

Spironolactone


Amiloride


Triamterene


Salbutamol

Decreases

Unknown

Macrolide antibiotics (erythromycin, clarithromycin)

Increases

Altered gut flora, renal clearance

Tetracycline

Increases

Altered gut flora

Indomethacin


Alprazolam

Increases

Itraconazole

Increases

? Renal clearance Renal clearance

Rifampin

Decreases

Induction of gut P-glycoprotein

Sucralfate

Decreases

Decreased gut absorption

Cholestyramine

Decreases

Decreased gut absorption

Cyclosporine


Saint Johns wort


MANAGEMENT.

Oral potassium administration is often useful for atrial, AV junctional, or ventricular ectopic rhythms, even when the serum potassium is in the normal range, unless

high-grade AV block is also present. However, [K+ ] must be monitored carefully to avoid hyperkalemia, especially in patients with renal failure. Magnesium may be useful in patients with atrial fibrillation and an accessory pathway in whom digoxin administration has facilitated a rapid accessory pathway-mediated ventricular response; again, careful monitoring is required to avoid hypermagnesemia.[158] Lidocaine and phenytoin, which in conventional doses have minimal effects on AV conduction, are useful in the management of worsening ventricular arrhythmias that threaten hemodynamic compromise. Electrical cardioversion can precipitate severe rhythm disturbances in patients with overt digitalis toxicity and should be used with particular caution. Neurological or gastrointestinal complaints can also be manifestations of digitalis toxicity. Occasionally, gynecomastia results from digoxin administration, apparently because of the similarity of the glycoside structure to that of estrogens. ANTIDIGOXIN IMMUNOTHERAPY.

Potentially life-threatening digoxin or digitoxin toxicity can be reversed by antidigoxin immunotherapy. Purified Fab fragments from digoxin-specific antisera are available at most poison control centers and larger hospitals in North America and Europe. The smaller (molecular weight 50,000) Fab fragments have a larger volume of distribution, more rapid onset of action, and more rapid clearance, as well as reduced immunogenicity in comparison to intact IgG.[159] Clinical experience in adults and children has established the effectiveness and safety of antidigoxin Fab in treating life-threatening digoxin toxicity, including cases of massive ingestion with suicidal intent.[160] Doses of Fab are calculated by using a simple formula based on either the estimated dose of drug ingested or the total-body digoxin burden (Table 18-5) and are administered intravenously in saline over a period of 30 to 60 minutes. Recrudescent digoxin toxicity is unusual but can occur 24 to 48 hours after Fab administration in patients with normal renal function or later in patients with renal impairment. Determination of the efficacy and cost-effectiveness of less than complete neutralizing doses of digoxin-specific Fab fragments for suspected or moderate cases of digoxin toxicity awaits further assessment.[159] [161] ADRENERGIC AGONISTS The most powerful way to increase contractility in the human heart is by a beta-adrenergic receptor agonist. Beta-agonists operate through the mechanism that regulates contractility and heart rate on a beat-to-beat basis in the intact heart, the cardiac myocyte beta receptor pathways (see TABLE 18-5 -- DOSES OF FAB CALCULATED ON THE BASIS OF THE AMOUNT OF INGESTED DIGOXIN OR THE TOTAL-BODY DIGOXIN BURDEN Estimation of Total-Body Digoxin Burden (mg) Total drug ingested following acute digoxin poisoning (i.e., amount ingested×0.80 [average oral bioavailability of tablet formulations]) or

Known or suspected toxicity during chronic digoxin therapy: Serum digoxin concentration×volume of distribution (5.6 liter/kg)×weight in kg ÷ 1000 Calculation of Fab Fragment Dose Molecular mass of Fab fragments =50,000×64×total-body digoxin content (mg) ÷ Molecular mass of digoxin=781 =dose of Fab fragments (mg) or Use a standard formulation (e.g., Digibind [Burroughs Wellcome]) Estimated total-body load of digoxin (mg) ÷ 0.6 (mg/vial) =Digibind dose in numbers of vials For reversal of digitoxin toxicity, substitute 1.0 for oral bioavailability and 0.56 liter/kg for volume of distribution in the formulas above.

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Figure 18-3 Beta-adrenergic signal transduction in human cardiac myocytes. AC=adenylyl cyclase; AMP=adenosine monophosphate; beta 1 AR=beta1 -adrenergic receptor; beta2 AR=beta2 -adrenergic receptor; ATP=adenosine triphosphate; CAMK=calmodulin-activated kinase; cAMP=cyclic adenosine monophosphate; Gi =inhibitory G protein with alpha, beta, and gamma subunits; G s =stimulatory G protein with alpha, beta, and gamma subunits; PDEc =cytosolic phosphodiesterases; PDE p =particulate, SR-associated PDE III; PHLMBN=phospholamban; PKA=cAMP-dependent protein kinase A; SR=sarcoplasmic reticulum.

Chap. 14) . As depicted in Figure 18-3 , this system is composed of two cell surface membrane receptors (beta1 and beta2 ), two G proteins (the "stimulatory G protein G alpha s and the inhibitory G protein G alpha i), the adenylyl cyclase enzyme (which converts Mg-ATP to cAMP), cAMP-activated protein kinase (protein kinase A), and target structures whose phosphorylation leads to a positive inotropic effect by changes in Ca2+ handling (phospholamban, the ryanodine release channel, and slow inward current calcium channels). The end result is a powerful positive inotropic as well as positive chronotropic effect. In the failing human heart, beta-adrenergic pathways undergo desensitization, a pharmacological term encompassing the regulatory changes that occur in receptors, G proteins, and adenylyl cyclase.[162] [163] In advanced HF, the degree of desensitization approaches 50 to 60 percent of the maximum capacity of signal transduction,[164] [165] and in severe HF, beta-agonists may no longer be able to support myocardial function. [166] The degree of desensitization present in end-stage HF patients who underwent cardiac

transplantation can be appreciated in Figure 18-4 , which gives maximum responses to the full, nonselective beta-agonist isoproterenol and other agents in isolated right ventricular trabeculae removed from nonfailing and failing human hearts. However, the vast majority of patients with advanced HF still exhibit a substantial inotropic response to beta-agonists,[165] which is the basis for their usefulness as inotropic agents in the treatment of decompensated HF. All beta-agonists are given intravenously for short-term support in decompensated HF. They are all arrhythmogenic

Figure 18-4 Effects of various inotropic agents on the systolic tension response in nonfailing and failing human right ventricular trabeculae, mean+SEM. OPC 8212=vesnarinone; FLSQ=flosequinan; ENOX=enoximone; MIL=milrinone; ISO=isoproterenol.

577

to some extent via direct mechanisms, as well as through increasing the skeletal muscle deposition of potassium[68] and decreasing serum magnesium.[167] Obviously, their administration should be carefully monitored and the lowest possible effective doses used. In addition, all beta-agonists are subject to the development of desensitization phenomena when used continuously, another reason to keep the doses low and the use short term or intermittent. Beta-agonists all have short (in minutes) half-lives, which is an advantage for powerful inotropes that may have adverse effects. As shown in Table 18-6 , from a therapeutic standpoint it is important to understand how beta-agonists differ from one another with respect to intrinsic activity; affinity for binding to beta1 , beta2 , and alpha1 receptors; and affinity for the cardiac adrenergic neuronal reuptake system (uptake1 ). [168] Neuronal reuptake is an important consideration in the heart, which has the most active uptake1 system of any organ and uses neuronal reuptake to terminate the majority of the action of released norepinephrine.[173] [174] Although beta1 - and beta2 -adrenergic receptors are both coupled to positive inotropic and chronotropic responses via cAMP-dependent mechanisms, these two receptors have important differences. For one thing, beta1 receptors are positioned inside or near the synaptic cleft area to mediate the effects of released norepinephrine,[176] which also means that catecholamines that have high affinity for uptake 1 will not reach myocardial beta1 receptors unless neuronal reuptake is functionally decreased (as it is myocardial failure) or absent (as it is in a recently [10,000

9000

1.0

Norepinephrine 10-30

250-750

200

500,670

1.0

Phenylephrine

>10,000

1000

>10,000

0

>10,000

*Relative to isoproterenol=1.0 in nonfailing isolated human right ventricular trabeculae. Affinity data are based on radioligand-cold ligand competition curves in (1) human ventricular myocardial membrane preparations (beta1 , in nonfailing hearts with greater than 80 percent beta1 receptors; alpha 1 , norepinephrine, epinephrine [ 168] ), (2) human recombinant beta 2 receptors in COS cell membranes (isoproterenol, norepinephrine, and epinephrine), (3) DTT 1 cell membranes (beta2 , dobutamine and dopamine), and (4) rat heart membranes (alpha 1 , dobutamine). [ 169] Additional alpha1 -agonist affinity data are derived from irreversible dibenamine antagonism in rabbit aorta, with relative affinities corrected for human/rabbit alpha 1 receptor-norepinephrine K values (dopamine, phenylephrine, epinephrine). [ 170] Uptake 1 data are from the human recombinant protein cloned from SK-N-SH neuroblastoma cells (norepinephrine, dopamine), [ 171] rabbit brain synaptosomes (dobutamine, dopamine, isoproterenol), [ 172] or the original data in rat heart (epinephrine, norepinephrine, phenylephrine) from Iversen. [ 173] [ 174] Data on concentrations inhibiting 50 percent (IC 50 ) were converted to affinity constants by using the Cheng-Prusoff equation. [ 175]

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does not selectively alter renal blood flow.[184] The importance of the vascular effects of dobutamine has been demonstrated by experiments in animals[185] [186] with artificial hearts. Even in the presence of a mechanical heart, dobutamine increased cardiac output by 10 to 15 percent and decreased systemic vascular resistance. Interestingly, dobutamine also decreased venous capacitance and increased right atrial pressure, possibly as a result of alpha1 -adrenergic agonism of the (-) enantiomer.[186] These experiments also demonstrated that the (+) enantiomer is responsible for the racemic drug's effects on aortic input impedance, wave reflectance, and systemic vascular resistance.[185] These favorable actions on left ventricular afterload are also responsible for the reduction in functional mitral regurgitation often observed with dobutamine infusions in patients with large dilated ventricles and high left ventricular end-diastolic pressure.[187] Dobutamine also causes a mild decline in pulmonary vascular resistance that is present regardless of chronic background vasodilator therapy. At higher doses, the (-) isomer of dobutamine begins to exert alpha 1 -adrenergic agonist action, thereby preventing progressive vasodilation and usually leading to only minimal changes in afterload and preload. The advantage of this alpha-adrenergic effect of dobutamine is that since preload and afterload do not change dramatically, dobutamine can be administered without pulmonary artery catheter monitoring of left ventricular filling pressure. Another advantage of the relative lack of vasodilation coupled to the partial agonist action is that dobutamine does not produce much increase in the heart rate at doses of 10 mug/kg/min or less. Because of its partial agonist activity, desensitization to prolonged infusions of dobutamine is not pronounced.[188] Dobutamine infusions are initiated at 2 to 3 mug/kg/min and are titrated upward according to the patient's hemodynamic response (usually not higher than 20 mug/kg/min).[183] [184] The limitations of dobutamine are that it (1) is a relatively weak beta-agonist,[181] (2) only modestly lowers elevated pulmonary artery pressure, (3) eventually produces desensitization phenomena when used chronically,[188] [190] and (4) cannot be effectively used in the presence of high levels of beta-adrenergic receptor blockade.[190] The first three of these limitations can be overcome by combining dobutamine with a PDEI, which results in additive effects on myocardial performance,[191] [192] substantial reductions in pulmonary wedge and pulmonary artery pressure,[191] [192] and a protective effect on desensitization [190] related to being able to lower the dobutamine dose. Dopamine

Dopamine is an endogenous catecholamine that is the precursor to norepinephrine in the catecholamine synthetic pathway. When administered therapeutically, dopamine is a complex agent. Dopamine through its direct effects is a weak partial agonist. When initially administered, it releases norepinephrine through a tyramine-like effect.[192] It is a potent (relative to its receptor affinities) neuronal uptake inhibitor and by direct action acts as an agonist at dopamine D1 postsynaptic vasodilator receptors[193] and D2 presynaptic receptors on blood vessels and in the kidney.[194] The affinities for beta1 ,

beta2 , and alpha1B receptors are shown in Table 18-6 , where it can be seen that dopamine has extremely low affinity for all three adrenergic receptors. At lower doses ( 2 mug/kg/min), dopamine causes relatively selective vasodilation of splanchnic and renal arterial beds. This effect may be useful in promoting renal blood flow and maintaining the GFR in selected patients who become refractory to diuretics, especially when caused by marginal renal perfusion. Dopamine also has direct renal tubular effects that promote natriuresis. At intermediate (2 to 10 mug/kg/min) infusion rates, dopamine, by virtue of its tyramine and neuronal uptake-inhibiting properties, enhances norepinephrine release from vascular and myocardial adrenergic neurons, thereby resulting in increased cardiac beta-adrenergic receptor activation and an increase in peripheral vascular resistance. In patients with advanced HF, who often have depleted intracardiac norepinephrine stores, dopamine is a less effective positive inotropic drug than other "directly" acting inotropes are.[184] [185] At higher infusion rates (5 to 20 mug/kg/min), peripheral vasoconstriction occurs as a result of direct alpha-adrenergic receptor stimulation. Increases in systemic vascular resistance are common even at intermediate infusion rates. On initial administration, tachycardia and arrhythmia tend to be more pronounced than with dobutamine[184] and are related to cardiac norepinephrine release.[192] [195] In patients with advanced, decompensated HF, dopamine should not be used as a positive inotropic agent, but rather used in low doses for renal perfusion and in intermediate to high doses to increase peripheral resistance. The latter property is often necessary for a variety of reasons, including sepsis, iatrogenic overvasodilation, and brain injury. Epinephrine

Epinephrine is an endogenous full beta-agonist catecholamine that like dobutamine, produces relatively balanced effects between vasodilation and vasoconstriction. This balance between vasodilation and vasoconstriction occurs because epinephrine has relatively equal high affinities for beta1 , beta2 , and alpha1 receptors (see Table 18-6) . Epinephrine has moderately high affinity for neuronal reuptake, which means that the majority of administered drug may not reach beta1 -adrenergic receptors in the normal heart. However, neuronal reuptake is markedly reduced in the failing heart,[196] [197] which will allow epinephrine to reach more beta1 -adrenergic receptors in this setting. Epinephrine is an excellent positive inotropic agent in the denervated, transplanted heart[178] [179] because neuronal reuptake is no longer a factor. The dose of epinephrine usually ranges from 0.05 to 0.50 mug/kg/min. When cardiogenic shock is profound, calcium is often added to an epinephrine infusion to produce synergistic increases in contractility[198] and an increase in vascular tone. This combination, made by adding 1 gm of CaCl2 to 250 ml of intravenous solution containing epinephrine and called "Epi-Cal," has never been subjected to a clinical trial and should be used in resuscitative settings only.

Isoproterenol

Isoproterenol is a full, nonselective beta-agonist that produces powerful positive chronotropic, inotropic, and vasodilator responses. At therapeutic doses, isoproterenol does not bind to the neuronal uptake system (see Table 18-6) . As a therapeutic inotrope, isoproterenol has only one indication--postoperatively after heart transplantation. Isoproterenol is useful in this setting because an increase in heart rate is not a problem in the presence of normal coronary arteries, and the chronotropic stimulation is useful in the newly transplanted heart, which often has a sluggish sinus node mechanism. The pulmonary vasodilator properties of isoproterenol are also useful in this setting, where pulmonary artery pressure and pulmonary vascular resistance are usually elevated. The dose of isoproterenol ranges from 0.005 to 0.05 mug/kg/min. Norepinephrine

As shown in Table 18-6 , norepinephrine is a mildly (10- to 30-fold) beta1 vs. beta2 receptor-selective agonist with relatively high affinity for alpha1 receptors and for uptake 1 . This constellation of properties means that norepinephrine will be a powerful vasoconstrictor, but not a very powerful

579

inotrope in hearts with functioning neuronal uptake. Norepinephrine does not have any recommended uses in subjects with cardiac decompensation; subjects who need peripheral vascular resistance support (such as in sepsis, iatrogenic overvasodilation, or brain injury) are served better by dopamine or dopamine plus phenylephrine administration. Phenylephrine

Phenylephrine is a pure alpha-agonist with no beta-agonist activity and low affinity for uptake1 . Even though alpha1 receptors can mediate a small inotropic response in the human heart, phenylephrine should be used only to increase systemic vascular resistance in settings in which dopamine is not effective. The usual dose of phenylephrine ranges from 0.3 to 3 mug/kg/min. PHOSPHODIESTERASE INHIBITORS MECHANISMS OF ACTION.

As shown in Figure 18-3 , the enzyme phosphodiesterase type III is associated with the

sarcoplasmic reticulum (SR) in human cardiac myocytes[199] and vascular smooth muscle, where it breaks down cAMP into AMP. Type III phosphodiesterase is also found in platelets. It has an SR-anchoring moiety[200] that accounts for its compartmentation in cardiac myocytes and vascular smooth muscle. Elevations in cAMP in the vicinity of the SR can then activate locally compartmentalized[201] protein kinase A, which will phosphorylate phospholamban[197] and relieve this molecule's inhibition of SR function.[203] Thus, specific type III PDEIs, particularly at low doses, may have a relatively selective effect on phospholamban phosphorylation[202] [204] and SR function, which explains why they lower diastolic Ca2+ and increase systolic Ca2+ in cultured cardiac myocytes.[205] This SR-selective effect is probably the reason why highly type III-specific PDEIs increase contractile function without much increase in the heart rate,[206] similar to transgenic mice with phospholamban knockout, which exhibit an increase in contractility without an increase in heart rate.[207] However, PDEIs also increase the calcium channel current,[208] and higher doses increase the phosphorylation of sarcolemmal proteins, similar to beta-agonists.[209] Type III PDEIs are also potent vasodilators, particularly on venous capacitance and pulmonary vascular beds. The vasodilator properties of PDEIs substantially exceed that of beta-agonists,[191] [210] including isoproterenol.[210] The reason for this superior vasodilation appears to be that in vascular smooth muscle, PDEI-induced elevations in cAMP activate protein kinase G,[211] [212] which leads to prominent vasodilation that is not unlike a nitrovasodilator effect in its regional distribution. PDEIs are among the best agents for lowering pulmonary artery pressure and pulmonary vascular resistance, which is why they have assumed an important role in postoperative cardiac surgical regimens, including cardiac transplantation.[213] [214] [215] Type III PDEIs inhibit platelet aggregation[216] [217] and dilate epicardial coronary arteries and bypass grafts,[218] [219] and at least one of them has been shown to have potent antiischemic effects.[220] [221] In addition, type III PDEIs inhibit neointimal formation after vascular injury,[222] [223] and they inhibit proinflammatory cytokine formation[224] and the effects of endotoxin.[225] Thus, type III PDEIs have multiple properties that might prove valuable in the setting of advanced or severe HF. Similar to beta-agonists, a PDEI's inotropic response is blunted in failing versus nonfailing hearts[191] [226] (see Fig. 18-5) . In a failing human heart the reason for blunting of the response to PDEIs is not an alteration in myocardial type III phosphodiesterase,[199] but rather upregulation of the inhibitory G protein Galpha i[227] [228] [230] [229] because a decrease in G leads to augmentation of the PDEI response.[231] alpha i However, when compared with beta-agonists, little or no subsensitivity develops to the inotrope-vasodilator effects of more potent type III PDEIs such as milrinone[232] and enoximone.[190] [233] [234] HEMODYNAMIC EFFECTS.

As discussed above, the substantial preload- and pulmonary artery pressure-reducing properties of PDEIs are both a strength and a weakness of this class of agents, inasmuch as before their acute intravenous administration, it is necessary to be certain of an elevated left ventricular filling pressure. Therefore, in the absence of elevated

right-sided venous pressure in a subject with biventricular failure, pulmonary artery catheter-determined documentation of a pulmonary wedge mean pressure greater than 15 mm Hg is desirable before administering a PDEI intravenously. Otherwise, a precipitous drop in blood pressure may accompany drug administration. PDEIs are absorbed orally, and their attractive hemodynamic profile has led to multiple clinical trials in chronic HF. The increase in cardiac output from PDEIs is preferentially distributed to skeletal muscle,[235] [236] which should theoretically increase maximum exercise responses. Such does appear to be the case.[234] [237] In addition, in a dilated, failing heart, PDEIs have a favorable energetic effect, [238] [239] and PDEIs improve diastolic[240] [241] as well as systolic[242] [243] function. All these observations suggest that PDEIs would be useful in the long-term treatment of chronic HF. CLINICAL EFFECTS.

However, when subjected to placebo-controlled clinical trials, selective type III PDEIs given in doses that produce large hemodynamic effects have increased mortality.[244] [245] [246] Moreover, agents with PDEI activity and K+ channel antagonism (vesnarinone), [247] as well PDEI activity and Ca2+ sensitization (pimobendan),[248] are also associated with increased mortality. The basis for the increase in mortality is increased sudden death,[246] [249] presumably on an arrhythmic basis. Despite these discouraging results, PDEIs continue in development for the treatment of chronic HF via two new approaches. One is a "low-dose" approach[250] that takes advantage of the fact that doses that are one-sixth to one-third those used in earlier clinical trials are hemodynamically active,[251] increase exercise tolerance,[234] do not increase the heart rate, [234] are not proarrhythmic,[234] and apparently do not increase mortality.[190] [234] That a positive inotropic agent can increase mortality at higher doses but be safely given at low doses has been established by the DIG Trial, but it remains to be seen whether the same will be true for PDEIs. The second approach to the safe, long-term use of PDEIs in chronic HF is to combine them with a beta-blocking agent.[252] [253] This combination is possible because the site of action of PDEIs is beyond the beta-adrenergic receptor (see Fig. 18-3) and the combination appears to produce additive efficacy and subtractive adverse effects.[252] Treatment with beta-blocking agents actually enhances the hemodynamic effects of PDEIs[231] [246] [254] because of a beta blocker-related reduction in upregulated Galpha i. [230] One practical consequence of these findings and realizations is that subjects chronically receiving beta-blocking agents who decompensate to the point of needing positive inotropic support should be treated with a PDEI rather than dobutamine or some other beta-agonist. [252] Individual PDEIs available for use or in late-stage development will now be discussed. AMRINONE.

Originally, the mechanism of action of amrinone and its more potent analog milrinone was unkown,[255] then ascribed to a direct effect on Ca 2+ influx,[256] [257] and ultimately attributed to type III phosphodiesterase inhibition.[258] [259] Because amrinone causes

thrombocytopenia[260] and may be associated with rapid subsensitivity in subjects with advanced HF,[261] it is no longer widely used to treat decompensated heart failure.

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MILRINONE.

Unlike amrinone, milrinone does not commonly cause thrombocytopenia.[262] The incidence of thrombocytopenia reported with milrinone use is 0.4 percent.[263] Although milrinone is a highly selective type III PDEI,[258] [259] other actions capable of producing an inotropic effect have been described, including stimulation of the Ca2+ release channel,[264] Ca2+ channel agonism,[257] and effects on sarcolemmal Ca2+ -ATPase.[265] Milrinone produces sustained inotropic and vasodilator effects when administered intravenously.[266] [266A] The elimination half-life is 2.3 hours, and milrinone is usually administered as a 25- to 75-mug/kg bolus over a 10- to 20-minute period, followed by a 0.375- to 0.75-mug/kg/min continuous infusion.[263] Development of oral milrinone has been abandoned because of the increase in mortality in the Prospective Randomized Milrinone Survival Evaluation (PROMISE) Trial,[244] which was conducted at doses that are at least four times higher than the minimum effective hemodynamic dose. [267] Milrinone is mostly (80 percent) excreted by the kidney unchanged, and in renal failure, the continuous-infusion dose should be decreased by 50 percent. ENOXIMONE.*

Enoximone is approved for intravenous use in Europe and is in development in the United States for oral use as both low-dose enoximone alone and in combination with beta1 -selective blockade. Enoximone is a highly selective type III PDEI[268] with no other known pharmacological actions at therapeutic plasma concentrations. Enoximone rarely causes thrombocytopenia and produces sustained hemodynamic effects with intravenous[269] or oral[233] [234] administration. Enoximone is about one-tenth as potent as milrinone for inhibiting type III phosphodiesterase, which translates to oral and intravenous doses of enoximone being approximately 10 times those of milrinone. The intravenous loading dose is 0.25 to 0.75 mg/kg, with the continuous infusion rate being 1.25 to 7.5 mug/kg/min. Enoximone is extensively metabolized by the liver to sulfoxide derivatives, including at least one active metabolite.[270] [271] Sulfoxide metabolites (about 75 percent within 24 hours in HF subjects) are eliminated by the kidney, and dose reductions in renal failure are the same as with milrinone.[272] Enoximone doses should also be reduced in patients with hepatic failure. VESNARINONE AND OTHER QUINOLINONE INOTROPES.*

This class of compounds has recently had members in development in the United

States for advanced, chronic HF in oral (vesnarinone) and intravenous (toborinone) formulations. Vesnarinone is approved for the treatment of HF in Japan. Several unique features about the pharmacology and clinical trial experience are associated with these agents. In human myocardium, therapeutic concentrations of these agents produces phosphodiesterase inhibition and K+ channel (delayed rectifier current) antagonism.[273] This action results in a hemodynamic profile similar to that of enoximone or milrinone, but coupled with type III antiarrhythmic properties. The benefit of this combination is that the heart rate will not be increased and may even decrease slightly in response to treatment, thus providing an energetic advantage.[274] The disadvantage of this combination of properties is that the quinolinone inotropic agents have two potentially proarrhythmic properties, and in fact, torsades de pointes was a frequent adverse event with higher doses of these agents.[275] Evidence has also been presented that members of this class have more potent anti-proinflammatory cytokine properties than other PDEIs do,[276] but such did not prove to be the case when subjected to testing in a large multicenter trial.[277] In the first phase III trial conducted in the United States, vesnarinone lowered the primary endpoint of mortality plus HF hospitalization requiring intravenous inotropic agents by 50 percent and also lowered mortality alone.[278] Unfortunately, this experience could not be repeated in a subsequent mortality trial (Vesnarinone Survival Trial [VEST]) that had longer follow-up.[247] VEST demonstrated that vesnarinone produced small, but dose-related increases in mortality at 30 mg (by 11 percent) and 60 mg (by 21 percent) orally daily.[247] After these results, vesnarinone's development in the United States was discontinued. The fact that two consecutive HF trials can result in diametrically opposite effects on mortality with the same drug dose (60 mg/d) highlights the vagaries of HF clinical trials, where patient selection, subtle details of ancillary treatment, length of follow-up, and other factors can greatly influence results. PHOSPHODIESTERASE INHIBITORS WITH CALCIUM SENSITIZER ACTIVITY

These positive inotropic agents act in part by increasing the sensitivity of troponin C or some other part of the myofibrillar Ca 2+ -binding apparatus to ionized calcium. This property alone would prolong contraction time and decrease diastolic function, which would not be desirable in an inotropic agent. However, all agents that have gone on to clinical development are also PDEIs, and this property will "cancel" the increased contraction time and provide favorable effects on diastolic function.[279] Under these circumstances, the advantage of calcium sensitization is that the pharmacological effect of the drug does not rely on increasing systolic calcium concentrations, although this action will occur if the compound also has PDEI activity. Another advantage would be in not increasing the heart rate, but again, PDEI activity would lead to a chronotropic effect at higher doses. The combination of not increasing intracellular Ca2+ or the heart rate would confer an energetic advantage to Ca2+ sensitizers. The mixed-action Ca2+ sensitizers levosimendan and pimobendan have undergone the most clinical experience, and their hemodynamic profile,[280] [281] including increasing the heart rate at higher doses, does not differ from that of milrinone and enoximone. This similarity occurs because, as discussed below, the dominant pharmacological action of

both compounds is type III phosphodiesterase inhibition. PIMOBENDAN.*

Pimobendan is available in oral form for the treatment of HF only in Japan. Pimobendan has weak Ca2+ -sensitizing properties through facilitating the interaction of Ca2+ with troponin C,[282] but its major mechanism of action is phosphodiesterase inhibition.[283] In several medium-sized trials, pimobendan increased exercise performance and/or improved quality of life,[284] [285] [286] but its development in the Unites States and Europe was put on hold when a strong trend (relative risk 1.8, confidence interval 0.9 to 3.5) toward an increase in mortality was noted in the Pimobendan in Congestive Heart Failure (PICO) Trial, which was conducted in subjects with mild to moderate HF.[248] LEVOSIMENDAN.*

Levosimendan was discovered as part of a screening strategy for identifying compounds that bind to a troponin C affinity column,[287] and levosimendan does bind to free troponin C.[288] However, recent data indicate that levosimendan does not bind to the human troponin C-troponin I complex,[289] which is the natural state of the regulatory thin filament proteins. Pharmacological studies clearly demonstrate that levosimendan is a potent (IC50 of 25 nM) and specific type III PDEI. [290] In model systems, the positive inotropic effects of levosimendan have been shown to be exclusively via phosphodiesterase inhibition[289] or through a combination of phosphodiesterase inhibition and calcium sensitization.[291] [292] In human ventricular myocardium, one study has found evidence of calcium sensitization at smaller inotropic effects of levosimendan, with evidence of positive inotropy via phosphodiesterase inhibition for larger increases in inotropic response.[293] However, another study in isolated human ventricular myocardium found no evidence of calcium sensitization for an inotropic effect that was associated with phosphodiesterase inhibition.[294] Finally, very recent work in isolated human heart preparations has demonstrated that levosimendan stimulates L-type Ca2+ current at low concentrations (10 nM), which indicates that it is acting as a type III PDEI at concentrations that produce positive inotropic effects.[295] Thus, without question, levosimendan is a potent and selective type III PDEI, but it is not clear whether calcium sensitization is contributing to its inotropic action in the human heart. Levosimendan is a potent vasodilator that also increases heart rate at higher doses.[296] While these effects may well be due to phosphodiesterase inhibition, levosimendan has also recently been found at somewhat higher concentrations than those that produce phosphodiesterase inhibition to activate vascular smooth muscle ATP-sensitive K+ channels [297] in a manner similar to cromakalim, nicorandil, or diazoxide. These effects also occur in the heart,[298] which appeared to explain why levosimendan reduced infarct size in a dog model.[299] However, other studies of levosimendan's vasodilator effects have not found evidence for ATP-sensitive K+ channel activity while demonstrating phosphodiesterase inhibition, [300] and in human cardiac cells, activation of ATP-sensitive K+ channels by levosimendan occurs at substantially higher concentrations (10 muM)

than therapeutic concentrations ( 20 nM).[295] In addition, other PDEIs have reduced infarct size in model systems,[301] and a direct comparison of levosimendan to milrinone and amrinone in an infarct rabbit model found no difference in the antiischemic effects of the three agents.[302] Thus, ATP-sensitive K+ channel activation, the newest addition to the pharmacological profile of levosimendan, is an unproved candidate for the mechanism of vasodilation and for protection against ischemic damage. Since it is not operative in the human heart at therapeutic concentrations, it is unlikely that this mechanism will provide cardioprotection from ischemic injury. Levosimendan is in clinical development in both oral and intravenous forms. In intravenous form, levosimendan has been evaluated in two clinical trials that have been presented at national meetings but not yet published. In an acute myocardial infarction study conducted in Russia, levosimendan was randomized against placebo, and not surprisingly, the positive inotropic agent produced better circulatory support.[303] In another study where approximately 40 percent of the subjects were taking beta blockers, levosimendan performed better than dobutamine in hemodynamic response.[304] This result is also expected *Not approved by the FDA.

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since by virtue of their respective sites of action, beta blockade would inhibit the response to dobutamine but not to levosimendan. These studies do not provide evidence that levosimendan is superior to other PDEI-positive inotropic agents currently available in intravenous form. CALCIUM SENSITIZERS

Some compounds are in development whose principal or dominant action is calcium sensitization, and they may have potential as positive inotropic agents, provided that diastolic function is not adversely affected and that vasoconstriction is not part of their pharmacological profile. One such compound is CGP 48506,[294] and another is EMD 57033.[305] EMD 57033 is the (+) enantiomer of EMD 53998, a racemic thiadiazinone compound whose other, (-) isomer (EMD 57439) is a pure type III PDEI.[305] In model systems, EMD 57033 increases systolic function without affecting blood pressure or the heart rate, which are respectively decreased and increased by EMD 57439.[305] Moreover, EMD 57033 binds to the human troponin I-troponin C complex.[289] The problem is that EMD 57033 causes diastolic dysfunction in human ventricular myocardium, with failing hearts much more adversely affected than nonfailing hearts.[306] Moreover, the racemic compound EMD 53998, even though it contains the phosphodiesterase III enantiomer, causes diastolic dysfunction that becomes more pronounced in ischemia.[307] However, some evidence indicates that the calcium sensitizer CGP 48506 does not inhibit relaxation.[308] Thus, it is unclear whether pure calcium sensitizers will have a therapeutic role as positive inotropic agents.




Neurohormonal Cytokine Inhibitors Without question, the greatest advance in the treatment of chronic HF has been the application of agents that inhibit harmful neurohormonal systems that are activated to support the failing heart (see Chaps. 16 and 21) . This generally useful paradigm had multiple origins, including work done by the Minnesota group in the late 1970s and early 1980s that documented the nature and extent of neurohormonal activation in chronic HF,[309] [310] the association of systemic neurohormonal activation with adverse outcomes,[311] [312] observations in the failing human heart that excessive adrenergic activation produces harmful biological effects,[164] [313] and astute clinical observations regarding the degree of improvement effected by inhibitors of the adrenergic[314] [315] [316] and renin-angiotensin[317] [318] [319] systems. By the mid to late 1980s, influential commentaries on the validity of the "neurohormonal hypothesis" were being articulated,[309] [320] [321] [322] and all these developments ultimately culminated in the performance of large-scale clinical trials that demonstrated that inhibition of the renin-angiotensin[323] [324] and adrenergic[325] [326] [327] [328] [329] systems improved the natural history of chronic HF caused by a dilated cardiomyopathy (primary or secondary) phenotype. The success with inhibition of the adrenergic and renin-angiotensin systems has led to extension of the general paradigm to other neurohormonal or cytokine systems that promote growth and remodeling in the failing heart, such as endothelin antagonists and inhibitors of tumor necrosis factor-alpha (TNF-alpha). The general mechanisms by which neurohormonal activation worsens and neurohormonal inhibition improves the natural history of myocardial dysfunction and remodeling are discussed in Chapter 21 . In essence, multiple neurohormonal signaling pathways, such as beta1 -, beta2 -, and alpha1 -adrenergic receptor,[177] angiotensin II AT1 receptor,[330] endothelin-1 ETA receptor,[331] and TNF-alpha receptor pathways,[332] are activated in the failing heart and promote maladaptive growth, remodeling, and

progressive myocardial dysfunction.[108] Inhibition of these systems prevents or reverses these adverse biological processes, thereby leading to improvement in the natural history of HF. Therapy targeting individual neurohormonal or cytokine systems will now be discussed. INHIBITORS OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (See also Chap. 29) Angiotensin-Converting Enzyme Inhibitors

ACE inhibitors were the first consistent and substantial success story for medical therapy to improve the natural history of chronic HF, and this class of neurohormonal inhibitors remains a mainstay in HF treatment. ACE inhibitors were originally developed within the vasodilator paradigm,[317] but when their clinical results proved to be out of proportion to their relatively weak vasodilator effects (see Table 18-3) , it became apparent that another mechanism was operative. That mechanism, as elucidated by the Pfeffers' laboratory in elegant studies in myocardial infarction animal models[333] [334] and humans[318] [319] and then confirmed in chronic HF,[335] is the prevention of angiotensin II-mediated remodeling.[108] MECHANISMS OF ACTION.

Figure 18-5 shows the pathways for angiotensin II formation, which occurs systemically as well as locally in cardiac and vascular tissue. Note that generation of angiotensin II is accomplished by two pathways, one that uses converting enzyme found in high abundance in endothelium and one that uses the protease chymase, which is found in interstitial cells. Transmyocardial studies in the intact human heart have indicated that greater than 80 percent of the generation of angiotensin II is via the ACE pathway,[336] but studies in isolated human heart preparations[337] and in model systems[338] have emphasized the contribution of the chymase pathway. If the chymase pathway is important in producing ventricular remodeling in the failing heart, angiotensin receptor-blocking agents (ARBs) would be more effective than ACE inhibitors in decreasing angiotensin II signaling. If, on the other hand, ACE inhibitors are just as effective clinically as ARBs, by inference, the ACE pathway is the dominant mechanism for generating angiotensin II in the failing heart. Finally, if ACE inhibitors are superior to ARBs, additional properties of

Figure 18-5 Pathways of angiotensin II formation. ACE=angiotensin-converting enzyme; Ang-1=angiotensin I; AT 1 R=angiotensin II type 1 receptor; NE=norepinephrine.

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TABLE 18-7 -- BIOLOGICAL RESPONSES MEDIATED BY ANGIOTENSIN II RECEPTORS IN THE HUMAN CARDIOVASCULAR SYSTEM BIOLOGICAL RESPONSE RECEPTOR MEDIATION Cardiac myocyte growth

AT1

Positive inotropic response (minimal)

AT1

Myocyte apoptosis

AT1 , AT2

Aldosterone release

AT1

Norepinephrine release

AT1

Cardiac myocyte toxicity

Beta-adrenergic via norepinephrine release

Fibroblast proliferation

AT1

Smooth muscle proliferation

AT1

Vasoconstriction

AT1

ACE inhibitors, such as increasing bradykinin,[339] are presumably responsible. Based on the results of the Evaluation of Losartan in the Elderly Study II (ELITE-II, see below), at present it would seem that the ACE pathway is the predominant means of generating angiotensin II in the human heart and that enhancement of bradykinin levels may well be important. Studies in the failing human heart indicate that ACE gene[340] [341] and protein[341] expression and enzyme activity [336] [341] are increased, but chymase gene expression is not.[340] Systemically increased renin is taken up by failing human ventricles in larger amounts than by nonfailing ventricles,[342] and failing human hearts also exhibit lower angiotensinogen protein levels compatible with substrate depletion.[342] Finally, angiotensin II type 1 (AT1 ) receptors are selectively downregulated in the failing human heart at the protein[343] and mRNA[344] levels, probably as a result of increased exposure to angiotensin II. These data indicate that the local myocardial renin-augiotensin system (RAS) is induced in the failing human heart, which adds to the increased systemic activation. No such induction seems to occur with the chymase system. As shown in Table 18-7 , increased levels of angiotensin II have several adverse effects on the cardiovascular system, including cardiac myocyte hypertrophy, myocyte apoptosis, presynaptic facilitation of norepinephrine release, and mitogenic effects on fibroblasts. Most, if not all of these effects are mediated via the AT1 subtype. In addition, most of these biological effects of angiotensin II contribute to the development of hypertrophy and remodeling. CLINICAL OBSERVATIONS.

Two types of studies demonstrate the consistent efficacy of ACE inhibitors in HF: post-myocardial infarction studies and clinical trials in chronic HF. As shown in Table

18-8 , more of the former studies than the latter have been conducted. All placebo-controlled chronic HF trials, with the exception of the "asymptomatic" Studies of Left Ventricular Dysfunction (SOLVD) Prevention Study,[345] demonstrated a reduction in mortality. As can be observed in Table 18-8 , the Class IV Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS I) had a much larger effect size than did the SOLVD Treatment Trial (Fig. 18-6) , which in turn had a larger effect size than the SOLVD Prevention Trial did. Although only these three placebo-controlled mortality trials have been conducted in patients with chronic HF, it seems obvious that ACE inhibitors reduce mortality in direct relation to the degree of severity of chronic HF. Although not placebo controlled, the V-HeFT-II Trial provided evidence that ACE inhibitors improve the natural history of HF through mechanisms other than vasodilation, inasmuch as subjects treated with enalapril had significantly lower mortality than did subjects treated with the nonneurohormonal inhibitor-vasodilator combination of hydralazine plus isosorbide dinitrate.[103] Although only one ACE inhibitor, enalapril, has been used in placebo-controlled mortality trials in chronic HF, as can be observed in Table 18-8 , multiple ACE inhibitors have proved to be more or less equally effective when administered in oral form within the first week of the ischemic event in post-myocardial infarction trials. [346] [347] [348] This observation leads to the conclusion that the effects of ACE inhibition on the natural history of chronic HF or post-myocardial infarction left ventricular dysfunction are class effects. In summary, an ACE inhibitor is considered mandatory treatment in chronic HF or in asymptomatic left ventricular systolic dysfunction. The doses employed should be at least the average dose used to lower mortality in heart failure or post-myocardial infarction trials. The only consistent adverse effect noted with ACE inhibitors is a low-level (5 percent greater than placebo) increase in cough. In such patients, an angiotensin II AT1 receptor-blocking agent can be substituted. Aldosterone Antagonists

It has been shown in numerous studies that ACE inhibitors do not completely inhibit tissue-based RAS systems[349] [350] [350A] and that after several months of treatment, "escape" can TABLE 18-8 -- COMPARISON OF CRUDE, ANNUALIZED MORTALITY RATES IN ANGIOTENSIN-CONVERTING ENZYME INHIBITOR TRIALS* TRIAL NAME AGENT NYHA SUBJECTS 12-MO 12-MO PVALUE AT CLASS ENROLLED PLACEBO EFFECT 12 MO (FULL (N) MORTALITY SIZE FOLLOW-UP) (%) (%) Chronic Heart Failure CONSENSUS-I[323] Enalapril

IV

253

52

0.01 (0.003) 31

SOLVD-Rx[324]

Enalapril

I-III

2569

15

0.02 (0.004) 21

SOLVD-Asx[345]

Enalapril

Totals

I, II

4228

5

I-IV

7050

11

0

0.82 (0.30) 0.02

16 Post-Myocardial Infarction SAVE[346]

Captopril

--

2231

12

0.11 (0.02) 18

AIRE[347]

Ramipril

--

1986

20

0.01 (0.002) 22

TRACE[348]

Trandolapril --

1749

26

0.046 (0.001) 16

Totals

5966

19

0.001 18

AIRE=Acute Infarction Ramipril Efficacy; CONSENSUS=Cooperative North Scandinavian Enalapril Survival Study; SAVE=Survival and Ventricular Enlargement; SOLVD=Studies of Left Ventricular Dysfunction; SOLVD-Asx=SOLVD Asymptomatic LV Dysfunction Trial; SOLVD-Rx=SOLVD Treatment Trial; TRACE=Trandolapril Cardiac Evaluation. *The trials were conducted in post-myocardial infarction or chronic heart failure subjects, with 12-month mortality rates taken from survival curves when data were not directly available in published material.

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Figure 18-6 Cumulative probability of death in the placebo and enalapril groups in the CONSENSUS Trial (A) and in the SOLVD Trial (B). (From Smith TW, Kelly RA, Stevenson LW, Braunwald E: Management of heart failure. In Braunwald E (ed): Heart Disease, 5th ed. Philadelphia, WB Saunders, 1997, pp 492-514. A, Modified from CONSENSUS Trial Study Group: Effects of enalapril on mortality in severe congestive heart failure; results of the Cooperative North Scandinavian Enalapril Survival Study [CONSENSUS]. N Engl J Med 316:1429, 1987. B, Modified from SOLVD Investigators: Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 325:293, 1991.)

occur with an increase in systemic angiotensin II[351] or aldosterone[352] levels. These observations set the stage for additional RAS inhibitor strategies, and one of them was addition of the competitive nanomolar-affinity aldosterone antagonist spironolactone[18] to ACE inhibitor therapy. This combination was used in the Randomized Aldactone Evaluation Study (RALES) Trial, which evaluated the addition of 25 mg of spironolactone vs. placebo to standard HF therapy

Figure 18-7 Results of the RALES Trial. (Reprinted, by permission, from Pitt B, Zannad F, Remme WJ, et al: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 341:709-717, 1999.)

in stage C (New York Heart Association [NYHA] Class III or IV) patients, with a primary endpoint of all-cause mortality.[23] As can be observed in Figure 18-7 , in RALES, spironolactone produced a 31 percent reduction in total mortality when compared with placebo (p=0.001). The beneficial effect of spironolactone appeared to be on both sudden and pump failure deaths. Although the mechanism behind the benefit of spironolactone has not been elucidated, prevention of extracellular matrix remodeling[353] and/or prevention of increasing potassium levels are leading contenders. In RALES, serum potassium levels were 0.3 mEq/liter higher in the spironolactone group than in the placebo group (p=0.001), [23] which could have played a major role in reducing sudden or even pump failure deaths. Although spironolactone was well tolerated in RALES, it is associated with a small incidence of gynecomastia, which may lead to discontinuation. Some newer-generation aldosterone antagonists have a much lower incidence of this adverse effect, and one of them, eplerenone, is currently being evaluated in a large-scale post-myocardial infarction clinical trial. Angiotensin II AT1 Receptor-Blocking Agents

Six angiotensin receptor blockers (ARBs) approved for the treatment of hypertension are now on the market in the United States. However, none of them has received approval for the treatment of HF. The rationale for the use of these agents is derived from information presented in Table 18-7 , which is that virtually all the adverse biological effects relevant to a failing, remodeled heart are mediated by the AT1 receptor. Moreover, ARBs antagonize the effects of

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angiotensin II regardless of its origin (via the ACE or chymase pathway). All these compounds are selective, high-affinity antagonists of AT1 receptors. Hemodynamic studies and studies with ARBs in HF have demonstrated effects that are similar to those of ACE inhibitors; that is, these agents reduce pulmonary wedge and pulmonary artery pressure moderately, are mild preload reducers, and increase cardiac output.[354] [355] [356] The heart rate is not affected unless baroreflexes are excessively activated by hypotension. Maximum exercise time is also improved to a similar degree with each type of RAS inhibitor.[356A] [357] [358]

Clinical trial data on ARBs are emerging, but the results thus far are limited and mixed. The initial comparison of an ARB (losartan) to an ACE inhibitor (captopril) was in ELITE (or ELITE-I); no difference in the primary endpoint of renal function was found in an elderly HF population, but unexpectedly, a 46 percent reduction in mortality (p=0.035) was noted in losartan-treated patients.[359] These results led to a mortality trial, ELITE-II, to test the hypothesis that losartan reduces mortality in comparison to captopril-treated patients. The results of ELITE-II are not consistent with ELITE-I in that losartan tended to increase mortality when compared with captopril.[359A] At this juncture, there is no reason to believe that ARBs will prove superior to ACE inhibitors in patients with HF, with the exception of the side effect of cough (4 percent with captopril, 0 percent with losartan in ELITE-I).[359] Moreover, based on bradykinin enhancement by ACE inhibitors, it is possible that ARBs will, in fact, be inferior to ACE inhibitors. The future of ARB treatment in chronic HF would appear to be in combination with ACE inhibitors (and potentially spironolactone) to provide more complete inhibition of the RAAS. This view is supported by the observation that the combination of an ACE inhibitor and an ARB produces additive hemodynamic effects.[360] [361] Recently reported clinical trial data also support this concept. The Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) Trial[362] compared enalapril, the ARB candesartan, and a combination of the two for their effects on remodeling and clinical parameters. In this trial, the combination of an ACE inhibitor plus an ARB produced the greatest degree of inhibition of remodeling.[362] Other studies investigating the combination of an ACE inhibitor and an ARB that have clinical primary endpoints (such as the Valsartan in Heart Failure Trial[363] [Val-HeFT]) are under way, and they will yield a definitive answer regarding ARBs in combination with ACE inhibitors. For the time being, recommendations for the use of ARBs in chronic HF are limited to patients who are ACE inhibitor intolerant, particularly those with an ACE inhibitor-induced cough. ANTIADRENERGIC AGENTS Beta-Adrenegic Receptor-Blocking Agents (See also Chap. 37)

The failing human heart is adrenergically activated[364] [365] to maintain cardiac performance over the short term by increasing contractility[366] and heart rate. In contrast, in the resting state, no adrenergic support occurs in normally functioning human left ventricles.[366] Multiple lines of evidence[367] [368] [369] indicate that it is increased cardiac adrenergic drive rather than an increase in circulating norepinephrine that is both initially supportive and then ultimately damaging to the failing human heart. BETA-ADRENERGIC RECEPTORS.

As shown in Table 18-9 , human cardiac myocytes have three adrenergic receptors (beta1 , beta2 , and alpha1 ) that are coupled to a positive

TABLE 18-9 -- BIOLOGICAL RESPONSES MEDIATED BY ADRENERGIC RECEPTORS IN THE HUMAN HEART BIOLOGICAL RESPONSE ADRENERGIC RECEPTOR MEDIATION Cardiac myocyte growth

beta1 , beta2 , alpha1

Positive inotropic response

beta1 , beta2 , alpha1 (minimal)

Positive chronotropic response

beta1 , beta2

Myocyte toxicity

beta1 , beta2 (?90 percent of the total) or Class IV symptoms, the annualized placebo mortality was only 13.2 percent[328] (Table 18-11) . This mortality rate is similar to that found in the enalapril arm of the SOLVD Treatment Trial,[324] which was composed of 68 percent Class I and II patients. In addition, the average blood pressure of patients enrolled in CIBIS-II was 130/80, which is higher than the blood pressures of the SOLVD patients[324] or the patients enrolled in the U.S. Carvedilol Trials, who were approximately 50/50 Class II/III.[326] A relatively large proportion of CIBIS-II patients were enrolled in Eastern Europe and Russia, where practice patterns, HF etiology, or symptom interpretation may not be comparable to that in Western Europe and the United States. Nevertheless, the results of CIBIS-II were internally consistent through all major demographic groups,[328] and the impressive results constitute a landmark clinical trial in the development of beta blockade as therapy for chronic HF. Carvedilol

As may be noted in Table 18-10 , carvedilol is a minimally beta1 receptor-selective beta-blocking agent that also has high affinity for alpha1 receptors and antioxidant action.[406A] Because carvedilol is a potent vasodilator, its side effect profile on initiation of therapy and during uptitration is different from that of highly beta 1 -selective second-generation agents, with orthostatic symptoms being more prominent.[397] At low doses ( 6.25 mg twice daily) carvedilol may exhibit some beta1 selectivity in humans with HF. [407] At higher target doses, carvedilol blocks all three adrenergic receptors coupled to hypertrophy and other adverse biological effects (see Table 18-9) that contribute to remodeling and myocardial dysfunction in the failing human heart. The idea that a comprehensive antiadrenergic profile is desirable is supported by the results of the Multicenter Oral Carvedilol Heart Failure Assessment (MOCHA) Trial, which demonstrated left ventricular functional and clinical superiority of 25 mg carvedilol twice daily over 6.25 mg twice daily.[327] In addition, because it blocks presynaptic beta2 receptors, carvedilol mildly reduces cardiac adrenergic drive.[408] Because of its potent, comprehensive antiadrenergic action, the beneficial effects of carvedilol on myocardial function and reversal of remodeling tend to be greater than for beta1 -selective compounds.[408] [409] [410] [411] [412] [412A] [412B] However, it is not yet clear whether this superiority translates into better clinical results in view of the excellent results of beta1 -selective compounds in the MERIT-HF[329] and CIBIS-II[328] trials. The answer to this question will be given by the outcome of the Carvedilol and Metroprolol European Trial (COMET) which is comparing the effects of metoprolol and carvedilol on all-cause mortality. Carvedilol is currently the only beta blocker approved for the treatment of chronic HF in the United States, and it is also approved in most other countries. The controlled clinical

trial data base for carvedilol is extensive. To date, 1748 patients have been enrolled in eight randomized, placebo-controlled phase II and III clinical trials with carvedilol. [326] [327] [413] [414] [415] [416] [417] [418] [419] [420] Although data on carvedilol are not yet

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TABLE 18-11 -- COMPARISON OF CRUDE, ANNUALIZED MORTALITY RATES IN ANGIOTENSIN-CONVERTING ENZYME INHIBITOR AND BETA BLOCKER TRIALS CONDUCTED IN CHRONIC HEART FAILURE* TRIAL NAME AGENT NYHA HEART SUBJECTS 12-MO 12-MO CLASS FAILURE ENROLLED PLACEBO EFFECT STAGE,A-D (N) MORTALITY SIZE(%) (%) Angiotensin-Converting Enzyme Inhibitors CONSENSUS-I[323] Enalapril

IV

D

253

52 31

SOLVD-Rx[324]

Enalapril

I-III

B

2569

15 21

SOLVD-Asx[325]

Enalapril

Totals

I, II

A

I-IV

4228

5

7050

11

0 16

Beta Blockers Stage B patient populations CIBIS-I[406]

Bisoprolol III, IV

B

641

11 20

[326]

Carvedilol U.S.

Carvedilol II, III

B

1094

10 66

[328]

CIBIS-II

Bisoprolol III, IV

B

2647

13 33

[329]

MERIT-HF

Metoprolol II-IV CR

B

3991

11 35

Stage C patient population BEST[424]

Bucindolol III, IV

C

2708

17 10

Totals

II-IV

11,081

13 30

Combined mortality reduction

18,131

12 41

BEST=beta-Blocker Evaluation Survival Trial; CIBIS=Cardiac Insufficiency Bisoprolol Study; CONSENSUS=Cooperative North Scandinavian Enalapril Survival Study; CR=continuous release; MERIT-HF=Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure; SOLVD=Studies of Left Ventricular Function; SOLVD-Asx=SOLVD Asymptomatic LV Dysfunction Trial; SOLVD-Rx=SOLVD Treatment Trial. *Twelve-month mortality rates were taken from survival curves when data were not directly available in published material. See Chapter 21 . Effect size at 2 years.

available from prospectively designed placebo-controlled mortality trials (one such trial, the Carvedilol Prospective Randomized Cumulative Survival Trial (COPERNICUS), is in progress), the phase III U.S. Carvedilol Trials Program was stopped prematurely by the Data and Safety Committee monitoring all four trials because of a highly significant (p < 0.0001) 65 percent reduction in mortality by carvedilol versus placebo.[326] In addition, one individual trial (MOCHA) demonstrated a highly statistically significant 73 percent reduction in mortality.[327] However, because these trials were relatively short-term and the number of events was small, the data from MOCHA or the rest of the U.S. Carvedilol Trials Program were not considered by the FDA to be conclusive for an indication of mortality reduction. Carvedilol has been approved by the FDA for delaying progression of the myocardial disease process and lowering the combined risk of morbidity plus mortality.[421] Approval was based on (1) results from the "Mild" HF trial,[417] which demonstrated that carvedilol reduced the probability of development of the combined endpoint of mortality, cardiovascular hospitalization, or an increase in associated HF medical treatment when compared with placebo, and (2) grouped analysis of all four U.S. trials[327] [416] [417] [418] and one conducted in Australia-New Zealand[420] in which carvedilol reduced the combined endpoint of mortality or cardiovascular hospitalization. To date, all the reported trials demonstrating unequivocal efficacy with carvedilol have been in stage A (asymptomatic to mild symptoms) or B (mild to moderate symptoms) HF. The two trials conducted in more advanced HF either had too many subjects eliminated up-front by carvedilol challenge[415] or were too small to reach conclusions.[418] The COPERNICUS mortality trial is investigating Class III to IV (stage C) HF, and this trial plus the Beta-Blocker Evaluation Survival Trial (BEST, see below) will provide the answer to whether beta blockers are indicated in patients with more advanced HF. BUCINDOLOL

Bucindolol is a completely nonselective third-generation beta-blocking agent with mild vasodilator activity that is probably due to weak alpha1 receptor-blocking properties.[177] The mild vasodilator properties of bucindolol coupled with its low "inverse-agonist" profile[177] [422] [423] make this beta blocker extremely well tolerated in HF subjects,[397] including those with advanced HF.[424] Inverse agonism is the ability of a receptor antagonist to inactivate "active-state" receptors that are precoupled to G proteins and

capable of transducing signals without agonist occupancy.[163] In the human heart, the percentage of such precoupled beta-adrenergic receptors identified by high-affinity agonist binding is on the order of 10 to 30 percent of the total. Antagonists such as metoprolol and to a lesser extent carvedilol have a greater ability than bucindolol to inactivate these active-state receptors, which is probably why bucindolol is associated with less intrinsic myocardial depression and lowers 24-hour Holter-monitored heart rates less than metoprolol or carvedilol does.[399] The latter property translates into less symptomatic bradycardia with bucindolol, which is why the BEST Trial had a much lower heart rate exclusion criterion (50 beats/min)[425] than other beta blocker HF trials did (typically 68 beats/min). Thus, a low inverse-agonist profile is a property that increases the tolerability of a beta blocker in subjects with HF. Although bucindolol has intrinsic sympathomimetic activity in some smaller animal species,[426] [427] because of differences in the stoichiometry of receptor-G protein coupling between animal models and humans, bucindolol has no intrinsic sympathomimetic activity in failing[315] [399] [428] [429] or nonfailing[430] human hearts. Finally, because of its potent beta2 receptor-blocking properties coupled with only mild vasodilation, bucindolol is the only beta-blocking agent that has been shown to lower systemic adrenergic activity in subjects with HF.[315] [424] Thus, the unique pharmacological profile of bucindolol allows an agent with comprehensive antiadrenergic activity to be given to patients with advanced, stage C HF.[424] [425] CLINICAL OBSERVATIONS.

The third-generation nonselective compound bucindolol was the first beta-blocking agent shown to improve left ventricular function in a placebo-controlled trial,[315] and it was the first beta-blocking agent shown to improve load-independent, intrinsic systolic function.[316] In those[315] and subsequent phase II trials, [431] [432] bucindolol was well tolerated, in marked contrast to previous[433] [434] and subsequent[435] experience with the nonselective first-generation agent propranolol. Bucindolol was the second beta-blocking agent to be evaluated in a multicenter trial in which bucindolol produced a dose-related improvement in left ventricular function and a dose-unrelated prevention of deterioration in left ventricular function in subjects with symptomatic ischemic and nonischemic cardiomyopathy treated for a 12-week period.[432] Based on these data, doses of bucindolol with very high degrees of beta blockade[432] (100 mg twice daily for subjects heavier than 75 kg, 50 mg twice daily for subjects less than 75 kg) were chosen for use in phase III trials. THE BEST TRIAL.

The largest of these phase III trials, the recently completed BEST Trial[419] randomized 2708 subjects with advanced (Class III and IV) HF to placebo or bucindolol. As can be observed by the 12-month placebo mortality rates in Table 18-11 , the BEST Trial was conducted in subjects with much more advanced HF than the subjects enrolled in other beta blocker trials where mortality was reported. A 12-month mortality of 17 percent was observed in comparison

589

to 10 percent for the U.S. Carvedilol Trials, for example. Note in Table 18-11 that the CIBIS-II Trial, which purported to enroll subjects with NYHA Class III or IV symptoms, had a 12-month placebo mortality that is substantially less than that in BEST, which had internal controls to ensure that subjects with advanced HF were being enrolled. In the BEST subject population as a whole, bucindolol produced a statistically nonsignificant (p=0.10), 10 percent reduction in total mortality that was heterogeneous with respect to race.[424] That is, the 76 percent of subjects in BEST who were not black had a statistically significant (p=0.01), 19 percent reduction in mortality, whereas the 24 percent who were black had a nonsignificant trend for an increase (by 17 percent) in mortality (interaction p value 5.0 mg/dl Chronic lung disease Chronic liver disease Metastatic cancer Systemic sepsis Neurological deficit Technically incomplete cardiac operative procedure (if postcardiotomy cardiogenic shock) Age >65 yr (if bridge to transplant) of patients with cardiovascular disease. In 1993, nearly 100,000 IABs were inserted in the United States alone.[14] The dawn of complete, clinical mechanical circulatory support occurred on May 6, 1953, when Gibbon successfully closed a secundum atrial septal defect in a patient supported with cardiopulmonary bypass.[15] The majority of patients with ventricular dysfunction, however, do not require pulmonary support with an in-line oxygenator. Roller pump left ventricular assistance using atrial transseptal uptake and femoral arterial return was

introduced by Dennis and colleagues in 1962.[16] Subsequently, DeBakey successfully employed left atrial to aortic bypass in patients who could not be weaned from cardiopulmonary bypass.[17] By the late 1970s, a variety of intracorporeal and extracorporeal mechanical blood pumps were being tested for both "support to weaning"[18] and "bridge to transplant"[19] indications. Patient selection and hemodynamic criteria were developed, and cannulation techniques, blood-biomaterial interactions, and control strategies were evaluated. During the 1980s, patient management techniques were refined and clinical results improved. Advances in myocardial preservation resulted in fewer blood pumps being required for postcardiotomy cardiogenic shock. However, a disparity in the ratio of cardiac donors to recipients increased the need for long-term circulatory support in patients requiring a bridge to cardiac transplantation. Results in this patient population proved gratifying, with survival statistics approaching those achieved with conventional cardiac transplantation.[20] The 1990s saw research efforts focus on the development of implantable VADs suitable for permanent implantation in patients with end-stage cardiomyopathy. While IAB and VAD development were in their infancy, investigators also initiated laboratory efforts to develop a cardiac replacement device. In 1958, Akutsu and Kolff described an experiment in which a pneumatic TAH was implanted in a dog.[21] By the mid 1960s, Nose and coworkers had achieved 24-hour survival with sac-type hearts implanted in calves.[22] By the end of the decade survival times approached 3 to 5 days.[23] Experimental animals with TAHs have now lived for up to 1 year. The TAH entered the clinical arena in 1969 when Cooley and associates introduced the concept of staged cardiac replacement.[24] Joyce and coworkers were the first to implant a TAH as a permanent cardiac replacement.[25] INTRAAORTIC BALLOON COUNTERPULSATION The design and function of the IAB has not changed substantially during the past three decades. The IAB is an intravascular, catheter-mounted, counterpulsation device with a balloon volume between 30 and 50 ml. A central lumen allows passage of the balloon catheter over a small diameter guidewire and subsequent monitoring of central blood pressure. The IAB is attached to a small bedside console and timed to the patient's arterial pressure curve or electrocardiogram. The shuttle gas is helium, as its viscosity allows rapid balloon inflation and deflation, which facilitates counterpulsation in patients with tachyarrhythmias. The IAB is positioned in the descending thoracic aorta and set to inflate at the dicrotic notch of the arterial pressure waveform when monitoring the aortic pressure (Fig. 19-1) . The diastolic rise in aortic root pressure augments coronary blood flow and myocardial oxygen supply. The increase in systemic perfusion may be less than 0.5 liter/min. The IAB is deflated during the isovolumetric phase of left ventricular contraction. The reduction in the afterload component of cardiac work decreases peak left ventricular pressure and myocardial oxygen consumption. The net effect is a favorable shift in the myocardial oxygen supply/demand ratio, with a small increase in systemic perfusion. Indications and Results of Clinical Use

Traditional indications for IAB counterpulsation include refractory cardiogenic shock after cardiac surgery or acute myocardial infarction (Table 19-3) . The latter indication includes patients suffering from primary pump failure in addition to those with mechanical complications, such as acute mitral regurgitation or a postinfarction ventricular septal defect. Five to 10 percent of patients who suffer an acute myocardial infarction develop cardiogenic shock.[26] Seventy-five percent of patients with an acute myocardial infarction who develop cardiogenic shock not amenable to conventional medical therapy will improve hemodynamically with IAB

Figure 19-1 The intraaortic balloon is inserted through the common femoral artery and positioned in the descending thoracic aorta. The tip is located just distal to the left subclavian artery. The balloon is inflated during cardiac diastole thereby increasing coronary artery perfusion (A). Left ventricular afterload is decreased as the balloon is deflated during cardiac systole (B). Proper balloon timing improves the ratio between myocardial oxygen supply and demand. (From Richenbacher WE: Intraaortic balloon counterpulsation. In Richenbacher WE [ed]: Mechanical Circulatory Support. Georgetown, TX, Landes Bioscience, 1999, p 33.).

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TABLE 19-3 -- INDICATIONS FOR INTRAAORTIC BALLOON COUNTERPULSATION Cardiogenic shock Postcardiotomy Associated with an acute myocardial infarction Mechanical complication of an acute myocardial infarction Mitral regurgitation Ventricular septal defect In association with coronary artery bypass surgery Preoperative insertion Patients with severe left ventricular dysfunction Patients undergoing repeat bypass surgery Postoperative insertion Postcardiotomy cardiogenic shock In association with nonsurgical revascularization Hemodynamically unstable infarct patients High-risk coronary angioplasty

Patients with severe left ventricular dysfunction Complex coronary artery disease Stabilization of cardiac transplant recipient before insertion of ventricular assist device Postinfarction angina Ventricular arrhythmias related to ischemia counterpulsation.[27] Although it has been suggested that prolonged IAB support in such patients may improve hospital and long-term survival rates, [28] the role of IAB counterpulsation in this patient population is to facilitate early catheterization and reperfusion strategies. Patients with an acute myocardial infarction complicated by cardiogenic shock have a hospital survival rate of 5 to 21 percent.[26] If such patients can be revascularized either by coronary artery bypass or by thrombolysis and percutaneous transluminal coronary angioplasty, survival rates improve dramatically. Patients with an acute myocardial infarction and cardiogenic shock who are treated with early IAB counterpulsation and coronary artery bypass grafting achieve an early survival rate of 88 to 93 percent. [26] [29] Patients who develop a mechanical complication after an acute myocardial infarction are best managed with IAB counterpulsation, urgent cardiac catheterization, and immediate surgical repair. IAB counterpulsation reduces the left-to-right shunt and maintains coronary perfusion in patients with a postinfarction ventricular septal defect. Hospital mortality in patients managed with an IAB and urgent operation is 25 to 47 percent.[30] [31] [32] Patients with postinfarction mitral regurgitation secondary to papillary muscle dysfunction or rupture also benefit from IAB insertion. IAB counterpulsation increases coronary perfusion and reduces ischemic ventricular dysfunction, mitral regurgitation, and the pulmonary capillary wedge pressure. Outcome is related to the extent of cardiac dysfunction, with surgical mortality approaching 55 percent.[33] POSTCARDIOTOMY CARDIOGENIC SHOCK.

IAB counterpulsation is employed in association with coronary artery bypass surgery in up to 13 percent of cases.[34] Preoperative IAB insertion is thought to be efficacious in patients with profound left ventricular dysfunction and in certain patients who have had previous bypass surgery.[35] [36] Refractory postcardiotomy cardiogenic shock is related to preoperative left ventricular dysfunction, inadequate myocardial preservation, intraoperative myocardial infarction, prolonged cardiopulmonary bypass and intraoperative ischemic times, or technical difficulties with the conduct of the operation. With maximal medical support and IAB counterpulsation, survival rates average 52 to 66 percent.[37] Predictors of death with intraoperative or postoperative IAB use include age, mitral valve replacement, urgent or emergent operation, preoperative renal dysfunction, complex ventricular ectopy, right ventricular failure, and transthoracic IAB insertion.[38] IAB counterpulsation has also been used in conjunction with nonsurgical revascularization. In addition to the use of the IAB in hemodynamically unstable infarct patients just described, IAB counterpulsation has been employed prophylactically in patients requiring high-risk coronary angioplasty.[39] Prophylactic IAB support has been

used in patients with severe left ventricular dysfunction and complex coronary artery disease, a population that comprises 1 to 2 percent of the total number of angioplasty procedures. Using this management algorithm, successful angioplasty has been performed in 86 to 100 percent of patients, with a hospital mortality of 6 to 19 percent. [39] HEART FAILURE.

The use of IAB counterpulsation in heart failure patients awaiting cardiac transplantation has decreased as the waiting time for donor hearts has increased. The rationale for IAB counterpulsation in this clinical setting is to maintain systemic perfusion and preserve end organ function until cardiac transplantation occurs. Long-term IAB use is, however, impractical because patients are not afforded an opportunity for rehabilitation and the IAB represents a significant ongoing infection risk. VAD support is now the standard of care in the patient requiring a bridge to transplantation. The role of IAB counterpulsation in this patient population has now been reduced to stabilization of the occasional patient with marked hemodynamic instability to allow time for VAD insertion. UNSTABLE ANGINA (See also Chap. 36) .

IAB support has also been offered to patients who do not fulfill hemodynamic selection criteria but who suffer from unstable angina or malignant ventricular tachyarrhythmias. Although nonrandomized trials suggest that IAB counterpulsation and subsequent myocardial revascularization may be of some benefit in patients with unstable angina,[40] aggressive preoperative medical management and a judicious cardiac anesthetic may eliminate the need for an IAB with equally good results. The role of IAB counterpulsation in patients with postinfarction angina is equally controversial.[41] In general, IAB support is reserved for patients with deteriorating hemodynamics or ongoing ischemia, as evidenced by rest pain or electrocardiogram changes in the region of the infarct, prior to myocardial revascularization. IAB counterpulsation may be beneficial in patients with ventricular tachyarrhythmias, particularly when the ventricular tachyarrhythmias are related to ischemia.[42] Ectopic impulses originate in the ischemic area surrounding an infarct zone, and the IAB may reduce the frequency of such arrhythmias by increasing myocardial perfusion and oxygenation in the ischemic zone. The use of IAB counterpulsation in the pediatric patient population remains problematic. Balloon catheters and consoles have been modified for use in children. However, the complex anatomy associated with congenital cardiac anomalies often results in biventricular failure for which IAB counterpulsation is not particularly effective. Even so, survival rates exceeding 50 percent in children supported with an IAB after a cardiac operation have been reported.[43] CONTRAINDICATIONS.

Absolute contraindications to IAB counterpulsation include aortic insufficiency and aortic dissection (Table 19-4) . Contraindications to IAB insertion through the femoral arterial route include the presence of an abdominal aortic aneurysm or severe calcific aortoiliac or femoral arterial disease. The percutaneous insertion technique should not be

employed in patients who have a recent groin incision with violation of the subcutaneous tissue at the proposed puncture site. The percutaneous insertion technique should be used with caution in the morbidly obese patient because the peritoneal reflection may be quite caudad, resulting in transperitoneal passage of the balloon catheter. INSERTION TECHNIQUE

The IAB is most commonly inserted in a percutaneous fashion through the common femoral artery.[44] Preinsertion evaluation of the

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TABLE 19-4 -- CONTRAINDICATIONS TO THE USE OF INTRAAORTIC BALLOON COUNTERPULSATION Absolute Contraindications Aortic valve insufficiency Aortic dissection Relative Contraindications Femoral arterial insertion Abdominal aortic aneurysm Severe calcific aortoiliac or femoral arterial disease Percutaneous insertion Recent ipsilateral groin incision Morbid obesity patient's femoral arterial and pedal pulses facilitates rapid recognition of limb ischemia after balloon insertion. With the use of strict aseptic technique the femoral artery is accessed using the Seldinger technique. The femoral arterial puncture should occur below the inguinal ligament, to avoid a transperitoneal puncture, and above the profunda femoris artery, to reduce the potential for superficial femoral arterial cannulation. The common femoral artery is dilated, and the final dilator and sheath are advanced over a guidewire into the descending thoracic aorta. The final dilator is withdrawn, and the IAB is inserted into the introducer sheath. The radiopaque tip of the IAB is positioned just distal to the left subclavian artery. The balloon is unwound, purged, connected to the bedside console, and pulsed. Proper augmentation is best accomplished with the IAB synchronized 1:2 with the patient's arterial pressure trace. Once inflation and deflation times are determined, augmentation is set at 1:1. Postinsertion anticoagulation is usually accomplished with a continuous heparin sodium infusion (1000 U heparin sodium in 500 ml normal saline, 3 ml/hr). Heparin sodium

administration is not necessary in postcardiotomy patients. Alternatively, the IAB may be inserted into the femoral artery using an open technique. The femoral artery is exposed, and a 5-cm segment of an 8- to 10-mm diameter vascular graft is anastomosed, at a 45-degree angle, to the common femoral artery. The IAB is passed through the vascular graft and into the artery and positioned as described previously. The IAB is fixed in position by tying umbilical tapes around the vascular graft. When an abdominal aortic aneurysm or severe peripheral vascular disease precludes femoral arterial insertion, the IAB may be inserted directly into the ascending aorta or transverse arch.[45] Access is obtained through a median sternotomy, usually at the time of cardiotomy. The balloon is inserted through a vascular graft in a manner identical to that described in the open femoral arterial technique. The balloon is advanced across the transverse arch into the descending thoracic aorta. Alternatively, the IAB can simply be inserted through two concentric pursestring sutures. A "sheathless" insertion technique may be employed in the nonanticoagulated patient. With this technique, the IAB is inserted into the common femoral artery after dilation with the small diameter dilator. The large dilator and sheath assembly are not employed. This technique minimizes the obstruction to blood flow in the common femoral artery facilitating IAB use in patients with a small body habitus and in those with known or suspected peripheral vascular disease. REMOVAL TECHNIQUE

As the patient's hemodynamic status improves, balloon augmentation is serially decreased. If the patient tolerates augmentation of every third to eighth cardiac cycle (1:3 to 1:8), the IAB can be safely withdrawn.[44] Balloon inflation is discontinued and the balloon aspirated to ensure deflation is complete. The balloon is withdrawn until it touches the sheath. Manual pressure is applied to the femoral artery distal to the insertion site, and the balloon and insertion sheath are withdrawn as a single unit. Blood is permitted to eject from the insertion site for one or two heartbeats to clear any thrombotic debris from the vascular space. Pressure is then applied to the insertion site: manually for 30 minutes and with a sandbag for an additional 8 hours. One must make certain the limb is adequately perfused during IAB removal. Withdrawal of an IAB inserted by the open technique requires surgical groin exploration, balloon and vascular graft removal, and femoral artery repair, usually with a vein patch. Open removal is also recommended when there has been a high (proximal) percutaneous insertion in morbidly obese patients, and in patients who develop limb ischemia after percutaneous insertion. Balloons inserted into the ascending aorta can be removed under local anesthesia if the side arm graft is brought into the subcutaneous space.[46] The authors, however, recommend a repeat sternotomy with direct visualization of the insertion site.

COMPLICATIONS OF IAB USE

The complication rate from IAB counterpulsation ranges from 5 to 47 percent.[47] [48] Major complications, including limb ischemia necessitating thrombectomy or amputation, aortic dissection, aortoiliac laceration or perforation, and deep wound infection requiring debridement, occur in 4 to 17 percent of patients.[49] Major complications lead to an additional operative procedure, prolonged hospitalization, long-term morbidity, or death. Minor complications, including bleeding at the insertion site, superficial wound infections, asymptomatic loss of peripheral pulse or lymphocele, occur in 7 to 42 percent of patients. [49] Minor complications are usually self-limited or resolve after IAB removal. Although the overall complication rate has not changed appreciably in the recent past, it appears that the severity of complications and the mortality directly attributable to IAB insertion have decreased significantly.[50] The most common complications related to femoral IAB use are vascular. [47] [48] [50] [51] [52] [53] [54] Vascular complication rates vary from 8 to 20 percent and are related to mechanical trauma to the vessel wall during IAB insertion, flow obstruction by the balloon catheter, and low cardiac output with peripheral vasoconstriction.[47] [50] [51] [52] [53] Risk factors for developing a major vascular complication after femoral IAB insertion are controversial but generally include peripheral vascular disease, diabetes mellitus, female gender, and small body surface area. In the past few years there has been a trend toward a lower incidence of limb ischemia associated with IAB use. This trend may be explained by an increased use of small-diameter balloon catheters. When percutaneous IAB insertion was introduced, a sheath as large as 12.5F was employed. Currently, sheaths as small as 8.5F to 9.5F are used, whereas sheath pull-back insertion techniques reduce the cross-sectional area of the catheter within the vascular space. These improvements in catheter design and insertion technique should have a significant positive impact on the vascular complication rate. Unfortunately, some series report no improvement in the vascular complication rate when a smaller catheter is employed[54] or when a sheathless insertion technique is used.[53] LEG ISCHEMIA.

When a patient develops leg ischemia after femoral IAB insertion, the IAB should be removed. Persistent limb ischemia after IAB removal requires emergent femoral arterial exploration, thrombectomy, and vein patch angioplasty. Balloon-dependent patients with limb ischemia benefit from moving the IAB to the contralateral leg or undergoing a femoral-femoral crossover graft.[55] The reported complication rate of transthoracic IAB counterpulsation is 0 to 13 percent.[49] [56] Complications associated with IAB insertion in the ascending aorta include bleeding at the insertion site, mediastinitis, transient ischemic attack, cerebrovascular accident, and an inability to close the sternum secondary to mechanical tamponade. Proponents of this route for IAB insertion note that the problem with leg ischemia is eliminated and placement of the IAB under direct vision reduces the potential for vessel

perforation and risk of aortic dissection.[56] VENTRICULAR ASSIST DEVICES Unlike the IAB, which is designed to improve the ratio between myocardial oxygen supply and demand while supporting systemic perfusion to only a modest degree, ventricular assist devices (VADs) are designed to effectively unload either the right or left ventricle while completely supporting the pulmonary or systemic circulation. The term VAD describes any of a variety of mechanical blood pumps that are employed singly to replace the function of either the right or the left ventricle. Two blood pumps can be used for biventricular support. For right ventricular assistance, blood is withdrawn from the right atrium and returned to the main pulmonary artery. For left ventricular assistance, blood is withdrawn from either the left atrium or the apex of the left ventricle. The blood passes through the left VAD and is returned to the ascending aorta. There is a wealth of information in the literature regarding the advantages and disadvantages of left atrial versus left ventricular inflow (with respect to the VAD) cannulation.[57] [58] In general, left atrial inflow cannulation is technically easier to perform, may employ cannulas readily available to any open-heart surgical team, but is thought to provide incomplete ventricular decompression. Left ventricular inflow cannulation requires a custom-designed cannula but provides very effective left ventricular decompression. The reduction in myocardial oxygen demand is offset by the fact that left ventricular apical cannulation damages the myocardium, an important consideration in a patient with marginal ventricular function. A left ventricular apex cannula is, however, ideally suited to patients who receive

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TABLE 19-5 -- COMPARISON OF VENTRICULAR ASSIST PUMPS VAD Type Advantage Disadvantage Centrifugal

Readily available Simple to use Relatively inexpensive

Nonpulsatile Systemic anticoagulation Constant supervision required Not FDA approved as a VAD

Pneumatic pulsatile

No blood trauma ±anticoagulation Pulsatile flow Minimal supervision required

Limited patient mobility with current approved drive consoles Expensive

Electric pulsatile Same as pneumatic pulsatile

Highly portable Hospital discharge permittted

VAD=ventricular assist device; FDA=Food and Drug Administration.

mechanical circulatory support as a bridge to cardiac transplantation. In this patient population, ventricular recovery is not expected and the apical cannula is removed in its entirety at the time of recipient cardiectomy. REGULATORY AFFAIRS

To better understand the enormous amount of effort that has been expended developing mechanical blood pumps, and limitations imposed on clinicians who desire access to a VAD, it is important to become familiar with the process by which medical devices are evaluated and approved for clinical use.[59] [60] The Medical Device Amendment of 1976 amended the federal Food, Drug and Cosmetic Act to require the FDA to approve clinical investigation of new medical devices and to approve new medical devices before they could be sold for general use. To prove that a new medical device is both safe and effective, the device must be the subject of a carefully controlled clinical trial. An investigator/manufacturer first conducts extensive in vitro device testing followed by in vivo animal experimentation. The data derived from the preclinical evaluation are submitted to the FDA along with results, if any, from foreign clinical trials. The investigator must also submit a formal clinical protocol and informed consent material that have been approved by the Institutional Review Board at the site of the proposed clinical trial. If the application for clinical investigation of the device is deemed satisfactory by the FDA, an Investigational Device Exemption (IDE) is granted to the investigator. It is expected that the clinical protocol will answer specific questions concerning the proposed indications and contraindications for use of the device. Because of the inordinate expense of device research and development, and the cost incurred during the conduct of a clinical trial (under an approved IDE), most investigators have an industrial partner. Assuming the clinical trial shows the device to be safe and effective for a well-defined set of indications, the next step will be to seek approval from the FDA for commercial sale of the device. In general, the industrial partner will submit a Pre-Market Approval (PMA) request to the FDA. The focus of the PMA application is to provide more extensive durability testing, an important consideration in devices intended for long-term clinical use. Durability testing is most often accomplished by accelerated in vitro experimentation, frequently performed under conditions more severe than those experienced when the device is in actual clinical use. Approval of a PMA by the FDA allows the manufacturer to release the medical device for commercial sale. Description of Devices

Mechanical blood pumps capable of replacing the function of a single ventricle can be divided into three categories. The advantages and disadvantages of each category of blood pump are summarized in Table 19-5 . Representative members of each class of VAD are listed in Table 19-6 . Specific design features and functional characteristics of each VAD are described here. Specific details regarding implantation and explantation

technique are described in the section entitled Management Considerations. Centrifugal Pumps

Centrifugal pumps are simple to use and readily available to most cardiac surgeons.[61] [62] [63] [64] Standard cardiopulmonary bypass atrial and arterial cannulas are connected to the centrifugal head by short lengths of medical grade polyvinyl chloride tubing. The centrifugal head imparts forward flow to blood by creating a vortex with a rapidly spinning series of cones or impeller blades that are located within the rigid pump housing. The nonocclusive pump head has excellent blood handling characteristics, and the system is pressure limited, virtually eliminating the potential for air embolus or tubing disruption.[63] [65] Centrifugal blood pumps provide nonpulsatile blood flow and require full systemic anticoagulation and constant driver supervision.[66] The centrifugal pump can provide left- or right-sided heart support, or two pumps can be used for biventricular assistance. Centrifugal pumps entered the clinical arena before the Medical Device Amendment of 1976. However, centrifugal blood pumps are considered a Class III medical device, subject to the constraints imposed by this amendment to the federal Food, Drug and Cosmetic Act. Currently, the three centrifugal blood pumps available in the United States are approved by the FDA for only up to 6 hours of use, which makes them suitable for cardiopulmonary bypass but not TABLE 19-6 -- REPRESENTATIVE MEMBERS OF EACH VAD TYPE VAD Type Name Manufacturer Centrifugal

BioPump Sarns Lifestream

Medtronic BioMedicus, Inc. 3M Health Care St. Jude Medical, Inc.

Pneumatic pulsatile

BVS 5000 biventricular support system Thoratec VAD system HeartMate 1000 IP LVAS

Abiomed, Inc. Thoratec Laboratories Corp. Thermo Cardiosystems, Inc.

Electric pulsatile Novacor N100 LVAS HeartMate VE LVAS LionHeart

Novacor Medical Division, Baxter Healthcare Corp. Thermo Cardiosystems, Inc. Arrow International, Inc.

VAD=ventricular assist device.

605

for short-term temporary ventricular assistance (see Table 19-6) . Pneumatic Pulsatile Blood Pumps

Complex, air-driven, pulsatile VADs are considerably more expensive than a centrifugal

pump but are capable of producing pulsatile flow with no trauma to formed blood elements. Furthermore, integral sophisticated control systems are largely self regulating, and beyond the first few days after device insertion minimal supervision is required. As drive units become more refined and portable drivers are developed, patient mobility and lifestyle will improve dramatically. ABIOMED BVS 5000 BIVENTRICULAR SUPPORT SYSTEM.

The Abiomed BVS 5000 Biventricular Support System (Abiomed, Inc., Danvers, MA) received PMA approval from the FDA for the treatment of patients with postcardiotomy cardiogenic shock.[67] [68] [69] The BVS 5000 blood pump is an external, dual-chamber device that is capable of providing short-term univentricular or biventricular circulatory support. Each chamber contains a 100-ml polyurethane blood sac. Trileaflet polyurethane valves are located at the inlet and outlet side of the ventricular chamber. The atrial chamber fills passively throughout pump systole and diastole while the ventricular chamber is intermittently pulsed with air from the drive console. Custom-designed cannulas provide right or left atrial inflow. The distal portion of the outlet cannula is a coated vascular prosthesis that is anastomosed to either the pulmonary artery or aorta. The cannulas traverse the skin subcostally. The drive unit functions asynchronously with respect to the patient's native cardiac rhythm. The control system maintains a constant 80-ml stroke volume by automatically adjusting the duration of pump systole and diastole in response to changes in preload and afterload. HEARTMATE 1000 IP LVAS.

The Heart.Mate 1000 IP LVAS (Thermo Cardiosystems, Inc., Woburn, MA) has received PMA approval from the FDA for use as a mechanical bridge to cardiac transplantation.[70] [71] [72] [72A] This implantable blood pump is connected to an external drive unit by a percutaneous air drive line. The titanium VAD housing contains a flexible segmented polyurethane diaphragm that is bonded to a rigid pusher plate. The unique, textured blood contacting surface promotes the formation of a stable neointima.[73] Patients do not require systemic anticoagulation and instead receive only antiplatelet agents. Intermittent air pulses from the external drive console actuate the pusher-plate diaphragm, and eject blood from the VAD housing. The pump has a maximum stroke volume of 83 ml and a maximum pump output of 10 liters/min. Valved conduits containing 25-mm porcine valves are located at the inlet and outlet ports of the VAD housing. The VAD is only designed for left ventricular support, withdrawing blood from the left ventricular apex. Blood is returned to the ascending aorta. The device may be implanted intraperitoneally, but more typically it is positioned preperitoneally, in the patient's abdominal wall.[74] When the blood pump is placed in a preperitoneal position, the potential visceral complications associated with peritoneal implantation are avoided. The drive console runs on standard alternating current, as well as internal rechargeable batteries. The batteries provide up to 40 minutes of support. The control system allows the VAD to function in a fixed rate or pump-on-full mode. The latter is a rate-responsive mode in which the VAD is automatically pulsed when the pump chamber is approximately 90 percent filled.

THORATEC VAD SYSTEM.

The Thoratec VAD System (Thoratec Laboratories Corp., Berkeley, CA, Fig. 19-2) is the only VAD approved by the FDA both for the treatment of postcardiotomy cardiogenic shock and as a bridge to cardiac transplantation.[75] [76] [77] [77A] This versatile paracorporeal blood pump can be used for right, left, or biventricular assistance. In the case of left ventricular assistance, custom-designed cannulas allow blood to be withdrawn from either

Figure 19-2 The paracorporeal Thoratec ventricular assist device is located on the patient's anterior abdominal wall. The inlet and outlet cannulas traverse the skin in the subcostal region. The biventricular assistance configuration shown here would be used in a patient requiring a bridge to cardiac transplantation. The left ventricular assist device inflow cannula is inserted into the left ventricular apex. The left ventricular assist device outflow graft is sutured to the ascending aorta. The right ventricular assist device withdraws blood from the right atrium. Right ventricular assist device outflow is to the main pulmonary artery. (From Richenbacher WE: Ventricular assistance as a bridge to cardiac transplantation. In Richenbacher WE [ed]: Mechanical Circulatory Support. Georgetown, TX, Landes Bioscience, 1999, p 125.)

606

the left atrium or the apex of the left ventricle. The blood pump consists of a machined polycarbonate housing that contains a polyurethane blood sac and Bjork-Shiley monostrut inlet and outlet valves (Shiley, Inc., Irvine, CA). Patients are maintained on sodium warfarin. The blood pump has a stroke volume of 65 ml with a dynamic ejection fraction of approximately 0.75. Air pulses from the drive unit intermittently compress the flexible blood sac ejecting blood from the VAD housing. The control system allows the device to function in one of three modes: a manual fixed-rate mode, a synchronized mode in which the R-wave of the patient's electrocardiogram serves as an electronic trigger, and an asynchronous full-to-empty mode in which the VAD enters systole each time the blood sac fills. The latter mode maximizes cardiac output by allowing the VAD pump rate to be determined by preload. Electric Pulsatile Blood Pumps

In the past few years great progress has been made in the development and clinical application of electric VADs. The current generation of electric blood pumps are intracorporeal devices that are capable of providing months, or even 1 or 2 years, of ventricular support. These devices provide left ventricular apex-to-aortic left ventricular assistance and are not designed for right ventricular assistance. Electric VADs are powered by a highly portable external controller and battery pack. In 1998, two electric VAD systems were approved by the FDA for the bridge to transplant application. Both approved systems employ a percutaneous drive line that connects the intracorporeal blood pump to the external electronics. Patients may now be discharged from the

hospital to await their cardiac transplant at home.[78] [79] The conversion from a bulky external pneumatic drive unit to a small portable battery pack, with the possibility of hospital discharge, represents a dramatic improvement in the quality of life experienced by the patients who require mechanical circulatory support as a bridge to cardiac transplantation. The next-generation electric VAD will be completely implantable and capable of providing years of tether-free left ventricular support. The electric VAD system will have an implantable controller and backup battery. An external, portable battery pack will serve as the primary power source. The external battery pack will be carried in a shoulder bag and transfer energy to the implantable controller and blood pump using transcutaneous energy transmission.[80] Energy will be passed from an external primary coil located on the surface of the skin to a subcutaneous secondary coil by inductive coupling. There will be no break in the integument, eliminating the potential for an ascending drive line infection. The internal, rechargeable battery will allow brief periods of entirely tether-free VAD function. Because these systems will be completely sealed, air displaced from the blood pump housing during VAD diastole will move to an implanted reservoir known as a compliance chamber.[81] As the final technological barriers to the development of implantable electric VADs are overcome, these systems will be permanently implanted in patients with unreconstructable coronary artery disease or end-stage cardiomyopathy not amenable to cardiac transplantation. Recently, a clinical trial (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure [REMATCH]) was initiated.[82] The trial seeks to enroll patients with NYHA functional Class IV heart failure who are not candidates for cardiac transplantation. Patients are randomized to one of two treatment arms: medical therapy or permanent electric VAD insertion. The purpose of the study is to evaluate the efficacy, safety, and cost effectiveness of wearable VADs versus optimal medical therapy in the treatment of end-stage heart failure. As implantable VAD systems reach the clinical arena the goal of using mechanical blood pumps as an alternate to transplant will be realized.[83] NOVACOR N100 LVAS.

The Novacor N100 LVAS (Novacor Medical Division, Baxter Healthcare Corporation, Oakland, CA) was approved by the FDA for the bridge to transplant application (Fig. 19-3) . This ventricular assist system contains a polyurethane blood sac that is compressed by dual, symmetrically opposed pusher plates.[84] The pump is actuated by a spring-decoupled solenoid energy converter. The blood pump and energy converter are contained within a lightweight fiberglass/epoxy housing that is implanted in a preperitoneal position in the left upper quadrant of the patient's abdomen.[84] [85] The inflow and outflow conduits each contain a bioprosthetic, pericardial valve. Patients require full anticoagulation with sodium warfarin. The Novacor blood pump has a maximum stroke volume of 67 ml. The tethered configuration employs a percutaneous vented tube containing power and control wires.[84] The external console-based controller typically allows the device to function in a fill-rate trigger mode that provides synchronized counterpulsation to the native heart.

The device may also be powered by a wearable, microprocessor-based controller and external batteries.[86] [87] [88] The compact controller and rechargeable batteries are worn as a belt and can support the blood pump for up to 6 hours. HEARTMATE VE LVAS.

The HeartMate VE LVAS (Thermo Cardiosystems, Inc., Woburn, MA) has been approved by the FDA for the bridge to transplant application (Fig. 19-4) . This left ventricular assist system utilizes a

Figure 19-3 The implantable Novacor N100 LVAS. The blood pump is located in the preperitoneal position in the left upper quadrant of the patient's abdomen. The device is designed to provide left-sided heart support. Blood is withdrawn from the left ventricular apex and is returned to the ascending aorta. The percutaneous drive line connects the blood pump to the external controller and primary and reserve power packs. (Courtesy of the Novacor Division, Cardiovascular Group, Baxter Healthcare Corporation, Oakland, CA.)

607

Figure 19-4 The implantable Thermo Cardiosystems VE LVAS. The blood pump is positioned preperitoneally in the left upper quadrant of the patient's abdomen. The device is configured for left ventricular assistance with a left ventricular apex inflow cannula and an aortic outflow graft. The percutaneous drive line exits the skin in the right upper quadrant. The external controller is clipped to a belt. The two batteries are worn in shoulder holsters. (From Richenbacher WE: Ventricular assistance as a bridge to cardiac transplantation. In Richenbacher WE [ed]: Mechanical Circulatory Support. Georgetown, TX, Landes Bioscience, 1999, p 123.)

blood pump similar to that employed in the pneumatically powered ventricular assist system produced by the same manufacturer. [71] [72] [89] In the vented electric version, however, the diaphragm pusher-plate mechanism is pulsed by a low-speed high-torque motor. The percutaneous electrical leads connect the blood pump to the external controller and batteries. The rechargeable batteries, capable of providing 4 to 6 hours of tether-free operation, are carried in a shoulder holster, or the device may be connected to a stationary power base unit. ARROW LIONHEART LVAS.

The completely implantable, sealed system being developed at The Pennsylvania State University and Arrow International (Arrow International, Inc, Reading, PA) contains a segmented polyurethane blood sac that is contained in a rigid housing.[90] [91] Bjork-Shiley monostrut inlet and outlet valves provide unidirectional blood flow. The blood sac is compressed by a pusher plate driven by a brushless direct current motor. Air displaced from the pump housing during VAD diastole is managed by a polyurethane

compliance chamber.[81] Control electronics and a 30-minute battery pack are contained in an implantable cannister that receives power from a subcutaneous energy transmission coil. The external battery pack carried by the patient transfers energy to the implanted coil using transcutaneous energy transmission.[80] The device has a stroke volume of 62 ml and can pump up to 8.5 liters/min. The controller adjusts the VAD beat rate in response to physiologic conditions, ensuring that the blood pump functions in a full-to-empty mode. The Pennsylvania State University electric VAD has run continuously for more than 1 year on a mock circulatory system.[90] The system has been tested in vivo for up to 90 days.[92] Clinical implants began in Europe in the fall of 1999. An IDE has been submitted to the FDA in preparation for the initial feasibility study in the United States. Indications and Results of Clinical Use POSTCARDIOTOMY CARDIOGENIC SHOCK.

The original indication for VAD support was postcardiotomy cardiogenic shock. Approximately 1 percent of patients cannot be separated from cardiopulmonary bypass after an open-heart operation despite maximum medical therapy and IAB counterpulsation.[7] [93] [94] These patients are considered potential candidates for VAD insertion. The goal of mechanical circulatory support in this clinical setting is to alter the balance between myocardial oxygen supply and demand to create a milieu that favors myocardial recovery. At the same time, systemic perfusion is maintained. The end point in this scenario is a return of ventricular function, with the expectation that following a few days of mechanical circulatory support the VAD(s) could be removed. The results achieved with mechanical blood pump support for postcardiotomy cardiogenic shock are summarized in Table 19-7 . The Combined Registry for the Clinical Use of Mechanical Ventricular Assist Devices and the Total Artificial Heart was developed in 1988 under the auspices of the International Society for Heart Transplantation and the American Society for Artificial Internal Organs.[7] The responsibility for the Registry was transferred to the Society of Thoracic Surgery in 1993. Clinicians from 62 centers worldwide voluntarily submit data to this registry. Postcardiotomy cardiogenic shock remains the most frequent indication for mechanical circulatory support, although the number of blood pumps implanted for this clinical indication has declined steadily during the past decade.[7] Whether this reflects more strict implantation criteria, advances in myocardial preservation, improved medical TABLE 19-7 -- RESULTS OF MECHANICAL BLOOD PUMP SUPPORT FOR POSTCARDIOTOMY CARDIOGENIC SHOCK Author Device No. of Patients Weaned Survived* Golding, et al[95] [96]

Lee, et al

BioPump

79

49 (62%)

20 (25%)

BioPump

28

N/A

9 (32%)

Curtis, et al[64]

Sarns 1986-1989 1989-1994 Overall

33 32 65

11 (33%) 17 (53%) 28 (43%)

Mehta, et al[7]

Centrifugal

905

422 (47%) 236 (26%)

Korfer, et al[94]

Abiomed BVS 5000 50

5 (15%) 9 (28%) 14 (22%)

N/A

25 (50%)

Gray and Champsaur[67] Abiomed BVS 5000 211

87 (41%)

N/A

Guyton, et al[68]

Abiomed BVS 5000 31

17 (55%)

9 (29%)

Thoratec

158

59 (37%)

33 (21%)

Pneumatic

335

152 (45%) 82 (25%)

[97]

Thoratec

Mehta, et al

[7]

*Successfully weaned and survived to hospital discharge.

608

management of postcardiotomy heart failure, or underreporting to the voluntary registry is unknown. Mechanical circulatory support for postcardiotomy cardiogenic shock is most frequently required after coronary revascularization. The duration of support is brief, varying between 1.4 and 5.7 days.[7] [64] [98] Recent trends suggest that the duration of support required is independent of the need for left, right, or biventricular assistance.[7] In general, lower survival is associated with an unsuccessful operation,[93] perioperative myocardial infarction,[93] advanced age,[7] renal failure,[7] [93] [95] neurologic complications,[7] biventricular failure,[7] [95] multisystem organ failure,[98] and sepsis.[98] Patients who are subjected to prolonged cardiopulmonary bypass times or who require late VAD insertion (hemodynamic collapse after having been moved out of the operating room) have very poor survival rates.[7] [93] Survival does not appear to be influenced by the type of operation performed before VAD insertion, the need for right versus left versus biventricular support, or the type of device used. [7] Survival is similar regardless of whether the patient receives a centrifugal or pulsatile blood pump. Although an overall salvage rate of approximately 25 percent seems low, it must be understood that without mechanical circulatory support, patients with refractory postcardiotomy cardiogenic shock would die. Although registry data show that weaning and survival rates have not improved in the past decade, Curtis and colleagues have shown that there is a trend toward increased hospital survival when an early versus recent cohort of patients at a single institution are compared.[64] Recently, Korfer and associates described 50 patients who received mechanical circulatory support for postcardiotomy cardiogenic shock with a hospital discharge rate of 50 percent.[98] Of note, the survival curve levels off after hospital discharge. The Registry reports a 24 percent 6-month survival and a 22 percent 5-year survival.[7] The majority of long-term survivors achieve NYHA functional Class II

or better.[64] ADJUNCT TO CARDIAC TRANSPLANTATION (See alsoChap. 20) .

With the introduction of cyclosporine-based immunosuppressive regimens, and the resurgence of interest in cardiac transplantation in the early 1980s, a second patient population that could potentially benefit from mechanical ventricular assistance was identified. The number of patients with end-stage cardiomyopathy quickly exceeded the number of donor hearts available. The list of approved cardiac transplant candidates grew, and the time a patient spent waiting for a donor heart increased. At year-end 1998, 4185 potential cardiac transplant recipients were listed with the United Network for Organ Sharing (UNOS).[99] During the same year, 767 potential cardiac transplant recipients died while on the UNOS waiting list.[99] Cardiac transplant recipients who decompensate hemodynamically before the availability of a donor heart are potential candidates for VAD implantation. The role of mechanical circulatory support in this clinical setting is to maintain systemic perfusion and end organ function until a donor heart is available. The recipient's heart and VAD are removed at the time of cardiac transplantation.[99A] Results of mechanical blood pump support as a bridge to cardiac transplantation are summarized in Table 19-8 . Although the length of time a cardiac transplant candidate waits for a suitable donor heart varies with UNOS status, blood type, and weight, the average waiting time is a number of months and can be as long as 1 to 2 years. Pulsatile devices, in particular implantable VADs, are designed to provide long-term support. The average duration of support for the series summarized in Table 19-8 varied between 41 and 108 days.[71] [72] [76] [98] [103] Fifty-five percent of patients who receive support with a pulsatile device that is approved by the FDA for the bridge application survive to hospital discharge after cardiac transplantation.[76] [97] [98] [101] [102] [103] Some would question the wisdom of allocating hearts to this critically ill patient population when the 1-year survival after conventional heart transplantation now exceeds 80 percent.[5] It has been suggested that VAD support intensifies the donor shortage by including recipients who otherwise would not have survived to transplantation.[104] The Registry of the International Society for Heart and Lung Transplantation notes that VAD support before transplantation is a recipient factor that has a significant negative impact on 1-year patient survival after transplantation.[5] If the cumulative experience of the bridge patients is reviewed, approximately two thirds of patients requiring VAD support survive to transplantation. More importantly, 86 percent of patients who require VAD support, and who are successfully transplanted, will survive to hospital discharge.[76] [97] [98] [101] [102] [103] Others have shown that posttransplant survival in bridge patients meets,[101] [102] [104] or exceeds,[105] the survival rate in non-bridge patients. Risk factors associated with reduced survival in patients requiring VAD support as a bridge to cardiac transplantation include a preoperative need for mechanical ventilation; significant end organ dysfunction as evidenced by an elevated blood urea nitrogen, creatinine (with or without the need for dialysis), or bilirubin level; the need for a reoperation for bleeding after VAD insertion; right-sided heart failure requiring mechanical right ventricular assistance in addition to left VAD insertion; infection; and device failure.[71] [103] [106] The incidence of device failure is low, a tribute to extensive

preclinical device testing. Technical refinements in device design have largely eliminated the causes of device malfunction that appeared in the early clinical experience. [71] [107] [108] The benefits of an extended period of VAD support are well defined. Patients undergo vigorous nutritional and physical rehabilitation.[109] Hemodynamic parameters, exercise tolerance, and end organ function improve.[110] [111] [112] [113] The recent approval by the FDA of two intracorporeal, electric VAD systems now allows VAD supported patients to be TABLE 19-8 -- RESULTS OF MECHANICAL BLOOD PUMP SUPPORT AS A BRIDGE TO CARDIAC TRANSPLANTATION Author Device No. of Transplanted Survived* Survival after Patients Transplant McBride[100]

Centrifugal

77

56 (73%)

36 (47%)

36/56 (64%)

Gray and Champsaur[67]

Abiomed BVS 5000

94

66 (70%)

39 (41%)

39/66 (59%)

Kormos, et al[101] Novacor N100

43

30 (70%)

28 (65%)

28/30 (93%)

McCarthy, et al[71]

HeartMate

97

74 (76%)

N/A

N/A

Sun, et al[72]

HeartMate

95

62/88 (70%)

N/A

N/A

Frazier, et al[89]

HeartMate

1387

810/1214 (67%)

N/A

N/A

Hill, et al[102]

Thoratec

300

187/287 (65%)

159/287 (55%)

159/187 (85%)

McBride, et al[76] Thoratec

67

39/64 (61%)

39/64 (61%)

39/39 (100%)

Korfer, et al[98]

Thoratec

84

56 (74%)

51 (61%)

51/56 (91%)

Thoratec

608

365 (60%)

315 (52%) 315/365 (86%)

Pulsatile

315

221 (70%)

183 (58%) 183/221 (83%)

[97]

Thoratec

Mehta, et al

[103]

*= Survived to successful transplanatation; = survived to hospital discharge after transplantation.

609

discharged from the hospital. Home-based care has significant psychological and

emotional benefits for patients and their families.[114] [115] Outpatient VAD care also has a positive impact on health care economics.[116] Mechanical circulatory support has been employed in two additional subpopulations of patients requiring cardiac transplantation: both after donor heart implantation. According to the Registry, 40 patients have been treated with circulatory support during a rejection episode complicated by hemodynamic compromise.[117] Only 23 of the patients (58 percent) underwent a second cardiac transplant. Eight of the 23 patients (35 percent) were discharged from the hospital. This represents an absolute salvage rate of 20 percent. Sixty-eight other posttransplant patients suffered from presumed reversible cardiogenic shock unrelated to rejection.[117] VAD support in this patient population resulted in an absolute salvage rate of 19 percent, statistically equal to the survival rate when ventricular assistance was employed in patients with postcardiotomy cardiogenic shock after other types of procedures. ACUTE MYOCARDIAL INFARCTION (See also Chap. 35) .

Patients in cardiogenic shock after acute myocardial infarction treated with mechanical circulatory support alone have a mortality rate of 80 percent, the same as patients treated medically.[118] Ventricular assistance has been used in this patient population to stabilize the patient's condition to allow cardiac catheterization and emergent revascularization, treat cardiogenic shock after urgent revascularization, or support patients with irreparable cardiac damage until cardiac transplantation can be performed.[119] Mortality in certain subsets of patients may be reduced to 25 to 40 percent.[118] [119] [120] Because the therapeutic end point is unknown, proper device selection can be problematic. If ventricular apex cannulation is employed, the surgical technique must be modified when dealing with necrotic myocardium.[121] In general, less than optimal results leave the role for mechanical circulatory support in this clinical setting poorly defined. LONG-TERM BRIDGE TO RECOVERY.

Most large series in which a pulsatile VAD has been inserted as a bridge to cardiac transplantation include patients who have recovered ventricular function after a protracted period of mechanical circulatory support.[72] [76] [89] [122] [123] [123A] In this situation the VAD is removed, obviating the need for cardiac transplantation. In most instances the VAD is removed when the patient develops a contraindication to transplantation or device malfunction. Observational studies describe a variety of morphological and physiological changes that are associated with chronic ventricular unloading.[124] [125] Indicators of ventricular recovery, however, are unknown. It is also unclear if the improvement in left ventricular function is sustained after VAD explantation. At this time, the role of ventricular assistance in the management of the patient with chronic heart failure, other than as a bridge to transplantation, must be considered experimental. Complications Associated with VAD Use

Hemorrhage, usually defined as the need for a reexploration for bleeding, occurs in 14

to 50 percent of patients who require mechanical ventricular assistance.[64] [71] [76] [77] [89] [98] [103] Postimplant bleeding occurs more frequently in patients who receive a VAD for postcardiotomy cardiogenic shock versus a VAD as a bridge to transplant.[126] There is also a device-related prevalence in that bleeding occurs more frequently in the patients supported with a centrifugal pump for postcardiotomy cardiogenic shock than in patients supported with a pulsatile device for the same indication.[7] The etiology of bleeding associated with VAD implantation is multifactorial and includes preoperative hepatic failure or coagulopathy, technical surgical ability, hematologic abnormalities related to a prolonged cardiopulmonary bypass time, hypothermia, hemodilution, and platelet activation or disseminated intravascular coagulation secondary to blood-biomaterial interaction in the heart-lung machine or VAD.[126] [127] Use of the bovine serine protease inhibitor aprotinin has reduced blood loss associated with VAD implantation.[128] Stasis of blood within the blood pump and inadequate anticoagulation may lead to thrombus deposition.[129] Thromboembolic complications occur in 6 to 47 percent of patients.[64] [72] [76] [98] [103] [130] Not all thromboembolic events result in a neurological deficit, and, in fact, many thromboembolic events are not clinically evident.[64] [130] [131] Multisystem organ failure is usually related to preimplantation end organ hypoperfusion but may be exacerbated by postimplantation low-flow states. Renal failure, in most instances defined as the need for dialysis, occurs in 5 to 29 percent of patients. [64] [76] [77] [98] [103] After left VAD insertion, systemic hypoperfusion is most often related to right ventricular failure and inadequate left VAD filling. Right ventricular dysfunction secondary to pulmonary hypertension is most effectively treated with inhaled nitric oxide.[132] [133] Medically refractory right-sided heart failure requiring right VAD insertion occurs in 11 to 37 percent of patients.[71] [72] [77] Infection occurs in up to 59 percent of patients receiving mechanical circulatory support.[64] [71] [72] [76] [98] [103] Infection is often attributed to prolonged hospitalization, indwelling lines and catheters, and percutaneous drive lines or cannulas. Device-related infections occur in 11 to 27 percent of patients.[71] [72] [76] Device-related infections include percutaneous drive line colonization, intracorporeal VAD pocket infections, and VAD endocarditis. VAD endocarditis, best treated with chronic antibiotic therapy and early VAD removal, is associated with a poor outcome.[134] [135] Septic complications in the patient receiving VAD support as a bridge to transplantation should not influence the decision to proceed with transplantation. Transplantation in the face of infection is the most effective treatment option because survival rates are not significantly different in patients who are transplanted with or without an infectious complication during the period of VAD support.[134] [136] Management Considerations POSTCARDIOTOMY CARDIOGENIC SHOCK.

Patients who have preexisting ventricular dysfunction and who are at risk for intractable heart failure after an open-heart procedure have a femoral arterial line placed before the initiation of cardiopulmonary bypass. The presence of a femoral arterial line facilitates subsequent IAB insertion. Selected patients also undergo a cursory pretransplant evaluation. Of 965 postcardiotomy cardiogenic shock patients reported to the Registry

for Mechanical Circulatory Support, 43 patients (4.5 percent) were activated as potential cardiac transplant recipients when they developed device dependency and had no contraindication to transplant.[6] On completion of the cardiac operation, acid-base balance and electrolyte abnormalities are corrected. A functional cardiac rhythm is restored utilizing temporary cardiac pacing, if necessary. A patient is considered a candidate for VAD insertion when he or she fulfills the hemodynamic criteria outlined in Table 19-1 , has no contraindication to VAD insertion as outlined in Table 19-2 , and cannot be weaned from cardiopulmonary bypass despite moderate inotropic support and IAB counterpulsation. It is imperative that operative decision-making be performed rapidly, and VAD insertion undertaken expeditiously, to avoid the complications associated with a prolonged cardiopulmonary bypass time.[137] Standard cardiopulmonary bypass cannulas are employed for centrifugal VAD support.[138] [139] [140] Custom-designed cannulas are used with pulsatile VADs. For left ventricular

610

TABLE 19-9 -- HEMODYNAMIC STATUS DURING MECHANICAL LEFT VENTRICULAR ASSISTANCE CVP LAP Systolic AoP (mm CI Diagnosis [2] (mm Hg) (mm Hg) (liters/min/m Hg) ) 15-20

90

>2.0

Satisfactory pumping

140 percent of ideal body weight), which carries risks of worse graft coronary disease, hypertension, and wound infection, is a relative contraindication. Osteoporosis may contribute to spontaneous fractures associated with prednisone use, so candidates at risk should be evaluated with a bone density study. Sarcoidosis and some types of muscular dystrophy are considered a contraindication to transplantation. Systemic amyloidosis, because of its frequent multiorgan involvement as well as documented recurrence in the allograft, remains an unlikely condition for permitting transplantation at

most centers. All programs inevitably exercise some subjectivity in the selection process, determined by the prior experience of the transplant team with the many clinical, physiological, and social variables involved. Although the evaluation of potential candidates for cardiac transplantation is difficult, these established criteria have led to certain predictable outcomes in terms of quality of life and actuarial survival. Deviations from these protocols usually produce less favorable results. As with any medical or surgical procedure, the final decision ultimately rests with the patient, in accordance with the concept of informed consent. TREATMENT OF PATIENTS AWAITING TRANSPLANTATION Because a number of patients are awaiting transplantation at any point in time, their management is important. The UNOS patient waiting list for needed organs in October 1998 totaled nearly 4000 patients awaiting heart transplantation worldwide.[26] Because approximately 3400 procedures were performed per year during 1997 to 1999, a number of awaiting recipients will not survive to receive a needed organ. Most centers experience between 10 and 20 percent mortality of patients on the waiting list. Worldwide heart-lung transplantations, after peaking at 241 in 1990, have declined to an average of 130 per year 1997 to 1999, while lung transplantations have steadily risen and stabilized at an annual rate of close to 1200.[1] The management of end-stage congestive heart failure is described in Chapter 18 . Although digitalis remains the only generally available oral inotropic agent, the use of intravenous low-dose dopamine or dobutamine has been a helpful tool for treating some of these patients.[36] Some controversy surrounds the use of outpatient inotrope infusion, because some studies have noted increased mortality,[37] especially with higher doses. [38] More recent reports, however, have demonstrated safe and effective use of these agents.[39] [40] [41] With brief hospitalizations for hemodynamic monitoring to optimize use of vasodilators, diuretics, and intravenous inotropes, patients often sustain improvement lasting for weeks or even months. The use of anticoagulants as prophylaxis against systemic or pulmonary thromboembolism is practiced routinely at some centers. Finally, beta blockers have produced hemodynamic and symptomatic improvement in chronic heart failure and have been demonstrated to decrease mortality in patients who are also taking digoxin, diuretics, and an angiotensin-converting enzyme (ACE)-inhibitor (see Chap. 18 ).[42] MECHANICAL DEVICES FOR BRIDGING.

Patients in whom conventional medical therapy fails may require intraaortic balloon counterpulsation or possibly a mechanical assist device for bridging to transplantation (see Chap. 19 ). The major devices currently being used all have been recently reviewed and include the total artificial heart (TAH, CardioWest, Tucson, AZ),[43] [44] Thoratec (Thoratec Laboratories, Pleasanton, CA),[45] TCI Heartmate (Thermo Cardiosystems, Woburn, MA),[46] [47] [48] [49] and Novacor Left Ventricular Assist System (Baxter Healthcare, Oakland, CA).[50] [51] In addition, the Arrow Lionheart and the Abiomed Abiocor will soon be clinically available as destination therapy for patients who

are not candidates for cardiac transplantation. More than 2000 ventricular assist devices have been implanted,

618

TABLE 20-2 -- ADULT THORACIC TRANSPLANTATION CANDIDATE STATUS STATUS CRITERIA 1A

Inpatient+ MCS (VAD 30 d; TAH; IABP; ECMO) or MCS >30 days+significant device-related complications or Mechanical ventilation or Continuous infusion of one high-dose or multiple IV inotropesor Life expectancy 30 d or Continuous infusion of IV inotropes or Justified exceptional case

2

Does not meet status 1A or 1B criteria

7

Temporarily unsuitable to receive organ

MCS=mechanical circulatory support; VAD=ventricular assist device; TAH=total artificial heart; IABP=intraaortic balloon pump; ECMO=extracorporeal membrane oxygenation; IV=intravenous. and more than 500 have been used as a bridge to transplantation.[52] Although bleeding and thromboembolism remain important complications, 69 percent of intention-to-bridge patients go on to successful transplantation. For patients requiring only left-sided support, the short- and long-term transplantation survival is comparable to that of nonbridged transplant recipients. Over time, more compact systems for outpatient management have developed, and the use of all of these devices as portable bridges to transplantation, to recovery, or as permanent replacement therapy has become a more real possibility. Once selected, patients are categorized on the basis of size, ABO blood group, time on the waiting list, and clinical status. Clinical status divisions include IA, IB, 2, and 7 and are described in Table 20-2 . Patients are "delisted" if they improve or if they suffer complications (e.g., cerebral or pulmonary embolism) or superimposed illnesses (e.g., infections, gastrointestinal bleeding), which increase the risk of operation and immunosuppression or which compromise rehabilitation or survival. They are reactivated when clinically appropriate. Current UNOS policy allows for all time accumulated on the waiting list to be held forever by a patient and to be accrued if the

patient is delisted and reactivated. EVALUATION AND TREATMENT OF THE HEART DONOR The factor limiting the number of heart transplant performed is the availability of donor organs. Thus, it is imperative to obtain as high a percentage of potential donor organs as possible by increasing the donation rate and to consider all donor organs that might possibly be suitable for transplantation. Cardiologists frequently are asked to take part in the donor evaluation process so that the adequate function of the graft can be predicted before transplantation. Brain death has been accepted as the legal definition of death throughout the United States.[53] The diagnosis should not involve physicians caring for a potential candidate, and it requires the absence of hypothermia (core temperature >32.5°C) or drugs capable of altering neurological or neuromuscular function.[54] The specific neurological catastrophe that has resulted in brain death may include blunt traumatic injury to the head, intracranial hemorrhage, or penetrating traumatic injury. The characteristics of all organ donors are listed in Table 20-3 . Heart and heart-lung transplant donor criteria once were very selective. The upper age limit was usually 35 years, and there were a number of other criteria. With the need to increase the number of transplants, these criteria have been modified. Most centers evaluate any potential donor up to as old as 55 years of age. Especially with older or suboptimal donors, a careful cardiac history must be obtained from the next of kin and adequate cardiac function ensured, including potential evaluation with coronary arteriography for men older than 40 or women older than 45 years. Sweeney and colleagues reported on the use of hearts from donors who did not meet the standard criteria.[55] Recipients received grafts from older donors (> age 40) or from patients with a history of prolonged cardiac arrest or septicemia. Their results indicate that selective use of such donors is possible, with reasonable outcomes. In addition, Drinkwater and associates[56] demonstrated similar early and late outcomes when using organs with a mean donor age of 51 years compared with younger donors. In some cases, the older donor organs simultaneously received bypass grafts, and incidence of rejection, infection, and graft coronary artery disease were similar between the two groups.[56] The most recent Registry of the International Society of Heart and Lung Transplantation, however, includes increasing donor age among risk factors for 1- and 5-year mortality and demonstrates a significant interaction between ischemic time and donor age.[1] Hearts from older donors should, whenever possible, be reserved for older recipients because of inherent loss of function with age. The evaluation of potential donors includes obtaining adequate background data, a physical examination, a 12-lead electrocardiogram, and an echocardiogram. Brain death and increased intracranial pressure often result in nonspecific ST and T wave changes. These also may be seen with hypothermia. The echocardiogram has assumed an even greater role in evaluating cardiac function. This evaluation should be done at a time when doses of intravenous inotropic agents have been lowered to as low as is compatible with adequate blood pressure and cardiac output, and after adequate fluid

resuscitation. Current matching criteria of donors and recipients include only ABO compatibility and appropriate size match. A prospective specific crossmatch between donor and recipient is performed only where recipients have been identified as having more than 5 percent of reactivity when evaluated against a panel of random donors. A recent large multicenter retrospective analysis showed modest predictive value of HLA mismatch on survival of cardiac allografts.[56A] With respect to size, fairly wide limits are acceptable, although donors who weigh less than 80 percent of the recipient's weight should not be accepted for those patients who have higher levels of pulmonary vascular resistance. Vital signs in patients with brain death frequently are unstable, and close attention to fluid balance is required, owing to diabetes insipidus. This necessitates monitoring of central venous pressure and adequate fluid resuscitation, administration of vasopressin, and replacement of fluid lost TABLE 20-3 -- CALIFORNIA TRANSPLANT DONOR NETWORK DONOR CHARACTERISTICS (1995-1998)* CAUSE OF DEATH NUMBER OF DONORS % Intracranial bleed

356

44.3

Motor vehicle accident

144

17.9

Gunshot wound

116

14.4

Closed head injury

87

10.8

Anoxia

68

8.5

Other medical

33

4.1

804

100

Total *Mean age 36.7 years (0.3-78.0); 59.5% male, 40.5% female.

619

through urine output. If hypotension occurs despite adequate volume replacement, a vasopressor is infused. Dopamine is the standard inotropic agent used, but some donors are better maintained on an alpha-adrenergic agent. Donor evaluation currently also includes various serology results. These are for human immunodeficiency virus (HIV), hepatitis B antigen, cytomegalovirus (CMV), and toxoplasmosis. The finding of HIV antibody rules out a potential donor, and the presence of CMV antibody may disqualify a potential heart-lung donor for a

CMV-negative recipient at some centers. Present consensus also excludes donors with carbon monoxide-hemoglobin levels above 20 percent, arterial oxygen saturation less than 80 percent, previous myocardial infarction, or severe coronary or structural heart disease. The presence of metastatic malignancy is also an exclusion at many centers, although those with primary brain tumors and skin cancers may be excepted. Relative contraindications include sepsis, prolonged (>6 hours) severe (20 mug/kg/min) for 24 hours.[53] Distant procurement of the heart and heart-lung for transplantation is now routine in almost all transplant centers. The technique for heart preservation remains simple, with cold crystalloid or blood cardioplegia infusion combined with topical cold for extended preservation. Average ischemic times are between 3 and 4 hours, with excellent function in most cases. Data from the Registry of the International Society for Heart Transplantation show some relation between ischemic time and survival, although most experienced centers see no particular relation for up to 6 hours of ischemia.[1] Techniques for distant heart-lung procurement and preservation of isolated lung grafts include flush solutions in the pulmonary artery with potent pulmonary vasodilators,[57] the use of cold blood for flush, [58] placing the donor on cardiopulmonary bypass,[59] and the use of an autoperfusing heart-lung preparation for maintaining the organs at normothermia in a working state.[60] Again, distant procurement is limited to 6 hours or less, with most procurements having an ischemic period between 3 and 4 hours. This length of allowable ischemic time has usually kept procurement between centers of not more than 1000 miles distance. The tendency to use donor organs within the local region also has limited times. Allocation of organs begins with status 1 patients in ever-widening zones. It is offered first to candidates in the local Organ Procurement Organization (OPO) and then to patients within a 500-mile and then 1000-mile radius. If no recipient is found, the process is repeated for the status 2 list. Regional OPOs are available to assist doctors and hospitals with all medical and legal considerations involved in organ donation. A listing of OPOs with contact information can be found via the Association of Organ Procurement Organizations (website www.aopo.org). OPERATIVE TECHNIQUE

The current technique for orthotopic heart transplantation was described in 1960 by Lower and Shumway.[5] The method involves retaining a large portion of the posterior wall of the right and left atrium in the recipient and implanting the donor heart with relatively long suture lines in the atria, together with direct end-to-end anastomoses of the aorta and the pulmonary artery. Modification of this technique with venous anastomoses at the level of the cavae and the pulmonary veins permits a more

physiological atrial contribution to ventricular fitting and causes less distortion of the mitral and tricuspid annuli, with less tendency to atrioventricular valve regurgitation and rhythm disturbances.[61] [62] In addition, Blanche and colleagues demonstrated significantly greater short- and long-term survival using this total reimplantation technique.[63] This technique is reviewed by Trento and associates[64] and is illustrated in Figure 20-2 . Many types of congenital anomalies have been dealt with during cardiac transplantation. For example, absence of the right superior vena cava or persistent left superior vena cava can easily be accommodated.[65] Corrected transposition of the great vessels requires extra length of the donor aorta and pulmonary artery. [66] The operation is performed by way of a median sternotomy incision, with routine cannulation of the aorta and both venae cavae. Cardiopulmonary bypass is usually performed with moderate hypothermia of between 28° and 30°C. The implantation procedure usually requires from 45 to 80 minutes, and after careful attention to de-airing maneuvers and resuscitation of the heart, cardiopulmonary bypass is weaned. The incision is closed after placement of temporary pacing wires and chest drainage catheters. PHYSIOLOGY OF THE TRANSPLANTED HEART The transplanted heart initially is completely denervated. It is generally believed that partial reinnervation of the transplanted

Figure 20-2 Total heart replacement by pulmonary venous anastomoses on right or left and caval anastomosis at the superior and inferior vena cava. Aorta and pulmonary artery attached as in the previous biatrial transplantation technique.

620

heart begins within 1 year. Evidence exists for both sympathetic[67] [68] and parasympathetic[69] function, but most authorities agree that these phenomena are incomplete and variable from patient to patient, and the data are less clear for the parasympathetic system in particular.[70] [71] Various studies document the transplanted cardiac response to exercise or stress, which is less than normal but adequate for almost all activities (Fig. 20-3) . The heart rate accelerates slowly during the first stages of exercise, accompanied by an immediate increase in filling pressures as a result of augmented venous return from exercising muscles and decreased compliance. The latter may result from rejection, arteriopathy, arterial hypertension, small donor heart size, or cyclosporine use. Atrial contribution to end-diastolic filling is compromised by the dissociation between host and donor atrial contractions. The midatrial anastomosis may partially deform the atrioventricular annuli, leading to mitral and tricuspid regurgitation. In the absence of hypertension or rejection, ventricular ejection fractions

are normal to high.[72] [73] Incomplete innervation abolishes or blunts the heart's anatomically mediated reflexes while enhancing its sensitivity to circulating norepinephrine. The resting heart rate is generally higher owing to absence of vagal tone. Respiratory sinus arrhythmia and carotid sinus-mediated reflex bradycardia are absent. The more gradual increase of heart rate with exercise parallels the rise in circulating catecholamines, which also leads to an increase in the inotropic state of the myocardium. With augmented venous return and higher filling pressures, the stroke volume increases, contributing to the necessary increase in cardiac output during exercise.

Figure 20-3 The relationship between cardiac output (C.O.) and oxygen consumption in seven patients 1 year after cardiac transplantation (dots and solid line) and in 27 normal subjects ages 14 to 41 (dashed line). (From Hosenpud JD, Novick RJ, Breen TJ, Daily OP: The Registry of the International Society for Heart and Lung Transplantation Eleventh Official Report--1994. J Heart Lung Transplant 13:561, 1994. Reprinted with permission from Mosby-Year Book.)

Cardiac denervation results in an increase in beta-adrenergic receptor density.[74] In laboratory animals, denervation results in increased responsiveness to noradrenaline and isoproterenol. This supersensitivity appears to be due both to upregulation of beta receptors and to a loss of norepinephrine uptake in postganglionic sympathetic neurons. In a study by Borow and associates, the heart rate response to dobutamine was compared with that of normal subjects pretreated with atropine and found to be greater in the group of transplant recipients.[75] In other studies, infusions of isoproterenol produced a greater increase in heart rate than in normal controls. [76] This slight supersensitivity of the chronically denervated heart may be important in maintaining the necessary inotropic and chronotropic response to exercise and other stresses. All of the mechanisms underlying this supersensitivity have not been fully defined. Denervation of the allograft also blunts systemic responses to volume changes. Failure to reduce sympathetic tone during hypervolemia may contribute to hypertension and persistence of edema,[77] and blunted rate response to hypovolemia may predispose to orthostatic hypotension. Arrhythmias are uncommon. Sinus node dysfunction occurs in 10 to 20 percent of patients in the immediate perioperative period but is readily repaired in most cases with theophylline.[78] When this falls, permanent pacing may be necessary. With the adoption of the bicaval anastomosis technique there has been a trend toward decreased requirements for permanent pacemaker insertions. Pronounced sinus tachycardia (16 mm Hg). The reason for this precaution is that PDEIs are such potent venodilators that in patients with normal or low filling pressure, they can drop preload to undesirably low levels. Finally, in decompensated subjects who are still receiving beta-blocking agents, a PDEI rather than a beta blocker is the treatment of choice because PDEIs retain full or even have enhanced activity in the presence of beta blockade.[133] If the situation has not stabilized, additional inotropic support with or without supplemental afterload reduction is indicated and best delivered with the aid of pulmonary artery catheter monitoring (Table 21-10) . The combination of dobutamine and a PDEI is additive for effects on cardiac output and, via the PDEI, will produce a reduction in pulmonary artery and left ventricular filling pressure.[134] [135] The latter may provide welcome unloading of the right ventricle inasmuch as high pulmonary artery pressure can produce limiting right ventricular dysfunction in some patients. Once optimal inotropic therapy is being delivered, pure vasodilators can be additionally administered to subjects with persistently high systemic or pulmonary vascular resistance. TABLE 21-10 -- SUGGESTED INDICATIONS FOR HEMODYNAMIC MONITORING DURING THERAPY FOR DECOMPENSATED HEART FAILURE PRESENCE OF HYPOPERFUSION SUSPECTED FROM :

Narrow pulse pressure Mental obtundation Declining renal function with high volume status INTENSE NEUROHORMONAL ACTIVATION SUGGESTED BY : Serum sodium below 133 mEq/L Persistent systemic hypotension with low doses of ACE inhibitors SYMPTOMS OF CONGESTION AT REST IN THE PRESENCE OF : Frequent angina or other evidence of ischemia Frequent symptomatic ventricular arrhythmias Baseline impairment in renal function Severe intrinsic pulmonary disease PERSISTENT OR RECURRENT SYMPTOMS OF CONGESTION AT REST OR DURING MINIMAL EXERTION DESPITE : Administration of high doses of loop diuretics Addition of metolazone or hydrochlorothiazide Salt and fluid restriction ACE=angiotensin-converting enzyme. Modified from Smith TW (ed): Cardiovascular Therapeutics: A Companion to Braunwald's Heart Disease. Philadelphia, WB Saunders, 1996, p 201. Vasodilators such as nitroprusside or nitroglycerin can also be used in lieu of a positive inotropic agent, particularly in patients with higher systemic vascular resistance. In addition to more traditional vasodilators, brain natriuretic peptide is a novel, mild vasodilator with the unique property of preferentially increasing renal blood flow.[136] [137] However, brain natriuretic peptide is still undergoing clinical trials and is not yet approved by the Food and Drug Administration. Finally, in patients with blood pressure so low that renal perfusion is compromised, dopamine may be added to increase perfusion pressure and renal blood flow via this agent's alpha-adrenergic and dopaminergic properties. However, dopamine should not be considered an effective positive inotropic agent because the majority of its weak, partial beta-agonist effect is mediated by norepinephrine release,[138] which results in tachyphylaxis within 12 hours of administration.[139] Nonpharmacological Therapy

Table 21-11 lists some nonpharmacological therapies that can be used to treat acute episodes of HF. In general, nonpharmacological therapy is used only if drug therapy does not stabilize the patient. Although its effectiveness has never been demonstrated in a controlled clinical trial, use of an intraaortic balloon pump (IABP) can increase

cardiac output modestly while increasing effective coronary perfusion pressure (see Chap. 19 ). This benefit and the ease of use of this device make it an attractive adjunct in myocardial failure occurring in the context of ischemia. The IABP is also helpful in nonischemic myocardial failure. However, contraindications to IABP use include significant aortic regurgitation and severe peripheral vascular disease. If pharmacological therapy plus IABP does not stabilize the patient, a ventricular assist device should be used in selected individuals, as discussed in Chapter 19 . Because of the success of treating acute myocardial infarction by primary angioplasty[140] with stenting [141] (see Chap. 35 ), percutaneous coronary intervention techniques (see Chap. 38 ) have assumed an important role in treating the most common cause of new-onset acute HF, that arising in the setting of myocardial infarction. In general, the primary goal of treating myocardial failure in the setting of infarction is to establish and maintain patency of the infarct artery in the most expeditious manner possible. The catheterization laboratory is also an ideal setting in which to initiate adjunctive treatment such as an IABP, mechanical ventilation, and optimal pharmacological support guided by hemodynamic monitoring. Other catheterization techniques used in acute HF treatment include pericardiocentesis for tamponade (see Chap. 50 ) and relief of severe mitral stenosis by balloon valvuloplasty (see Chap. 46 ) (see Table 21-11 ). Occasionally, urgent cardiac surgery is required for the treatment of acute HF. As outlined in Table 21-11 , these procedures include CABG in acute ischemic disorders involving left main disease or in patients in whom percutaneous coronary intervention is not a technical option, acute aortic or mitral valve surgery, and on rare occasion, transplantation. In general, it is neither desirable nor feasible to

649

TABLE 21-11 -- NONPHARMACOLOGICAL THERAPY FOR ACUTE, DECOMPENSATED HEART FAILURE TREATMENT MODALITY SPECIFIC EXAMPLES Oxygenation

Supplemental oxygen, mechanical ventilation

Balloon counterpulsation

Intraaortic balloon pump

Ventricular assist device

Pulsatile-flow LVAD

Pacing

AV sequential pacemaker

Urgent cardiac catheterization PTCA, mitral valvuloplasty, pericardiocentesis Urgent cardiac surgery

CABG, AVR, MV repair or replacement, transplantation

AV=atrioventricular; AVR=aortic valve replacement; CABG=coronary artery bypass grafting; LVAD=left ventricular assist device; MV=mitral valve; PTCA=percutaneous transluminal coronary angioplasty.

perform cardiac transplantation on someone during their initial experience with HF. Investigational Treatment and Future Directions

In the last 10 years, major progress has been made in the medical treatment of HF. In mild to moderate stage B HF, the use of ACE inhibitors and beta-adrenergic blocking agents has reduced mortality by nearly 50 percent. [52] The degree of the remaining challenge and the size of the pharmaceutical market will ensure that medical therapy will continue to improve for all degrees of HF. However, to attain such progress, subjects with HF will need to continue to be enrolled in investigational protocols, typically available at larger, well-organized HF centers. In addition, left ventricular assist devices will continue to become more practical and economical and will probably soon become standard treatment of advanced HF in selected individuals.

REFERENCES New York Heart Association: Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Blood Vessels. New York, New York Heart Association, 1963. 1.

Schocken DD, Arrieta MI, Leaverton PE, Ross EA: Prevalence and mortality of congestive heart failure in the United States. J Am Coll Cardiol 20:301-306, 1992. 2.

O'Connell JB, Bristow MR: Economic impact of heart failure in the United States: Time for a different approach. J Heart Lung Transplant 13(Suppl):107-112, 1994. 3.

Packer M, Bristow MR, Cohn JN, et al: Effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 334:1349-1355, 1996. 4.

CIBIS-II Investigators and Committees: The Cardiac Insufficiency Bisoprolol Study II: A (CIBIS-II): A randomised trial. Lancet 353:9-13, 1999. 5.

MERIT-HF Study Group: Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 353:2001-2006, 1999. 6.

Pitt B, Zannad F, Remme WJ, et al: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 341:709-717, 1999. 7.

BEST Trial Investigators: Effect of beta-adrenergic blockade on mortality in patients with advanced chronic heart failure: The beta-blocker Evaluation of Survival Trial. Submitted for publication. 8.

American Heart Association: 1999 Heart and Stroke Statistical Update. Dallas, Texas American Heart Association, 1999. 9.

Ho KKL, Anderson KM, Kannel WB, et al: Survival after the onset of congestive HF in Framingham Heart Study subjects. Circulation 88:107-115, 1993. 10.

McDonagh TA, Morrison CE, Lawrence A, et al: Symtomatic and asymptomatic left-ventricular systolic dysfunction in an urban population. Lancet 350:829-833, 1997. 11.

12.

Hayflick L: How and Why We Age. New York, Ballantine, 1994.

WHO/ISFC Task Force on Cardiomyopathies: Report of the WHO/ISFC Task Force on the Definition and Classification of Cardiomyopathies. Br Heart J 44:672-673, 1980. 13.

Richardson P, McKenna W, Bristow MR, et al: Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies. Circulation 93:841-842, 1996. 14.

PATHOPHYSIOLOGY OF HEART FAILURE Bristow MR: Why does the myocardium fail? New insights from basic science. Lancet 352:(Suppl 1):8-14, 1998. 15.

Eichhorn EJ, Bristow MR: Medical therapy can improve the biologic properties of the chronically failing heart: A new era in the treatment of heart failure. Circulation 94:2285-2296, 1996. 16.

Weber KT: Extracellular matrix remodeling in heart failure: A role for de novo angiotensin II generation. Circulation 96:4065-4082, 1997. 17.

Gerdes AM, Kellerman SE, Moore JA, et al: Structural remodeling of cardiac myocytes from patients with chronic ischemic heart disease. Circulation 86:426-430, 1992. 18.

Gerdes AM, Kellerman SE, Schocken DD: Implications of cardiomyocyte remodeling in heart dysfunction. In Dhalla NS, Beamish RE, Takeda N, Nagano N (eds): The Failing Heart. New York, Raven, 1995, pp 197-205. 19.

Davies CH, Davia K, Bennett JG, et al: Reduced contraction and altered frequency response of isolated ventricular myocytes from patients with heart failure. Circulation 92:2540-2549, 1995. 20.

Swynghedauw B: Developmental and functional adaptation of contractile proteins in cardiac and skeletal muscles. Physiol Rev 66:710-771, 1986. 21.

Lowes BD, Minobe WA, Abraham WT, et al: Changes in gene expression in the intact human heart: Down-regulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium. J Clin Invest 100:2315-2324, 1997. 22.

Nakao K, Minobe WA, Roden RL, et al: Myosin heavy chain gene expression in human heart failure. J Clin Invest 100:2362-2370, 1997. 23.

Mercadier JJ, Lompre AM, Duc P, et al: Altered sarcoplasmic reticulum Ca-ATPase gene expression in the human ventricle during end-stage heart failure. J Clin Invest 85:305-309, 1990. 24.

Miyata S, Minobe WA, Bristow MR, Leinwand LA: Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ Res 86:386-390, 2000. 25.

Nadal-Ginard B, Mahdavi V: Molecular basis of cardiac performance. Plasticity of the myocardium generated through protein isoform switches. J Clin Invest 84:1693-1700, 1989. 26.

Chang KC, Figueredo VM, Schreur JHM, et al: Thyroid hormone improves function and Ca 2+ handling in pressure overload hypertrophy. J Clin Invest 100:1742-1749, 1997. 27.

Cohn JN: Structural basis for heart failure: Ventricular remodeling and its pharmacological inhibition. Circulation 91:2504-2507, 1995. 28.

Cintron C, Johnson G, Francis G, et al: Prognostic significance of serial changes in left ventricular ejection fraction in patients with congestive heart failure. Circulation 87(Suppl 6):17-23, 1993. 29.

Cohn JN, Johnson GR, Shabetai R, et al: Ejection fraction, peak exercise oxygen consumption, cardiothoracic ratio, ventricular arrhythmias, and plasma norepinephrine as determinants of prognosis in heart failure. Circulation 87(Suppl 6):5-16, 1993. 30.

Bristow MR, Gilbert EM: Improvement in cardiac myocyte function by biologic effects of medical therapy: A new concept in the treatment of heart failure. Eur Heart J 16(Suppl F):20-31, 1995. 31.

White M, Yanowitz F, Gilbert EM, et al: Role of beta-adrenergic receptor downregulation in the peak exercise response in patients with heart failure due to idiopathic dilated cardiomyopathy. Am J Cardiol 76:1271-1276, 1995. 32.

DIAGNOSIS OF HEART FAILURE Remes J, Mietinnen H, Reunanen A, Pyorala K: Validity of clinical diagnosis of heart failure in primary health care. Eur Heart J 12:315-321, 1991. 33.

34.

Cleland JGF, Habib F: Assessment and diagnosis of heart failure. J Intern Med 239:317-325, 1996.

Cowie MR, Struthers AD, Wood DA, et al: Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet 350:1349-1353, 1997. 35.

de Groote P, Millaire A, Foucher-Hossein C, et al: Right ventricular ejection fraction is an independent predictor of survival in patients with moderate heart failure. J Am Coll Cardiol 32:948-954, 1998. 36.

650

Felker GM, Hu W, Hare LM, et al: The spectrum of dilated cardiomyopathy. The Johns Hopkins experience with 1,278 patients. Medicine (Baltimore) 78:270-283, 1999. 37.

Myers J, Gullestad L, Vagelos R, et al: Clinical, hemodynamic, and cardiopulmonary exercise test determinants of survival in patients referred for evaluation of heart failure. Ann Intern Med 129:286-293, 1998. 38.

MANAGEMENT OF ACUTE HEART FAILURE Hannen EL, Kilburn H, O'Donnell JF, et al: Adult open heart surgery in New York State. An analysis of risk factors and hospital mortality rates. JAMA 264:2768-1774, 1990. 39.

White M, Wiechmann RJ, Roden RL, et al: Cardiac beta-adrenergic neuroeffector systems in acute myocardial dysfunction related to brain injury: Evidence for catecholamine-mediated myocardial damage. Circulation 92:2183-2189, 1995. 40.

Pfeffer MA, Pfeffer JM, Fishbein MC, et al: Myocardial infarct size and ventricular function in rats. Circ Res 44:503-512, 1979. 41.

Hood WB, McCarthy B, Lown B: Myocardial infarction following coronary ligation in dogs. Circ Res 21:191-199, 1967. 42.

Bristow MR, Mason JW, Billingham ME, Daniels JR: Dose-effect and structure function relationships in doxorubicin cardiomyopathy. Am Heart J 102:709-718, 1981. 43.

Billingham ME, Mason JW, Bristow MR, Daniels JR: Anthracycline cardiomyopathy monitored by morphological changes. Cancer Treat Rep 62:865-872, 1978. 44.

Bristow MR, Lopez MB, Mason JW, et al: Efficacy and cost of cardiac monitoring in patients receiving doxorubicin. Cancer 50:32-41, 1982. 45.

Lewis W, Gonzalez B: Actin isoform synthesis by cultured cardiac myocytes. Effects of doxorubicin. Lab Invest 56:295-301, 1987. 46.

Bristow MR: Is too much or too little hypertrophy of individual cardiac myocytes the problem in the failing heart? Heart Fail 10:162-165, 1994. 47.

The SOLVD Investigators: Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 327:685-691, 1992. 48.

MANAGEMENT OF CHRONIC HEART FAILURE The SOLVD Investigators: Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 325:293-302, 1991. 49.

Packer M, Poole-Wilson PA, Armstrong PW, et al: Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation 100:2312-2318, 1999. 50.

Pfeffer MA: Angiotensin-converting enzyme inhibition in congestive heart failure: Benefit and perspective. Am Heart J 126:789-793, 1993. 51.

Bristow MR: beta-Adrenergic receptor blockade in chronic heart failure. Circulation 101:558-569, 2000. 52.

53.

Hauptman PJ, Kelly RA: Digitalis. Circulation 99:1265-1270, 1999.

Dibianco R, Shabetai R, Kostak W, et al: A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure. N Engl J Med 320:677-683, 1989. 54.

Kubo SH, Gollub S, Bourge R, et al: Beneficial effects of pimobendan on exercise tolerance and quality of life in patients with heart failure. Results of a multicenter trial. The Pimobendan Multicenter Research Group. Circulation 85:942-949, 1982. 55.

Lowes BD, Higginbotham M, Petrovich L, et al: Low dose enoximone improves exercise capacity in chronic heart failure. J Am Coll Cardiol 36:501-508, 2000. 56.

57.

Bristow MR, Lowes BD: Low-dose inotropic therapy of ambulatory heart failure. Coron Artery Dis

5:112-118, 1994. Shakar SF, Abraham WT, Gilbert EM, et al: Combined oral positive inotropic and beta-blocker therapy for the treatment of refractory Class IV heart failure. J Am Coll Cardiol 31:1336-1340, 1998. 58.

58A. Taylor

HS: Diuretic therapy in congestive heart failure. Cardiol Rev 8:104-114, 2000.

The CONSENSUS Trial Study Group: Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 316:1429-1435, 1987. 59.

Packer M, Carver JR, Chesebro JH, et al: Effect of milrinone on mortality in severe chronic heart failure. The prospective randomized milrinone survival evaluation (PROMISE). N Engl J Med 325:1468-1475, 1991. 60.

Cohn JN, Goldstein SO, Greenberg BH, et al: A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators. N Engl J Med 339:1810-1816, 1998. 61.

Uretsky BF, Jesup M, Konstam M, et al: Multicenter trial of oral enoximone in patients with moderate to moderately severe congestive heart failure: Lack of benefit compared to placebo. Circulation 82:774-780, 1990. 62.

Lee HR, Hershberger RE, Port JD, et al: Low-dose enoximone in subjects awaiting cardiac transplantation. Clinical results and effects on beta-adrenergic receptors. J Thorac Cardiovasc Surg 102:246-258, 1991. 63.

Nijhawan N, Nicolosi AC, Montgomery MW, et al: Levosimendan enhances cardiac performance after cardiopulmonary bypass: A prospective, randomized placebo-controlled study. J Cardiovasc Pharmacol 34:219-228, 1999. 64.

Sindone AP, Keogh AM, Macdonald PS, et al: Continuous home ambulatory intravenous inotropic therapy in severe heart failure: Safety and cost efficacy. Am Heart J 134:889-900, 1997. 65.

Milfred-LaForest SK, Shubert J, Mendoza B, et al: Tolerability of extended duration intravenous milrinone in patients hospitalized for advanced heart failure and the usefulness of uptitration of oral angiotensin-converting enzyme inhibitors. Am J Cardiol 84:894-899, 1999. 66.

Gibelein P, Dadoun-Dybal M, Candito M, et al: Hemodynamic effects of prolonged enoximone infusion (7 days) in patients with severe chronic heart failure. Cardiovasc Drugs Ther 7:333-336, 1993. 67.

Gibbs CR, Beevers DG, Lip GY: The management of hypertensive disease in black patients. Q J Med 92:187-192, 1999. 68.

Carson P, Ziesche S, Johnson G, Cohn J: Racial differences in response to therapy for heart failure: Analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group. J Card Fail 5:178-187, 1999. 69.

Yancy C, Fowler MB, Colluci WS, et al: Response of black heart failure patients to carvedilol (abstract). J Am Coll Cardiol 29:84, 1997. 70.

Dries DL, Exner DV, Gersh BJ, et al: Racial differences in the outcome of left ventricular dysfunction. N Engl J Med 340:609-616, 1999. 71.

Daida H, Allison TJ, Johnson BD, et al: Comparison of peak exercise oxygen uptake in men versus women in chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 80:85-88, 1997. 72.

Vaccarino V, Chen YT, Wang Y, et al: Sex differences in the clinical care and outcomes of congestive heart failure. Am Heart J 138:835-842, 1999. 73.

Bonow RO, Udelson JE: Left ventricular diastolic dysfunction as a cause of congestive heart failure. Mechanisms and management. Ann Intern Med 117:502-510, 1992. 74.

Diller PM, Smucker DR, David B, Graham RJ: Congestive heart failure due to diastolic dysfunction. Frequency and patient characteristics in an ambulatory setting. Arch Fam Med 8:414-420, 1999. 75.

Rich MW: Epidemiology, pathophysiology, and etiology of congestive heart failure in older adults. J Am Geriatr Soc 45:968-974, 1997. 76.

Iriarte M, Murga N, Sagastagoitia D, et al: Congestive heart failure from left ventricular diastolic dysfunction in systemic hypertension. Am J Cardiol 71:308-312, 1993. 77.

78.

Spector KS: Diabetic cardiomyopathy. Clin Cardiol 21:885-887, 1998.

Friedrich SP, Lorrell BH, Rousseau MF, et al: Intracardiac angiotensin-converting enzyme inhibition improves diastolic function in patients with left ventricular hypertrophy due to aortic stenosis. Circulation 90:2761-2771, 1994. 79.

Lang CC, McAlpine HM, Kennedy N, et al: Effects of lisinopril on congestive heart failure in normotensive patients with diastolic dysfunction but intact systolic function. Eur J Clin Pharmacol 49:15-19, 1995. 80.

Mitrovic V, Strasser R, Berwig K, et al: Acute effects of enoximone after intracoronary administration on hemodynamics, myocardial perfusion and regional wall motion. Z Kardiol 85:856-867, 1996. 81.

Echt DS, Liebson PR, Mitchell LB, et al: Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 324:781-788, 1991. 82.

The Cardiac Arrhythmia Suppression Trial Investigators: Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med 327:227-233, 1992. 83.

Mason JW: A comparison of seven antiarrhythmic drugs in patients with ventricular tachyarrhythmias. Electrophysiologic Study Versus Electrocardiographic Monitoring Investigators. N Engl J Med 329:452-458, 1993. 84.

Kaye DM, Dart AM, Jennings GI, Esler MD: Antiadrenergic effect of amiodarone therapy in human heart failure. J Am Coll Cardiol 33:1553-1559, 1999. 85.

Doval HC, Nul DR, Grancelli HO, et al: Randomised trial of low-dose amiodarone in severe congestive heart failure. Grupo de Estudio de la Sobrevida en la Insufficiencia Cardiaca en Argentina. Lancet 344:493-498, 1994. 86.

Singh SN, Fletcher RD, Fisher SG, et al: Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N Engl J Med 333:77-82, 1995. 87.

Dunkman WB, Johnson GR, Carson PE, et al: Incidence of thromboembolic events in congestive heart failure. The V-HeFT VA Cooperative Studies Group. Circulation 87(Suppl 6):94-101, 1993. 88.

Baker DW, Wright RF: Management of heart failure. IV: Anticoagulation for patients with heart failure due to left ventricular dysfunction. JAMA 272:1614-1618, 1994. 89.

Hart RG, Haperin JL: Atrial fibrillation and thromboembolism: A decade of progress in stroke prevention. Ann Intern Med 131:688-695, 1999. 90.

Falk RH, Foster E, Coats MH: Ventricular thrombi and thromboembolism in dilated cardiomyopathy. A prospective follow-up. Am Heart J 123:136-142, 1992. 91.

Garg RK, Gheorghiade M, Jafri SM: Antiplatelet and anticoagulant therapy in the prevention of thromboemboli in chronic heart failure. Prog Cardiovasc Dis 41:225-236, 1998. 92.

AVID Investigators: A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med 337:1576-1583, 1997. 93.

MADIT Investigators: Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med 335:1933-1940, 1996. 94.

651

Buxton AE, Lee KL, Fisher JD, et al: A randomized study of the prevention of sudden death in patients with coronary artery disease. N Engl J Med 341:1882-1890, 1999. 95.

Bristow MR, Feldman AM, Saxson L, for the COMPANION Steering Committee: Heart failure management with biventricular pacing: The Comparison of Medical Therapy, Pacing and Defibrillation in chronic heart failure (COMPANION) Trial. J Cardiac Failure (in press). 96.

Kass DA, Chen CH, Curry C, et al: Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation 99:1567-1573, 1999. 97.

Leclercq C, Cazeau S, LeBreton H, et al: Acute hemodynamic effects of biventricular DDD pacing in patients with end-stage heart failure. J Am Coll Cardiol 32:1825-1831, 1998. 98.

Saxson L, DeMarco T, Chatterjee K, et al: Chronic biventricular pacing decreases serum norepinephrine in dilated heart failure patients with the greatest sympathetic activation at baseline. Pacing Clin Electrophysiol 22:830, 1999. 99.

Rose EA, Moskowitz AJ, Packer M, et al: The REMATCH trial: Rationale, design, and end points. Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure. Ann Thorac Surg 67:723-730, 1999. 100.

Arora RR, Chou TM, Jain D, et al: The Multicenter Study of Enhanced External Counterpulsation (MUST-EECP): Effect of EECP on exercise-induced myocardial ischemia and anginal episodes. J Am Coll Cardiol 33:1833-1840, 1999. 101.

102.

Ozlem Z, DeMarco T, Crawford LE, et al: Efficacy and safety of enhanced external counterpulsation

in mild to moderate heart failure: A preliminary report. J Card Fail 5:53, 1999. Sabbah HN, Maltsev VA, Chaudhry P, et al: Contractile function of cardiomyocytes isolated from dogs with heart failure is enhanced after chronic therapy with passive ventricular constraint using the Acorn cardiac support device. Circulation 100(Suppl 1):429, 1999. 103.

Robbins RC, Barlow CW, Oyer PE, et al: Thirty years of cardiac transplantation at Stanford University. J Thorac Cardiovasc Surg 117:939-951, 1999. 104.

105.

Hunt SA: Current status of cardiac transplantation. JAMA 280:1692-1698, 1998.

Passamani E, Davis KB, Gillespie MJ, Killip T: A randomized trial of coronary artery bypass surgery. Survival of patients with a low ejection fraction. N Engl J Med 312:1665-1671, 1985. 106.

Elefteriades JA, Morales DL, Gradel C, et al: Results of coronary artery bypass grafting by a single surgeon in patients with left ventricular ejection fractions or=30%. Am J Cardiol 79:1573-1578, 1997. 107.

Bax JJ, Poldermans D, Elhendy A, et al: Improvement of left ventricular ejection fraction, heart failure symptoms and prognosis after revascularization in patients with chronic coronary artery disease and viable myocardium detected by dobutamine stress echocardiography. J Am Coll Cardiol 34:163-169, 1999. 108.

Bolling SF, Pagani FD, Deeb GM, Bach DS: Intermediate-term outcome of mitral reconstruction in cardiomyopathy. J Thorac Cardiovasc Surg 115:381-386, 1998. 109.

Batista RJ, Santos JL, Takeshita N, et al: Partial left ventriculectomy to improve left ventricular function in end-stage heart disease. J Card Surg 11:96-97, 1996. 110.

McCarthy PM, Starling RC, Wong J, et al: Early results with partial left ventriculectomy. J Thorac Cardiovasc Surg 114:755-763, 1997. 111.

Athanasuleas CL, Stanley A, Clin N, et al: The role of surgical anterior ventricular restoration (SAVR) in ischemic dilated cardiomyopathy. Circulation 100(Suppl 1):801, 1999. 112.

Hanumanthu S, Butler J, Chomsky D, et al: Effect of a heart failure program on hospitalization frequency and exercise tolerance. Circulation 96:2842-2848, 1997. 113.

Chapman DB, Torpy J: Development of a heart failure center: A medical center and cardiology practice join forces to improve care and reduce costs. Am J Managed Care 3:431-437, 1997. 114.

Nohria A, Chen YT, Morton DJ, et al: Quality of care for patients hospitalized at academic medical centers. Am Heart J 137:1028-1034, 1999. 115.

Bristow MR, Abraham WT: Specialized centers for heart failure management. Circulation 96:2755-2757, 1997. 116.

Croft JB, Giles WH, Roegner RH, et al: Pharmacologic management of heart failure among older adults by office-based physicians in the United States. J Fam Pract 44:382-390, 1997. 117.

Luzier AB, DiTusa L: Underutilization of ACE inhibitors in heart failure. Pharmacotherapy 19:1296-1307, 1999. 118.

Roe CM, Motheral BR, Teitelbaum F, Rich MW: Angiotensin-converting enzyme inhibitor compliance and dosing among patients with heart failure. Am Heart J 138:818-825, 1999. 119.

Balk AH: The "heart failure nurse" to help us close the gap between what we can and what we do achieve. Eur Heart J 20:632-633, 1999. 120.

Burch GE, Giles TD: Prolonged bed rest in the management of patients with cardiomyopathy. Cardiovasc Clin 4:375-387, 1972. 121.

Coats AJ, Adamopoulos S, Radaelli A, et al: Controlled trial of physical training in chronic heart failure. Exercise performance, hemodynamics, ventilation, and autonomic function. Circulation 85:2119-2131, 1992. 122.

Kiilavuaori K, Naveri H, Leinonen H, Harkonen M: The effect of physical training on hormonal status and exertional response in patients with congestive heart failure. Eur J Cardiol 20:456-464, 1999. 123.

Keteyian SJ, Brawner CA, Schairer, et al: Effects of exercise training on chronotropic incompetence in patients with heart failure. Am Heart J 138:233-240, 1999. 124.

Braith RW, Welsch MA, Feigenbaum MS, et al: Neuroendocrine activation in heart failure is modified by endurance exercise training. J Am Coll Cardiol 34:1170-1175, 1999. 125.

Coats AJ, Adamopoulous S, Meyer TE, et al: Effects of physical training in chronic heart failure. Lancet 335:63-66, 1990. 126.

Willenheimer R, Erhardt L, Cline C, et al: Exercise training in heart failure improves quality of life and exercise capacity. Eur Heart J 19:774-781, 1998. 127.

Leier CV, Ebel J, Bush CA: The cardiovascular effects of the continuous infusion of dobutamine in patients with severe cardiac failure. Circulation 56:468-472, 1977. 128.

Likoff MJ, Weber KT, Andrews V, et al: Milrinone in the treatment of chronic cardiac failure: A controlled trial. Am Heart J 110:1035-1042, 1985. 129.

Biddle TL, Benotti JR, Creager MA, et al: Comparison of intravenous milrinone and dobutamine for congestive heart failure secondary to either ischemic or dilated cardiomyopathy. Am J Cardiol 59:1345-1350, 1987. 130.

Gilbert E, for the Enoximone Working Group: Double-blind, placebo-controlled comparison of enoximone and dobutamine infusions in moderate to severe heart failure patients (NYHA III-IV) (abstract). J Am Coll Cardiol 17:274, 1991. 131.

Berti S, Palmieri C, Ravani M, et al: Acute enoximone effect on systemic and renal hemodynamics in patients with heart failure. Cardiovasc Drugs Ther 10:81-87, 1996. 132.

Lowes BD, Simon MA, Tsvetkova TO, Bristow MR: Inotropes in the beta-blocker era. Clin Cardiol 23(Suppl 3):11-16, 2000. 133.

Gage J, Rutman H, Lucido D, LeJemtel TH: Additive effects of dobutamine and amrinone on myocardial contractility and ventricular performance in patients with severe heart failure. Circulation 74:367-373, 1986. 134.

135.

Gilbert EM, Hershberger RE, Wiechmann RJ, et al: Pharmacologic and hemodynamic effects of

combined beta-agonist stimulation and phosphodiesterase inhibition in the failing human heart. Chest 108:1524-1532, 1995. Marcus LS, Hart D, Packer M, et al: Hemodynamic and renal excretory effects of human brain natriuretic peptide infusion in patients with congestive heart failure: A double-blind, placebo-controlled, cross-over trial. Circulation 94:3184-3189, 1996. 136.

Abraham WT, Lowes BD, Ferguson DA, et al: Systemic hemodynamic, neurohormonal, and renal effects of a steady-state infusion of human brain natriuretic peptide in patients with advanced hemodynamically decompensated heart failure. J Card Fail 4:37-44, 1998. 137.

Port JD, Gilbert EM, Larrabee P, et al: Neurotransmitter depletion compromises the ability of indirect-acting amines to provide inotropic support in the failing human heart. Circulation 81:929-938, 1990. 138.

Leier CV, Heban PT, Huss P, et al: Comparative systemic and regional hemodynamic effects of dobutamine in patients with cardiomyopathic heart failure. Circulation 58:466-475, 1978. 139.

Grines CI, Browne KF, Marco J, et al: A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. The Primary Angioplasty in Myocardial Infarction Study Group. N Engl J Med 328:673-679, 1993. 140.

Grines CI, Cox DA, Stone GW, et al: Coronary angioplasty with or without stent implantation for acute myocardial infarction. Stent Primary Angioplasty in Myocardial Infarction Study Group. N Engl J Med 341:1949-1956, 1999. 141.

Doval HC, Nul DR, Grancelli HO, et al: Randomized trial of low dose amiodarone in severe congestive heart failure. Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina. Lancet 344:493-498, 1994. 142.

Singh SN, Fletcher RD, Fisher SG, et al: Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N Engl J Med 333:77-82, 1995. 143.

Cohn JN, Archibald DG, Ziesche S, et al: Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med 314:1547-1552, 1986. 144.

Cohn JN, Johnston G, Ziesche S, et al: A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 325:303-310, 1991. 145.

Packer M, O'Connor CM, Ghali JK, et al: Effect of amlodipine on morbidity and mortality in severe chronic heart failure. Prospective Randomized Amlopidine Survival Evaluation Study Group. N Engl J Med 335:1107-1114, 1996. 146.

The Digitalis Investigation Group: The effect of digoxin on mortality and morbidity in heart failure. N Engl J Med 336:525-533, 1997. 147.

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GUIDELINES MANAGEMENT OF HEART FAILURE Thomas H. Lee Heart failure guidelines were published by the Agency for Health Care Policy and Research (AHCPR) in 1994,[1] by an American College of Cardiology/American Heart Association (ACC/AHA) task force in 1995,[2] and by a task force of the Heart Failure Society of America in 1999.[3] These guidelines preceded research on new strategies for heart failure, such as beta-blockers, spironolactone, angiotensin receptor blockers, and left ventriculoplasty, and therefore do not comment on their role. The guidelines are consistent and, in some ways, complementary. The ACC/AHA guidelines contain detailed information on management of acute syndromes, such as cardiogenic shock. In contrast, a focus of the AHCPR guidelines is improving care by reducing common errors in diagnosis and chronic management. Among the common errors in management and testing cited by the AHCPR panel are

Overuse of testing technologies Inadequate treatment of coexistent hypertension Inadequate education for patient, family, and caregivers Inappropriate treatment of heart failure not due to systolic dysfunction Suboptimal patient involvement in care and compliance

Delayed referral for transplantation Underutilization of exercise prescriptions Underutilization of angiotensin-converting enzyme (ACE) inhibitors Inadequate dosing of diuretics in patients with persistent volume overload Failure of clinicians to appreciate adverse effects of medications To reduce the frequency of these errors, the AHCPR panel formulated recommendations for a wide range of topics (excerpted in Table 21-G-1 ). [1] The multidisciplinary group that developed these guidelines used an A-B-C system to grade the strength of evidence in support of their recommendations. The focus of the AHCPR guidelines were patients with left ventricular systolic dysfunction leading to volume overload or inadequate tissue perfusion, but one of their most specific recommendations was aimed at preventing this syndrome: The guidelines recommend use of ACE inhibitors in patients with moderately or severely reduced left ventricular systolic function even if they are asymptomatic. TABLE 21--G-1 -- SELECTED RECOMMENDATIONS FROM GUIDELINES FOR HEART FAILURE Topic Recommendation Strength of Evidence Prevention in Asymptomatic patients with moderately or A asymptomatic patients severely reduced left-ventricular systolic function (ejection fraction 30 mm Hg Multicenter Study of Pacing Therapy for Hypertrophic Cardiomyopathy (M-PATHY)[50]

Symptomatic HCM despite maximal medical regimen

Quality of life

LVOT 50 mm Hg

Treadmill exercise duration Peak O2 consumption

vs.

No pacing (AAI at 30 beats/min)

Significant placebo effect

LVOT gradient of 40%

Delta LVOT gradient Delta LV wall thickness LV = left ventricular; LVOT = left ventricular outflow tract; NYHA = New York Heart Association. Data from Maron BJ, Nishimura RA, McKenna WJ, et al: Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy: A randomized, double-blind, crossover study (M-PATHY). Circulation 99:2927, 1999.

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Figure 24-11 Pressure tracings at different atrioventricular (AV) intervals in a patient with hypertrophic obstructive cardiomyopathy. In this example, the outflow gradient was minimized at an AV interval of 120 milliseconds.

concluded that pacing should not be regarded as a primary treatment for HCM and that subjective benefit without objective evidence of improvement should be interpreted cautiously. Pacing for the treatment of medically refractory HCM is currently a Class IIb indication for pacing by the ACC/AHA guidelines.[2] When pacing is applied in the patient with HCM, AVI programming is crucial to achieve optimal hemodynamic improvement. Ventricular depolarization must occur as a result of pacing. Therefore, the AVI must be short enough to result in depolarization by the paced event (Fig. 24-11) . However, the shortest AVI is not necessarily the best.[48] Some experts have advocated AV nodal ablation to ensure paced ventricular depolarization if rapid intrinsic AV nodal conduction prevents total ventricular depolarization by means of the pacing stimulus.[46] Dilated Cardiomyopathy (See Chap. 48. )

Treatment of idiopathic dilated cardiomyopathy with short AVI DDD pacing was first reported by Hochleitner and coworkers.[51] They treated 16 critically ill patients with idiopathic dilated cardiomyopathy refractory to pharmacological therapy who were in NYHA functional Class III or IV (see Chap. 18 ). They reported dramatic improvement in NYHA functional class and a reduction in mortality from that expected at 1 year. (Hochleitner and coworkers[52] subsequently published 5-year follow-up results for their original patient cohort. No deaths occurred from continued deterioration in ventricular function, and no patient needed rehospitalization because of worsening heart failure after pacemaker implantation.) Subsequent investigators have shown markedly discrepant responses to standard dual-chamber pacing, with great interindividual variability and no consistent benefit from dual-chamber pacing.[53] [54] [55] [56] Although the finding is not consistent, some patients receive hemodynamic benefit from standard dual-chamber pacing by optimization of AV timing.[57] Pacing for the treatment of medically refractory dilated cardiomyopathy has been designated a Class IIb indication for pacing by the ACC/AHA guidelines.[2] It was subsequently hypothesized that in addition to the need for optimization of AV synchrony, correction of intraventricular conduction disturbances might result in clinical improvement. Although estimates from limited studies vary on the proportion of patients with heart failure who also have ventricular dyssynchrony--usually left bundle branch--it appears to be fairly significant and certainly is in excess of the rate in the general population.[58] [59] Ventricular dyssynchrony has been associated with paradoxical septal wall motion, reduced left ventricular pressure, prolonged duration of mitral regurgitation,

and reduced diastolic filling times in patients with left bundle branch block. BIVENTRICULAR PACING.

Biventricular or left ventricular pacing may counter the decreased septal contribution to stroke volume caused by late left ventricular activation occurring as the septum has begun repolarizing and help to increase ejection fraction[59A] (Fig. 24-12) . One of the earliest studies of biventricular pacing prospectively assessed six patients with end-stage congestive heart failure, dilated cardiomyopathy, sinus rhythm, and left bundle branch block (LBBB).[60] In this study, biventricular pacing was accomplished with a transvenous right ventricular lead and an epicardial left ventricular lead. After 3 months of biventricular pacing, median NYHA class had significantly improved from 4.0 to 2.5 (p = 0.03). In a study of 47 patients with advanced heart failure (32 percent Class III, 68 percent Class IV), biventricular pacing resulted in improved quality of life, increased exercise tolerance, and improvement in NYHA functional class.[61] Auricchio and associates[62] studied pacing with transvenous right atrial and right ventricular leads and a left ventricular epicardial lead in 27 patients with severe left ventricular systolic dysfunction. Overall, they found that biventricular and left ventricular pacing increased maximum left ventricular pressure derivative and aortic pulse pressure more than right ventricular pacing. They concluded that patients with congestive heart failure who have sufficiently wide QRS on surface ECGs derive maximum short-term benefit from left ventricular stimulation at an optimized AVI. Although the data to date are promising, randomized prospective trials are necessary to prove the efficacy and safety of cardiac resynchronization. Trials currently under way are Multicenter InSync Randomized Clinical Evaluation (MIRACLE), Multisite Stimulation in Cardiomyopathy (MUSTIC), [63] Pacing Therapy in Congestive Heart Failure (PATH-CHF),[64] Right Ventricular Outflow Versus Apical Pacing (ROVA), and Vigor-Congestive Heart Failure (Vigor-CHF)[65] (Table 24-10) . Pacing to Prevent Atrial Fibrillation (See Chaps. 23 and 25. )

Dual-site atrial pacing has been used to prevent recurrent atrial tachyarrhythmias, presumably by decreasing the dispersion of refractoriness in the atrium.[65A] Daubert and colleagues[66] used biatrial synchronous pacing with leads in the right atrial appendage and coronary sinus. Sensing from the lead in the right atrial appendage led to immediate pacing at the coronary sinus site. In a trial of biatrial synchronous pacing (SYNBIAPACE),[67] there was a trend toward a decreased incidence of atrial arrhythmias but no real benefit was shown. Saksena and associates[68] used one lead in a standard right atrial position and the other lead in the coronary sinus or near the coronary sinus ostium (Fig. 24-13) . Both leads were connected to the same port, resulting in simultaneous pacing at both sites. Dual-site pacing has been shown to reduce the number of episodes of paroxysmal atrial fibrillation and flutter and to increase the

interval to recurrent atrial arrhythmias.[68] [69] When "no pacing" was compared with dual-site or single-site atrial pacing,

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Figure 24-12 Posteroanterior (A) and lateral (B) chest radiographs demonstrating a ventricular lead that courses posteriorly in the coronary sinus and into a cardiac vein, probably a tributary of the posterior cardiac vein. From the posteroanterior view alone, this determination cannot be made.

TABLE 24-10 -- CLINICAL TRIALS IN PACING FOR CONGESTIVE HEART FAILURE (CHF) STUDY PATIENT ENDPOINT(S) TREATMENT KEY RESULTS INCLUSION ARMS CRITERIA InSync[61]

MIRACLE

NYHA Class III or IV on stable drug regimen

Quality of life

LVEDD >60 mm, LVEF 0.35

NYHA Class

QRS width 150 msec

6-minute hall walk


Quality of life

LVEDD NYHA Class 55 mm, LVEF 0.35 QRS width 130 msec

6-minute hall walk

Nonrandomized

In a nonrandomized trial, biventricular pacing resulted in sustained improvement in all three endpoints

Randomized to pacing or no pacing for 6 mo and then to pacing

In progress

Vigor-CHF[65]

Symptomatic Oxygen CHF on consumption stable drugs

One arm, VDD pacing

QRS 160 msec

Quality of life

No bradycardia indication for pacing

Cost-effectiveness

In progress

NYHA Class PATH-CHF

[64]

DCM of any cause

Maximum LV Acute pressure derivative hemodynamic assessment of RV pacing

Biventricular and LV: LV pressure derivative and aortic pulse pressure more than RV pacing


Aortic pulse pressure

LV pacing: LV pressure derivative more than biventricular pacing

vs.

QRS 120 msec

LV pacing

PR 150 msec

vs. Biventricular pacing

ROVA

Standard indication for PPM

Quality of life

Chronic AF

VVIR pacing from RV apex vs. RV outflow tract

NYHA Class II or III

Blinded crossover from RV apical to RV outflow tract pacing

In progress

LVEF 0.40 MUSTIC[63]

NYHA Class III

Functional capacity

Biventricular pacing

Refractory Quality of life symptoms on stable drug therapy

In progress

vs.

LVEF 60 mm

Mortality or need for transplant or LVAD

150 msec or AF with paced QRS >200 msec AF = atrial fibrillation; DCM = dilated cardiomyopathy; LV = left ventricular; LVAD = left ventricular assist device; LVEDD = left ventricular end-diastolic dimension; LVEF = left ventricular ejection fraction; MIRACLE = Multicenter InSync Randomized Clinical Evaluation; MUSTIC = Multisite Stimulation in Cardiomyopathy; NSR = normal sinus rhythm; NYHA = New York Heart Association; PATH-CHF = Pacing Therapy in Congestive Heart Failure; PPM = permanent pacemaker; ROVA = Right Ventricular Outflow Versus Apical Pacing; RV = right ventricular; Vigor-CHF = Vigor-Congestive Heart Failure.

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dual-site pacing was better, but single-site atrial pacing also resulted in a significant improvement over "no pacing." Single-site atrial septal pacing[70] and Bachmann's bundle pacing[71] have also been tested. In the Atrial Pacing Periablation for Prevention of Paroxysmal Atrial Fibrillation (PA3) study, atrial rate-adaptive pacing did not prevent paroxysmal atrial fibrillation during short-term follow-up in patients with drug-resistant paroxysmal atrial fibrillation.[72] The best pacing approach will be determined by multiple trials already under way, including Dual-Site Atrial Pacing to Prevent Atrial Fibrillation (DPPAF),[73] Systematic Trial of Pacing for Atrial Fibrillation (STOP-AF),[74] Pacing in Prevention of Atrial Fibrillation (PIPAF), and Atrial Fibrillation Therapeutics Trial (AFT)[75] (Table 24-11) .

Pacing in Long QT Syndrome (See Chaps. 23 and 25. )

The long QT syndrome is characterized by abnormally prolonged ventricular repolarization and a risk of development of life-threatening ventricular tachyarrhythmias. Therapy must be individualized depending on the clinical situation. Therapeutic options include beta-blocker therapy, permanent pacing, and the ICD (see later and Chap. 25 ).[76] PULSE GENERATOR IMPLANTATION Only qualified physicians should undertake pacemaker or cardioverter-defibrillator implantation. The recommended training requirements for pacemaker implantation[77] [78] are as follows: a base of core knowledge for pacemaker follow-up, participation in at least 100 pacemaker follow-up visits, participation in at least 50 initial transvenous pacemaker implantations as the primary operator (recommended that at least one half of these be dual-chamber), participation in at least 20 revisions of pacing systems, exposure to lead extraction techniques (suggested), and thorough knowledge of recognition and treatment of pacemaker and surgical complications and emergencies. A detailed description of pacemaker and cardioverter-defibrillator implantation technique can be found in texts devoted to these disciplines.[79] However, certain information related to the implantation technique is important for the referring physician to know. Almost all pacemakers and defibrillators are now implanted transvenously, with the pulse generator placed in the upper anterior portion of the chest, just anterior to the pectoralis major muscle. Epicardial pacing is considered only in persons without reasonable venous access, that is, no access to the right ventricle because of an associated TABLE 24-11 -- CLINICAL TRIALS IN PACING FOR THE PREVENTION OF ATRIAL FIBRILLATION (AF) STUDY PATIENT ENDPOINT(S) TREATMENT KEY RESULTS INCLUSION ARMS CRITERIA SYNBIAPACE[67] 1 yr history of recurrent and drug-refractory AA P wave duration 120 msec and IACT 100 msec

Time to first AA BASP at 70 recurrence beats/min

vs.

Single-site HRA at 70 beats/min

Trend to a in incidence of AA with BASP, but no real benefit of BASP

or Single-site HRA at 40 beats/min DAPPAF[73]

Bradycardia Time to first requiring pacing recurrence of symptoms of AF Two documented episodes of AF in prior 3 mo

Quality of life

Safety of DAP

Dual-site right atrial pacing

Results pending

or

Single-site atrial pacing vs. Support pacing mode (control arm)

STOP-AF[74]

Time to recurrence of PAF

Physiological pacing

In progress

vs. VVI pacing PA3

[72]

History of PAF with three episodes within year before

Time to recurrence of PAF 5 min occurring 2 wk after entry

Most recent Intervals PAF within 3 mo between of entry successive episodes of PAF At least one episode of PAF documented by ECG

Frequency of PAF

Proportion of patients who chose to defer ablation

DDDR pacemaker implanted and randomized to atrial pacing or no pacing

Atrial RAP did not prevent PAF over short term in patients with drug-resistant PAF

PIPAF

Indication for pacing

Time to first recurrence of AA

Comparison of six different lead and algorithm combinations

In progress

Documented Cumulative paroxysmal AAs arrhythmia for at least 1 yr, duration three episodes Stable drug therapy < Two cardioversions in past year AFT[75]

Paroxysmal AF

Frequency of DDD pacing at In progress AF recurrences 40 beats/min (backup pacing) vs. DDD pacing at 70 beats/min with specific AF prevention algorithm

AA = atrial arrhythmia; AFT = Atrial Fibrillation Trial; BASP = biatrial synchronous pacing; DAP = dual-site atrial pacing; DAPPAF = Dual-Site Atrial Pacing to Prevent Atrial Fibrillation; ECG = electrocardiography; HRA = high right atrium; IACT = interatrial conduction time; PA3 = Atrial Pacing Periablation for Prevention of Paroxysmal Atrial Fibrillation; PAF = paroxysmal atrial fibrillation; PIPAF = Pacing in Prevention of Atrial Fibrillation; RAP = rate-adaptive pacing; STOP-AF = Systematic Trial of Pacing for Atrial Fibrillation; SYNBIAPACE = Synchronous Biatrial Pacing.

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Figure 24-13 Posteroanterior (A) and lateral (B) chest radiographs in a patient with a dual-site atrial pacing system for the prevention of paroxysmal atrial fibrillation. Leads are positioned in the right atrium, near the coronary sinus ostium, and in the right ventricular apex.

congenital anomaly, a prosthetic tricuspid valve, or an intracardiac right-to-left shunt. Although multiple venous routes have been used for lead placement, the subclavian and cephalic veins are most commonly used. The subclavian approach involves a

subclavian puncture and the use of one or more peel-away introducers. A lateral approach to the subclavian vein, often lateral enough to be the axillary vein, is preferred to minimize the risk of pneumothorax and to avoid subclavian crush injury to the lead, which is more common when a medial approach is used. The cephalic vein is often large enough to accept one or two pacing leads, and this approach avoids the risks associated with blind subclavian puncture. Potential complications of subclavian puncture include pneumothorax, hemopneumothorax, subclavian artery puncture, brachial nerve plexus injury, and thoracic duct injury. Specific measurements must be accomplished at the time of pacemaker or cardioverter-defibrillator implantation (Table 24-12) . After placement of the pulse generator, posteroanterior and lateral chest radiographs must be obtained to exclude pneumothorax and also to ensure adequate lead positioning. Before hospital dismissal, the pulse generator should be programmed to determine pacing and sensing thresholds for final programming with adequate safety margins. If the pulse generator is being programmed to a rate-adaptive pacing mode, adequate rate response should be assessed by formal or informal stress testing. TABLE 24-12 -- MEASUREMENTS DURING IMPLANTATION OF PACEMAKER OR CARDIOVERTER-DEFIBRILLATOR Threshold of stimulation Atrium* Ventricle Sensing threshold Atrium Ventricle Measurement of electrogram Atrium* Ventricle Measurement of antegrade conduction§ Wenckebach-block point Defibrillation threshold *Necessary only when an atrial lead is being placed. Necessary only when an atrial lead or a single-pass VDD lead is used. Considered optional by many, and these measurements may be accomplished noninvasively with many devices. §Necessary only when an AAI/R implant is considered. For ICD implantation only.

PACEMAKER PROGRAMMING Almost all pacemakers are capable of programming rate, pulse width, voltage amplitude, sensitivity, refractory period, and polarity (Table 24-13) . Many clinicians fail to take advantage of optimizing pacemaker function with programmable options, with estimates that up to 50 percent of all pacemakers implanted are never changed from nominal parameters. A few features deserve additional discussion. Programming Pulse Width and Voltage Amplitude

Output programming is probably the most important aspect of programming that should be performed routinely. The output must be high enough to allow an adequate pacing margin of safety but should also be programmed with the intent of maximizing pacemaker longevity. A strength-duration curve plots voltage and pulse width thresholds and

Figure 24-14 Programmer-generated strength-duration threshold curve. "X" notes the output parameter settings calculated by the programmer that would allow an adequate safety margin and maximize pacemaker longevity.

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TABLE 24-13 -- PROGRAMMABLE OPTIONS FOR PACEMAKERS PARAMETER DESCRIPTION TYPICAL VARIABLES Mode

Preset or programmed response from a pacemaker with or without intrinsic cardiac events

VOO, AOO, VVI, AAI, VDD, DVI, DDD, DDI, DOO, VVT, AAT (all but AAT, VVT could also have "R," or rate-adaptive, capability)

Lower rate limit

Preset or programmed rate at which a pacemaker emits an output pulse without intrinsic cardiac activity

30 to 150 beats/min (options faster than 150 beats/min available in some pulse generators)

Ventricular refractory period

An interval of the pacemaker timing 150 to 500 msec cycle following a sensed or paced ventricular event during which the ventricular sensing channel is totally or partially unresponsive to incoming signals

Pulse width

Duration, in milliseconds, over which 0.05 to 1.9 msec the output is delivered

Pulse amplitude

Magnitude of the voltage level reached during a pacemaker output pulse, usually expressed in volts

0.5 to 8.1 V

Sensitivity

Ability to sense an intrinsic electrical signal, which depends on the amplitude, slew rate, and frequency of the signal

Atrial: 0.18 to 8 mV

Ventricular: 1.0 to 14 mV Polarity

Stimulating electrode typically is the cathode, which has negative polarity relative to the indifferent electrode (anode)

Device may be programmable to only bipolar or unipolar; others may have more control by programming unipolar-bipolar pace-sense on either lead

Hysteresis

Extension of the escape interval after In single-chamber a sensed intrinsic event modes, commonly 40, 50, or 60 beats/min or off

Circadian lower rate limit

Reduces the lower rate limit during sleeping hours

Lower rates during sleep, programmable from 30 beats/min as the slowest rate usually offered

Mode switch

Capability of a dual-chamber pacemaker to automatically switch from an atrial tracking (P-synchronous) mode to a non-atrial-tracking mode when an atrial rhythm occurs that the pacemaker determines to be pathologic. When the atrial rhythm meets the criteria for a physiologic rhythm, the mode switches back to an atrial-tracking mode.

On or off; if on, the detection rates are often programmable for rates 120 to 190 beats/min

Fallback

An upper rate response in which the ventricular paced rate decelerates to, and is maintained at, a programmable fallback rate that is lower than the original programmed maximum tracking rate. Fallback mechanisms vary among pacemakers.

May be programmable on or off; if on, the rate to which the fallback occurs may be fixed or programmable (i.e., 50 to 80 beats/min)

Rate smoothing

Prevents atrial or ventricular paced rate from changing by more than a programmed percentage from one cardiac cycle to the next. This prevents large cycle-to-cycle intervals that can be seen at the upper rate limit or during rapid acceleration of atrial rate.

On or off; may then have options of % smoothing (i.e., 9% to 25% change per cycle length allowed); may also have option of being on or off for rate increments or decrements, or both

Atrioventricular interval Period between the initiation of the 30 to 350 msec (AVI) paced or sensed atrial event and the delivery of a consecutive ventricular output pulse. Differential AVI

Feature that permits a longer AVI Offset from 0 to 200 after a paced atrial event than after a msec sensed AVI. In some pacemakers, this differential is fixed; in others, it is programmable.

Rate-adaptive AVI

Shortens the AVI as the heart rate increases

On or off only in some devices; in others, able to set the minimum atrioventricular delay to as short as 30 msec

Postventricular atrial refractory period (PVARP)

Period after a paced or sensed ventricular event during which the atrial channel is refractory

150 to 500 msec; in some devices, auto-PVARP adjusts with cycle length

PVARP extension

Lengthening of the PVARP after a sensed premature ventricular contraction to prevent sensing of a retrograde P wave

On or off in some; others may program length of extension to as long as ~500 msec

Pacemaker-mediated tachycardia (PMT) algorithms

Manufacturer-specific algorithms to terminate PMT

On or off; in others, can choose how long the maximum tracking rate must persist before detection criteria are met

Blanking period

Temporary disabling of pacemaker-sensing amplifiers after an output pulse

Ventricular blanking: 20 to 50 msec Postventricular atrial blanking: 100 to 350 msec

Ventricular safety pacing

Delivery of a ventricular output pulse On or off after atrial pacing if a signal is sensed by the ventricular channel during the crosstalk sensing portion of the AVI

Maximum tracking rate The sum of the AVI and the PVARP

80 to 180 beats/min

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Figure 24-15 A, The paced atrioventricular interval (AVI) corresponds to the programmed value, that is, the interval allowed after a paced atrial beat before a ventricular pacing artifact is delivered. B, The initial portion of the AVI in most dual-chamber pacemakers is designated the blanking period, during which sensing is suspended. The blanking period is intended to prevent ventricular sensing of the atrial pacing artifact. Any event that occurs during the blanking period, even if it is an intrinsic ventricular event, as shown in this illustration, is not sensed and is followed by a ventricular pacing artifact delivered at the programmed AVI. C, If the ventricular sensing circuit senses activity during the crosstalk sensing window, a ventricular pacing artifact is delivered early, usually at 100 to 110 milliseconds after the atrial event, that is, "ventricular safety pacing." PVC = premature ventricular contraction. (From Hayes DL, Levine PA: Pacemaker timing cycles. In Ellenbogen KA [ed]: Cardiac Pacing, Boston, Blackwell Scientific Publications, 1992, p 263.)

allows determination of appropriate values to ensure an adequate safety margin. There is no consensus of the best way to program output parameters, but options [80] include doubling the voltage amplitude at threshold; tripling the pulse width at threshold; determining the threshold, obtaining a telemetered reading of threshold energy in microjoules, and programming output parameters to achieve a triple microjoule threshold; basing programmer-determined output parameters on autothreshold testing; and applying autocapture technology. At least one manufacturer has pacemakers capable of calculating and graphically displaying a strength-duration curve as well as suggesting optimal output parameters (Fig. 24-14) . Automatic programming of output functions, "autocapture," has been actively investigated for over a decade, but only recently have manufacturers developed this as a reliable option. It is too early to determine how widely this feature will be embraced by clinicians.[80A] Atrioventricular Interval

Several components of the AVI must be understood to optimally program the pacemaker ( Fig. 24-15 A). The initial portion of the AVI is the blanking period, during which all sensing is suspended. This period is necessary to prevent sensing of the atrial output pulse on the ventricular sensing circuit, that is, crosstalk. This interval is commonly in the range of 12 to 50 msec, depending on the pacemaker, and is programmable in many pacemakers. If the blanking period is too long, a spontaneous R wave, occurring soon after the atrial stimulus, is not sensed and a competitive ventricular stimulus is emitted (see Fig. 24-15 B). The period after the blanking period is the crosstalk-sensing window. After the relatively short blanking period, if an event is sensed on the ventricular sensing circuit, the pacemaker is unable to distinguish with certainty the source of the sensed event. Given the possibility of sensing the decay of the atrial pacing output, sensing in the crosstalk-sensing window forces ventricular safety pacing or the "nonphysiological AV delay" (see Fig. 24-15 C). Because the "safety" stimulus occurs at a fixed delay after the beginning of the "safety pacing" interval, the total AVI is likely to be abbreviated. Because several early pacemakers had a ventricular safety pacing interval of 110 milliseconds, the designation "110-msec phenomenon" has also been used. DIFFERENTIAL AVI.

Because the interatrial contraction after a sensed atrial event is shorter than that after a paced atrial event, an option exists for a differential AVI in an attempt to provide a PR interval of equal duration whether the atrial contraction is paced or sensed[81] (Fig. 24-16) . In some pacemakers, the differential is programmable, and in others, a preset differential is used when this feature is programmed "on." RATE-VARIABLE OR RATE-ADAPTIVE AVI.

DDDR pacemakers can shorten the AVI during AV sequential sensor-driven pacing. Rate-adaptive or rate-variable AVI is intended to optimize cardiac output by mimicking the normal physiological decrease in the PR interval that occurs in the normal heart as the atrial rate increases during exercise.[82] Mode Switching

Mode switching is the ability of the pacemaker to automatically change from one mode to another in response to an inappropriately rapid atrial rhythm[83] [83A] (Fig. 24-17) . Mode switching is particularly useful for patients with paroxysmal supraventricular rhythm disturbances.[83B] In the DDD or

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Figure 24-16 Differential atrioventricular interval (AVI) is demonstrated by a paced atrial event initiating an AVI of approximately 150 milliseconds and a sensed atrial event initiating an AVI of approximately 125 milliseconds. The measured AVI is numerically noted between the A and V markers. The numbers following the V marker reflect the measured VA interval (top) and VV interval (bottom).

DDDR pacing modes, if a supraventricular rhythm disturbance occurs and the pacemaker senses the pathological atrial rhythm, rapid ventricular pacing can occur. Any pacing mode that eliminates tracking of the pathological rhythm, that is, DDI, DDIR, DVI, or DVIR, also eliminates the ability to track normal sinus rhythm, which is usually the predominant rhythm. Mode switching avoids this limitation by switching from DDD or DDDR during sinus rhythm to a nontracking mode, such as DDIR, during the pathological atrial rhythm. Rate-Adaptive Parameters

The goal of programming rate-adaptive pacemakers is to optimize the patient's chronotropic response.[83C] It is inappropriate to implant a rate-modulating pacemaker and program the sensor "on" without assessing rate response. Pacemakers capable of rate modulation are packaged with the sensor "off"; and to effect rate modulation, the sensor must be programmed "on." Although the manufacturer usually states "nominal" values for rate response parameters, the nominal values are not appropriate for all patients. Some form of exercise is necessary to optimize rate-adaptive parameters. For patients who are limited to "activities of daily living," informal exercise testing, such as walking at casual and brisk paces in the hospital corridor or in the outpatient facility, is often adequate. In determining the appropriate heart rate response, the patient's age and "usual activities" must be taken into consideration.[84] If formal exercise testing is performed, the chronotropic exercise assessment protocol[85] or a low-intensity exercise protocol may be preferable to a standard Bruce protocol. The chronotropic exercise assessment protocol allows for a gradual increase in speed and grade and thus mimics levels of exercise that are likely to occur during activities of daily living. Alternatively, rate adaptation can be assessed and enhanced

Figure 24-17 Electrocardiographic tracing from a patient with a DDD pacemaker. In the initial portion of the tracing, the pacing is in sinus rhythm. This is followed by the onset of an atrial tachyarrhythmia with initial tracking, but mode switching causes reversion to a VVIR pacing mode. (The top tracing is the surface electrocardiogram, the middle tracing represents the atrial electrogram, and the lower tracing represents the ventricular electrogram.)

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by diagnostic tools incorporated within the pacemaker. There are many variations, including histograms of rate response and ambulatory monitoring capabilities. If the

pacemaker is capable of automatically optimizing rate response parameters, the patient must still be assessed to see if the automatically programmed parameters result in the appropriate rate response. PACEMAKER COMPLICATIONS Complications can be divided into those related to implantation and those related to failure of a component of the pacing system. [86] There are also problems encountered during follow-up that are actually pseudoabnormalities, that is, a normal response that appears abnormal because of unusual timing or because of idiosyncrasies of the device. Many complications are directly related to the experience of the implanter. One study demonstrated a significantly higher incidence of complications when implanters performed fewer than 12 implantations per year. [87] Implant-Related Complications

Most patients undergoing pacemaker implantation have some discomfort at the site of the incision in the early postoperative period. Mild analgesics may be required. Mild ecchymoses around the incision are not uncommon. As previously noted, if subclavian puncture is used for lead placement, several potential complications of this "blind" technique can occur, including the possibility of traumatic pneumothorax and hemopneumothorax, inadvertent arterial puncture, air embolism, arteriovenous fistula, thoracic duct injury, subcutaneous emphysema, and brachial plexus injury.[88] Hematoma formation at the pulse generator site most commonly occurs when anticoagulant therapy is initiated or reinstituted prematurely. A hematoma must be dealt with on the basis of its secondary consequences. Evacuation of the hematoma should be considered only if there is continued bleeding, potential compromise of the suture line or skin integrity, or pain from the hematoma that cannot be managed with analgesics. Aspiration is generally not advised. Introduction of the lead or leads into the subclavian artery, the aorta, and the left ventricle usually is readily recognized because of the pulsatile flow of saturated blood. A pacing lead may also be placed in the left ventricle by passing it across an unsuspected atrial or ventricular septal defect (Fig. 24-18) . Once the lead is within the subclavian artery, passage into the left ventricle is as easy as passage into the right ventricle via the venous system. Left ventricular lead placement should be recognized if lateral fluoroscopy is used or a lateral chest radiograph is obtained, because the lead is in the posterior aspect of the heart. The ECG during right ventricular pacing usually has an LBBB pattern and during left ventricular pacing most commonly an RBBB pattern. Although thresholds may be adequate, lead placement in the arterial circulation is associated with thrombus formation, embolization, and, consequently, stroke. Reports of long-term uncomplicated left ventricular endocardial pacing exist, but the risk of embolization continues. Removal of the left ventricular lead should be undertaken if this position is recognized early after implantation. If it is recognized years after uncomplicated pacing, the best approach may be to administer anticoagulants and

leave the lead in place. Management must be individualized. Patients undergoing device implantation should be made aware of the potential for lead perforation. Although cardiac tamponade is the most dramatic outcome from perforation, lack of symptoms after ventricular perforation by a lead is not uncommon. The only sign may be a rising stimulation threshold. In other patients, the signs may include RBBB pattern from a lead placed in the right ventricle, intercostal muscle, or diaphragmatic contraction; friction rub after implantation; and pericarditis, pericardial effusion, or cardiac tamponade. (Depending on lead position, an RBBB pattern is also possible when the lead is within the right ventricular cavity.) Ventricular perforation may be suggested by radiography, electrocardiography, and echocardiography. Once perforation is identified, lead withdrawal and repositioning are usually uncomplicated, although pericardial bleeding or tamponade results rarely. Partial or silent inconsequential venous thrombosis of the subclavian vein is not uncommon after transvenous lead placement and is usually clinically insignificant. Such partial or silent thrombosis may limit venous access at the time of pacing system revision.[89] Symptomatic thrombosis can be the result of occlusion of the superior vena cava, with superior vena cava syndrome; thrombosis of the superior vena cava, right atrium, or right ventricle, with hemodynamic compromise or pulmonary embolism; or symptomatic thrombosis of the subclavian vein, with an edematous, painful upper extremity. Lead-Related Complications

Several lead-related complications deserve attention, including lead dislodgment (Fig. 24-19) , loose connector pin

Figure 24-18 Posteroanterior chest radiographs of a dual-chamber pacemaker. A, Ventricular lead is passing through an atrial septal defect into the left ventricle. B, Lead is repositioned in the right ventricular apex.

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Figure 24-19 Posteroanterior chest radiographs of a dual-chamber pacemaker. A, Underpenetrated film makes it difficult to identify lead position. B, Lateral view demonstrates definite dislodgment of the atrial lead into the superior vena cava.

(Fig. 24-20) , conductor coil fracture, insulation break, and exit block. Active and passive fixation mechanisms common to current pacing leads have

significantly reduced the incidence of lead dislodgment. Acceptable dislodgment rates should probably be less than 1 percent for ventricular leads and no more than 2 to 3 percent for atrial leads. Dislodgment has been classified as "macrodislodgment" and "micro-dislodgment." Macrodislodgment is radiographically evident (see Fig. 24-19 ), microdislodgment is not. Adequate lead position is assessed by posteroanterior and lateral chest radiographs and comparison with any previous chest radiographs. Intermittent or complete failure of output can occur because of a loose connection at the interface of the lead and connector block (see Fig. 24-20 ), usually because the lead was inadequately secured at

Figure 24-20 A, Posteroanterior chest radiograph in a patient with a VVI pacemaker and a bifurcated bipolar ventricular lead. The patient presented with recurrent near-syncope and intermittent failure to output. (Arrowhead notes inadequate atrial lead positioning; that is, the J portion of the lead is too shallow.) B, Close-up of the pacemaker reveals that the lower connector pin is not securely in the connector block (arrow). (For comparison, the arrowhead notes an appropriately engaged connector pin.) (From Hayes DL: Pacemaker radiography. In Furman S, Hayes DL, Holmes DR Jr [eds]: A Practice of Cardiac Pacing. 3rd ed. Mount Kisco, NY, Futura Publishing Company, 1993, p 361. By permission of Mayo Foundation.)

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Figure 24-21 Posteroanterior chest radiographs in a patient with a dual-chamber pacemaker. A, Fracture of one lead (upper arrow) has occurred where the lead passes below the clavicle. Positioning of the atrial lead is shallow and suboptimal (lower arrow). B, Enlarged view of fracture (arrow). (From Hayes DL: Pacemaker complications. In Furman S, Hayes DL, Holmes DR Jr [eds]: A Practice of Cardiac Pacing. 3rd ed. Mount Kisco, NY, Futura Publishing Company, 1993, p 537. By permission of Mayo Foundation.)

the time of pacemaker implantation. When a connection is loose, manipulating the pulse generator or pocket may reproduce the problem. The poor connection may be evident radiographically. Lead fractures most often occur adjacent to the pacemaker or near the site of venous access, that is, at a stress point (Fig. 24-21) . Although uncommon, direct trauma may result in damage to the pacing lead. If a fracture of a bipolar lead occurs and the pacemaker is polarity programmable, it may be possible to restore pacing by reprogramming to the unipolar configuration. This is a short-term solution and should not be a substitute for replacing the lead. Loss of integrity of the insulating material has occurred because of flaws in the design or manufacturing process of the lead, "wear and tear," and crush injury. Insulation defects and conductor fractures may both be caused by crush injury, specifically at the

costoclavicular space when placement is by the subclavian puncture technique.[90] Thresholds, lead impedance, and electrograms are helpful in differentiating an insulation defect from a conductor fracture. This information may be obtained by measurements made during implantation or by telemetric capabilities of many pacemakers (Table 24-14) . Failure to capture due to exit block is uncommon. Exit block appears to be an abnormality at the myocardial tissue-electrode interface, resulting in a progressive rise in thresholds with normal radiographic appearance. Steroid-eluting leads are often effective in preventing exit block. Supraventricular and ventricular arrhythmias, often encountered during pacemaker implantation, are usually inconsequential. "Tip extrasystoles" can be seen in the early postimplantation period. These are ventricular complexes morphologically similar to the paced beats because they originate at the same site as the paced beats, but they are not preceded by a pacemaker stimulus. Tip extrasystoles most often occur during the first 24 to 48 hours after implantation and usually resolve spontaneously. Pharmacological suppression of tip extrasystoles is rarely necessary. "Runaway pacemaker" describes a sudden increase in pacing rate caused by circuit malfunction. This phenomenon is rare with current pacemakers. In recent years, the rare reports of runaway have usually described a complication of pacemaker exposure to therapeutic radiation, with subsequent damage to the circuit. [91] Endless-loop tachycardia, already described, is another well-recognized pacemaker-related rhythm disturbance. Extracardiac stimulation usually involves the diaphragm or pectoral muscle. Diaphragmatic stimulation may be due to direct stimulation of the diaphragm (usually stimulation of the left hemidiaphragm) or stimulation of the phrenic nerve (usually stimulation of the right hemidiaphragm). Diaphragmatic stimulation occurring during the early postimplantation period may be due to either microdislodgment or macrodislodgment of the pacing lead. Stimulation can be minimized or alleviated by decreasing the voltage output or pulse width (or both), but an adequate pacing margin of safety must be maintained after the output parameters are decreased. Local muscle stimulation occurs much more commonly with unipolar than with bipolar pacemakers and is usually noted in the early postimplantation period. Pectoral muscle stimulation can also be due to an insulation defect of the pacing lead, current leakage from the connector or sealing plugs, or erosion of the pacemaker's protective coating. If the problem is due to an insulation defect on either a unipolar pacemaker or the pacemaker lead, decreasing the voltage output or the pulse width (or both) may minimize the stimulation, but the defective portion of the system may have to be replaced. If pectoral muscle stimulation occurs in a polarity-programmable pacemaker that is programmed unipolar, reprogramming to the bipolar configuration may alleviate

the problem. Pacemaker System Infection

Erosion is an uncommon complication that most commonly occurs because of an indolent infection, although it may also be the result of a pacemaker pocket that is too "tight." If the patient seeks medical attention before the pacemaker has eroded through the skin, it may be possible to revise the pocket and reimplant the pacemaker. Impending erosion should be dealt with as an emergency, because once any portion of the pacemaker has eroded through the skin, the only choice is removal of the pacemaker system and placement of a new system in another site. Infection may be present even without purulent material; therefore, a specimen for culture should be obtained and proven negative before pocket revision. Adherence of the TABLE 24-14 -- INTRAOPERATIVE EVALUATION OF PACING SYSTEM DEFECT VOLTAGE CURRENT LEAD THRESHOLD THRESHOLD IMPEDANCE Wire fracture

High

High, normal, or low

High

Insulation break

Low

High

Low

Lead dislodgment

High

High

Normal

Exit block

High

High

Normal

Modified from Hayes DL, Osborn MJ: Pacing: A. Antibradycardia devices. In Giuliani ER, Gersh BJ, McGoon MD, et al (eds): Mayo Clinic Practice of Cardiology, 3rd ed. St. Louis, CV Mosby, 1996, p 961. By permission of Mayo Foundation.

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pacemaker to the skin strongly suggests an infection, and salvage of the site may not be possible. The incidence of infection after pacemaker implantation should certainly be less than 2 percent and in most series has been less than 1 percent. [92] Careful attention to surgical details and sterile procedures is of paramount importance in avoiding pacemaker site infection. Prophylactic use of antibiotics before implantation and in the immediate postoperative period remains controversial.[93] Most studies do not show any significant difference in the rate of infection between patients who have had prophylactic administration of antibiotics and those who have not. Irrigation of the pacemaker pocket with an antibiotic solution at the time of pacemaker implantation is probably more

important in the prevention of infection. Pacemaker infection may appear as local inflammation or abscess formation in the pacemaker pocket, erosion of part of the pacing system with secondary infection, or sepsis with positive blood culture findings with or without a focus of infection elsewhere. The most common clinical presentation is localized pocket infection; septicemia is uncommon. Many infectious agents can be responsible, but early infections are most commonly caused by Staphylococcus aureus, are aggressive, and are often associated with fever and systemic symptoms. Late infections commonly are caused by Staphylococcus epidermidis and are more indolent--usually without fever or systemic manifestation. Treatment for both organisms requires removal of the entire infected pacing system, pacemaker, and leads. A detailed description of lead extraction techniques is beyond the scope of this text.[94] [94A] The various approaches include simple traction, locking stylet and telescoping sheaths with countertraction,[95] laser-assisted extraction,[96] and open surgical techniques. Laser-assisted lead extraction has been the subject of a multicenter study, the Pacing Lead Extraction with Excimer Laser System (PLEXES) trial. Randomization of patients to laser-assisted extraction technique or to standard extraction techniques demonstrated efficacy of laser-assisted lead extraction.[96] When to extract leads is at times controversial. A question that arises frequently is how many noninfected leads can be abandoned and left in place. Multiple leads can usually safely be left in place as long as no one of them has been part of an infected system.[97] TROUBLESHOOTING ELECTROCARDIOGRAPHIC ABNORMALITIES Electrocardiographic (ECG) abnormalities in the paced patient can be broadly grouped into failure to capture, failure to output, sensing abnormalities (undersensing or oversensing), and inappropriate rate change.[98] [99] FAILURE TO CAPTURE.

Failure to capture indicates that a pacing artifact is present without subsequent cardiac depolarization (Fig. 24-22) . The possible causes of failure to capture are high thresholds with an inadequately programmed output, partial conductor coil fracture, insulation defect, lead dislodgment or perforation, impending total battery depletion, functional noncapture, poor or incompatible connection at the connector block, circuit failure, air in the pulse generator pocket (unipolar pacemaker), and elevated thresholds due to drugs or metabolic abnormality. FAILURE TO PACE.

Failure to pace, or failure to output, that is, failure to deliver an appropriate pacing stimulus, is often due to oversensing and inhibition of output but could also be due to true failure to output from the pacemaker or circuit interruption that prevents the electrical signal from reaching the heart (Fig. 24-23) . The reasons for failure to output are circuit failure, complete or intermittent conductor coil fracture, intermittent or permanently loose set screw, incompatible lead or header, total battery depletion, internal insulation failure (bipolar lead), oversensing of any noncardiac activity, crosstalk, and lack of anodal connector contact (e.g., unipolar lead in bipolar generator, bipolar lead in pacemaker programmed in unipolar mode, air in the pocket of a unipolar device, and unipolar pacemaker not in the pocket). The differential diagnoses of failure to capture and failure to pace obviously overlap somewhat. For example, ECG manifestations of a conductor coil fracture may include failure to capture due to significant leakage of current at the incomplete fracture site, with not enough current remaining to result in stimulation. Nonetheless, the pacemaker stimuli can appear. Alternatively, escaping current can be sensed by the pacemaker and inhibit pacemaker output. If the conductor coil is completely fractured, rendering the circuit incomplete, no pacemaker output will be detected on the ECG. Insulation defects can also be signaled by oversensing and failure to pace or by failure to capture, although the most common consequences of insulation failure are sensing abnormalities. As the pacemaker battery reaches end stages of depletion, either failure to capture due to decreasing voltage output or failure to pace due to total battery depletion can occur. This degree of battery depletion should be avoided by appropriate pacemaker follow-up. Apparent failure to capture is noted if a pacemaker stimulus occurs during the refractory period of a spontaneous beat. This is referred to as "functional noncapture." FAILURE TO SENSE.

Sensing abnormalities can be divided into true abnormalities, including undersensing, a failure to recognize normal intrinsic cardiac activity (Fig. 24-24) , and oversensing (see Fig. 24-23 ), unexpected sensing of an intrinsic or extrinsic electrical signal, and functional sensing abnormalities. The possible causes of sensing abnormalities are lead dislodgment or poor lead positioning, lead insulation failure, circuit failure, magnet application, malfunction of reed switch, electromagnetic interference, and battery depletion. The morphology of the intrinsic event is different from that measured at implantation. True undersensing is most commonly due to lead dislodgment or inadequate initial lead placement. Sensing abnormalities commonly can be seen secondary to insulation defects and to intermittent, "make or break" conductor fracture. A normally functioning pacing system at times fails to detect atrial or ventricular extrasystoles. The intrinsic events measured at the time of implantation generate an electrogram at the electrode tip. If an extrasystole is occurring elsewhere in the heart, the sensing vector is different from that of the normal intrinsic beat, and the resulting voltage generated may not be

great enough to be sensed by the pacemaker. This anomaly cannot be anticipated unless extrasystoles of the same morphology occur during implantation and can be measured. It is reasonable to attempt reprogramming the sensitivity to allow the extrasystoles to be sensed, but if this is unsuccessful, it is rarely, if ever, necessary to reposition the lead for this abnormality. Functional undersensing is present when an intrinsic cardiac event is not sensed because it falls within a programmed refractory period.[100] For example, if an intrinsic atrial event occurs within the PVARP, the event is not, and should not be, sensed. However, without a thorough understanding of the timing cycle, it may appear as though there is true undersensing. Fusion and pseudofusion beats occur as a result of superimposition of an ineffective pacemaker stimulus on a spontaneously occurring P wave or QRS complex (Fig. 24-25) . (Fusion is present when the

Figure 24-22 Electrocardiographic tracing from a patient with a VVIR pacemaker programmed to a lower rate of 60 beats/min (1000 milliseconds). The second ventricular pacing artifact fails to result in ventricular depolarization, failure to capture. This is followed by a pause longer than the programmed lower rate of 1000 milliseconds. This pause most likely is explained by oversensing of some event on the ventricular sensing circuit. Ventricular pacing then resumes at the programmed rate of 60 beats/min.

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Figure 24-23 Electrocardiographic tracings. A, Patient with a VVIR pacemaker with a lower rate of 70 beats/min. After an initial paced ventricular beat, there is a pause of approximately 2.8 seconds with significant baseline artifact. After two additional paced beats, another pause of approximately 2.8 seconds occurs. This patient had a pacemaker programmed to a unipolar sensing configuration. Sensing of myopotentials led to symptomatic pauses, and reprogramming the pacemaker to a bipolar sensing configuration prevented subsequent myopotential oversensing. B, Patient with a DDD pacemaker. After the third atrial pacing artifact, there is evidence of atrial depolarization, but there is no ventricular pacing output. Failure to deliver the ventricular pacing artifact is due to crosstalk; that is, the atrial pacing output is sensed by the ventricular sensing circuit, with subsequent inhibition.

morphology of the cardiac event is a hybrid of the intrinsic morphology and the paced morphology. Pseudofusion is present when the pacemaker artifact occurs late enough that the intrinsic morphology is not deformed, but it may appear so because of distortion on the ECG by the superimposed pacing artifact.) Pseudofusion is usually the consequence of pacemaker discharge during the refractory period of intrinsic P or QRS before sufficient intracardiac voltage is generated to activate the sensing circuit. This is most likely to occur when the pacing rate and the intrinsic rate are similar. Pseudofusion beats also can be the result of a delayed activation due to intraventricular conduction abnormalities.

INAPPROPRIATE PACING MODE.

Every pacing mode has a defined lower rate, and dual-chamber pacemakers and rate-adaptive pacemakers also require a defined upper rate. It is necessary to be familiar with the timing cycle of a particular pacing mode and any idiosyncrasies of the specific pacemaker to be able to determine whether the paced rate is appropriate. The possible causes of a paced rate that appears to be different from that programmed are circuit failure, battery failure, magnet application, hysteresis (Fig. 24-26) , crosstalk, undocumented reprogramming of the pacemaker, oversensing, runaway pacemaker, and malfunction of the ECG recording equipment, such as alteration in the paper speed. Drugs can affect sensing thresholds, pacing thresholds, and defibrillation thresholds and result in ECG abnormalities.[98] [101] Although many drugs have been reported to affect pacing thresholds, the Class 1C agents are the only drugs that commonly cause a problem. Encainide, flecainide, propafenone, and moricizine have the potential to increase pacing thresholds and sensing thresholds. If these drugs are administered to the patient with a pacemaker, especially a pacemaker-dependent patient, thresholds should be monitored for change. Electrolyte and metabolic abnormalities can also affect pacing and sensing thresholds. Hyperkalemia is the most common electrolyte abnormality to cause clinically significant problems, but severe acidosis or alkalosis, hypercapnia, severe hyperglycemia, hypoxemia, and myxedema may also result in threshold alteration.[98] ELECTROMAGNETIC INTERFERENCE Electromagnetic interference (EMI) is defined as any signal, biological or nonbiological, that is within a frequency spectrum that can be detected by the sensing circuitry of the pacemaker or ICD. EMI can result in rate alteration, sensing abnormalities, asynchronous pacing, noise reversion (Fig. 24-27) , or reprogramming. [101A] EMI can also result in failure to deliver antibradycardia pacing, inappropriate delivery of antitachycardia therapy, resetting of programmed parameters, and damage to the pulse generator or myocardial interface. Other cardiac and extracardiac signals that may be falsely interpreted as a P or QRS and result in oversensing include T waves (Fig. 24-28) , myopotential interference, afterpotential delay, and P waves. Nonbiological sources of EMI are best divided into sources of EMI within the hospital and outside the hospital. Although multiple sources of EMI in the nonhospital environment can potentially result in single-beat inhibition, few, if any, of these are clinically significant and truly represent a threat to the paced patient. Several potential sources of EMI require specific mention either because of their real potential for causing significant EMI or because of confusion or controversy that exists in or out of the medical community. Industrial-strength welding equipment, that is, more

than 500 A, certain degaussing equipment, and induction ovens are identified sources of EMI that can cause significant pacemaker or ICD interference. [101] Most welding equipment used for "hobby" welding should

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Figure 24-24 Electrocardiographic tracing from a patient with a VVI pacemaker with a programmed rate of 70 beats/min. After two paced ventricular complexes, a premature ventricular complex occurs. In approximately 260 milliseconds, a ventricular pacing artifact occurs. This is followed by a P wave with intrinsic atrioventricular nodal conduction and native QRS complex. A pacemaker artifact follows in approximately 220 milliseconds. This represents ventricular undersensing. In this patient, the abnormality occurred because of an insulation failure of the ventricular pacing lead.

Figure 24-25 Electrocardiographic tracing from a patient with a VVI pacemaker. The first two complexes represent fully paced ventricular depolarizations. The third ventricular event is an intrinsic QRS complex, and the fourth event represents a fusion beat. This is followed by two paced ventricular complexes.

Figure 24-26 Electrocardiographic tracing from a patient with a VVI pacemaker programmed to a lower rate of 60 beats/min and a hysteresis rate of 40 beats/min. The longer cycle follows an intrinsic ventricular beat.

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Figure 24-27 Electrocardiographic tracing from a patient with a DDD pacemaker during exposure to electromagnetic interference. This pacemaker responds with asynchronous pacing as the noise reversion mode.

not cause any significant problems. In the pacemaker-dependent patient who does hobby welding or any other activity that raises the clinician's concerns about EMI, attempts should be made to be certain that the environment is safe for the patient. Currently, there is much interest in the potential EMI that may emanate from cellular telephones[102] [103] and antitheft devices.[104] [105] [106] Available information suggests that analog cellular phones are safe for the paced patient. Digital cellular phones have greater potential for EMI, and some caution remains for the pacemaker-dependent patient using a telephone with digital technology. If the patient avoids having the cellular phone over the pacemaker, either from random motion of the phone or by carrying the activated phone in a breast pocket over the pacemaker, any adverse clinical event is

unlikely. Antitheft devices also have potential for pacemaker interference. [104] [105] [106] Practical suggestions are for patients with pacemakers or ICDs to be aware of electronic equipment for surveillance of articles and to avoid leaning on or lingering near such devices. If the patient passes through the equipment at a normal pace, adverse effects are unlikely. Any patient who feels unusual in any way when near electronic surveillance equipment should move away. Hospital sources of potentially significant EMI are electrocautery, cardioversion, defibrillation, magnetic resonance imaging, lithotripsy, radiofrequency ablation, electroshock therapy, and diathermy. The most important aspect of pacemaker or ICD care after exposure to any of these sources of EMI is to reassess the device to be certain that programmed parameters have not been changed. One of the most frequent questions asked is how to manage the patient with a pacemaker or ICD during an operative procedure, given the potential effects of electrocautery and guidelines for cardioversion and defibrillation. Routine interrogation of the device and deactivation of ICD therapy should be accomplished before the operation. After the procedure, the device should be reinterrogated and ICD therapy reinitiated. (During the time ICD therapy is "off," the patient must be monitored.) For pacemaker-dependent patients, it is reasonable to program the pacemaker to an asynchronous pacing mode, VOO or DOO, or to achieve the same effect by placing a magnet over the pacemaker throughout the procedure. The potential effects of electrocautery are reprogramming; permanent damage to the pulse generator; pacemaker inhibition; reversion to a fall-back mode, noise reversion mode, or electrical reset; and myocardial thermal damage. The guidelines for cardioversion and defibrillation in the patient with a pacemaker or ICD are as follows: Ideally, place paddles in the anterior-posterior position, try to keep the paddles at least 4 inches from the pulse generator, have the appropriate pacemaker programmer available, and interrogate the pacemaker after the procedure. DEVICE FOLLOW-UP Pacemakers and ICDs must be followed up on a regular schedule. There are different follow-up methods depending on clinician preference. Pacemaker and ICD follow-up schedules should be discussed separately because of the significant effect that transtelephonic monitoring has on pacemaker follow-up as opposed to essentially no use in ICD follow-up at this time. For pacemaker follow-up, some prefer regular office assessment, others predominantly transtelephonic follow-up, and still others a combination of the two techniques. Table 24-15 details the Medicare-approved follow-up schedule for reimbursement for transtelephonic monitoring. [106]

Figure 24-28 Electrocardiographic tracing from a patient with a VVI pacemaker programmed to a rate of 70 beats/min (857 milliseconds). The third and fourth VV cycles are longer than the programmed lower rate. Measuring 857 milliseconds backward from the ventricular pacing artifact at the end of the longer

cycles locates the point at which there was oversensing. In this case, probably the T wave is sensed. Definite retrograde P waves can be recognized by deformation of the T wave. Although it is possible that the retrograde P wave is being oversensed, the relationship of the P waves does not appear to consistently coincide with the point of oversensing.

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TABLE 24-15 -- FOLLOW-UP SCHEDULE FOR TRANSTELEPHONIC MONITORING OF PACEMAKERS* Single-chamber pacemakers 1st month

Every 2 weeks

2nd through 36th month

Every 8 weeks

37th month to battery depletion

Every 4 weeks

Dual-chamber pacemakers 1st month

Every 2 weeks

2nd through 6th month

Every 4 weeks

7th through 72nd month

Every 8 weeks

73rd month to battery depletion

Every 4 weeks

*This guideline is in effect for most pacemakers currently in use. A separate set of guidelines is available for specific pacing systems with sufficient long-term clinical information to meet certain standards for longevity and battery depletion characteristics.

Transtelephonic assessment should include collection of a nonmagnet ECG strip, an ECG strip with magnet applied to the pacemaker, and measurement of magnet rate and pulse duration (pulse duration on both atrial and ventricular channels should be measured for a dual-chamber pacemaker). During an office visit, the same information should be collected. In addition, on some periodic basis, for example, once a year, patients programmed to a rate-adaptive pacing mode should be assessed to determine whether rate-response is appropriate. IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR THERAPY Indications

The ACC/AHA Joint Committee has established indications for implantation of an ICD and for pacing.[2] The indications for ICD therapy continue to evolve on the basis of results of clinical trials.

Clinical trials have been designed to determine the effect of ICD therapy in secondary prevention of sudden cardiac death (Table 24-16) , that is, in patients who have already experienced a life-threatening ventricular rhythm disturbance, or in primary prevention (Table 24-17) , that is, in patients who are at high risk for sudden cardiac death. [119] The Antiarrhythmics Versus Implantable Defibrillators (AVID)[107] trial (secondary prevention), Multicenter Automatic Defibrillator Implantation Trial (MADIT)[111] [112] (primary prevention), Cardiac Arrest Study-Hamburg (CASH)[108] (secondary prevention), and Multicenter Unsustained Tachycardia Trial (MUSTT)[114] (primary prevention) have all demonstrated significant improvement in overall survival with ICD therapy compared with conventional or drug treatment. No significant difference in overall survival was seen with ICD therapy in the Canadian Implantable Defibrillator Study (CIDS) trial (secondary prevention, probably underpowered) or the Coronary Artery Bypass Graft-Implantable Cardioverter-Defibrillator (CABG-PATCH)[113] study TABLE 24-16 -- CLINICAL TRIALS OF PACING FOR THE SECONDARY PREVENTION OF SUDDEN CARDIAC DEATH STUDY PATIENT ENDPOINT(S) TREATMENT KEY INCLUSION ARMS RESULTS CRITERIA AVID[107]

Survivor of cardiac arrest

Total mortality

Amiodarone or sotalol

Significant improvement in overall survival with ICD

Total mortality

ICD

Significant improvement in overall survival with ICD

Recurrences of arrhythmias requiring CPR

Amiodarone, propafenone, or metoprolol

VT with syncope Mode of death Symptomatic sustained VT with LVEF 0.40

Quality of life

Cost benefit CASH[108]


Recurrence of unstable VT

CIDS


Total mortality

Amiodarone

No significant improvement in survival with ICD

Syncope with symptomatic sustained VT with LVEF 0.35 or syncope with inducible VT MAVERIC[109] Resuscitated VT/VF, SCD

All-cause mortality Empirical amiodarone

In progress

Sustained Event-free survival EP-guided therapy nonsyncopal VT (drug or nondrug) Dilated Costs nonischemic cardiomyopathy with EF 0.35, syncope, and NSVT or positive SAECG

Immediate ICD implantation

Quality of life Cost-effectiveness ASTRID[110]

Patients with Ventak AV1810 implanted for current indication

Time to first occurrence of inappropriate therapy

DFT 20%

Combined endpoint of symptomatic arrhythmia, appropriate ICD therapy, or death

ICD and metoprolol

ICD and sotalol

In progress

ICD without AAD or BB AAD = antiarrhythmia drugs; ASTRID = Atrial Sensing to Reduce Inappropriate Defibrillation; AVID = Antiarrhythmics Versus Implantable Defibrillators; BB = beta blockers; CASH = Cardiac Arrest Study-Hamburg; CIDS = Canadian Implantable Defibrillator Study; CPR = cardiopulmonary resuscitation; DFT = defibrillation threshold; EF = ejection fraction; EGM = electrogram; EP = electrophysiologic; ICD = implantable cardioverter-defibrillator; LVEF = left ventricular ejection fraction; MAVERIC = Midlands Trial of Empirical Amiodarone Versus Electrophysiologically Guided Intervention and Cardioverter Implant in Ventricular Arrhythmias; NSVT = nonsustained ventricular tachycardia; SAECG = signal-averaged electrocardiography; SCD = sudden cardiac death; VT = ventricular tachycardia; VT-MASS = Metoprolol and Sotalol for Sustained Ventricular Tachycardia.

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TABLE 24-17 -- CLINICAL TRIALS OF PACING FOR THE PRIMARY PREVENTION OF SUDDEN CARDIAC DEATH STUDY PATIENT ENDPOINT(S) TREATMENT KEY INCLUSION ARMS RESULTS CRITERIA MADIT[111] [112]

Q wave MI 3 weeks

Overall mortality

Asymptomatic NSVT

Costs and Conventional cost-effectiveness therapy (n = 101)

LVEF 0.35 Inducible and nonsuppressible VT on EPS with procainamide NYHA Class I-III

ICD (n = 95)

ICDs reduced overall mortality by 54% ICDs cost $16,900 per life-year saved vs. Conventional therapy

CABG-PATCH[113]

Scheduled for elective CABG surgery

Overall mortality

ICD (n = 446)Standard treatment (n = 454)

Survival not improved by prophylactic implantation of ICD at time of elective CABG

Sudden arrhythmic death or spontaneous sustained VT

ICD in In progress nonsuppressible group

LVEF 100 beats/min at admission

Quality of life

Conventional therapy

BRS = baroreceptor sensitivity; EF = ejection fraction; HR = heart rate; HRV = heart rate variability; ICD = implantable cardioverter-defibrillator; IRIS = Immediate Risk Stratification Improves Survival; MI = myocardial infarction; NSVT = nonsustained ventricular tachycardia; PVC = premature ventricular contraction; SEDET = South European Defibrillator Trial; VT = ventricular tachycardia. strategies may be necessary for the patient with arrhythmogenic right ventricular dysplasia, ICD therapy should be considered for prophylaxis against syncope due to hemodynamically unstable ventricular tachycardia and sudden cardiac death (see Chap. 25 ). Basics of Design and Selection

The basic components of the ICD are electronic circuitry, power source, and memory, with a microprocessor coordinating the various parts of the system. [119] [129] High-voltage capacitors transform the battery-provided voltage into discharges ranging from less than 1 V for pacing to 750 V for defibrillation. ICDs incorporate a different sensing circuit TABLE 24-19 -- IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR THERAPY ZONE TACHYCARDIA RATE (beats/min) THERAPY DELIVERED 1

126-160

ATP-1, ATP-2, 1 J, 5 J, 34 J

2

161-200

ATP, 10 J, 34 J

3

>200

34 J

ATP = antitachycardia pacing therapy; ATP-1 = first ATP; ATP-2 = second (and different) ATP.

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Figure 24-29 Posteroanterior (A) and lateral (B) chest radiographs of an implantable cardioverter-defibrillator (ICD) system in the left prepectoral position. The ICD is connected to a single-coil ventricular lead and a lead positioned in the superior vena cava (SVC). In this patient, adequate defibrillation thresholds (DFTs) could not be obtained with the single-coil ventricular lead. With the additional lead positioned high in the SVC, excellent DFTs were achieved.

than most pacemakers. Because of the need to reliably sense low-amplitude signals during ventricular fibrillation and to avoid sensing extracardiac noise and cardiac signals other than ventricular tachycardia or fibrillation, the sensing circuit is designed to automatically adjust either the gain or the sensing threshold. [119] [130]

ICD systems have evolved rapidly from thoracotomy to nonthoracotomy, that is, transvenous pectorally placed systems, and from ventricular bradycardia pacing to dual-chamber pacing with rate-adaptive options.[130A] In addition, atrial defibrillation capabilities are available in some devices. Longevity of ICDs depends on the frequency of shock

Figure 24-30 Posteroanterior (A) and lateral (B) chest radiographs from a patient with an implantable cardioverter-defibrillator. Unacceptable defibrillation thresholds necessitated placement of a subcutaneous array.

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delivery, the degree of pacemaker dependency, and other programmable options, but most are expected to last from 5 to 9 years. It is important to have an understanding of "shock waveforms." Biphasic waveforms are more efficient, that is, require lower energies, than monophasic shocks. All currently available ICDs use biphasic shock waveforms, but the specifics of the waveform differ among various manufacturers. The ICD functions by continuously monitoring the patient's cardiac rate and delivering therapy when the rate exceeds the programmed rate "cutoff." For example, if the ICD is programmed to deliver shocks for the treatment of tachyarrhythmias at a rate cutoff of 175 beats/min, once the patient's heart rate exceeds 175 beats/min and this event is detected by the ICD, the device delivers antitachycardia pacing (ATP) or charges and delivers a shock, depending on the programmed therapy. ATP has the advantage of terminating a rhythm disturbance without delivery of a shock. ICDs capable of ATP have significant programming flexibility to adjust many aspects of tachycardia detection and therapy and thereby customize therapy for the individual patient. Different "zones" or "tiers" of therapy can be programmed to detect ventricular tachyarrhythmias to allow slower arrhythmias to be treated with ATP before a shock is delivered but to still allow faster tachycardias to be treated more aggressively. Table 24-19 outlines programming for a hypothetical patient. In this patient, slower ventricular tachycardia in the range of 126 to 190 beats/min is treated with ATP therapies in zone 1. If initial ATP therapy (ATP-1) is unsuccessful, a second and different ATP therapy (ATP-2) is automatically delivered. If this is unsuccessful, lower energy shocks are attempted before high-energy (34 J) shocks are delivered. Shocks are synchronized during ventricular tachycardia (cardioversion) or are asynchronous

Figure 24-31 A and B, Printouts from an implantable cardioverterdefibrillator (ICD) programmer of a

specific episode detected by the ICD. The text includes 29 VV interval lengths before therapy for ventricular fibrillation and 20 VV cycle lengths after therapy, documenting return to a nonpathologic ventricular rhythm. FD = fibrillation detected; FS = fibrillation sensed; TS = tachycardia sensed; VS = ventricular sensed event.

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during ventricular fibrillation (defibrillation). A second zone of therapy is determined for a faster ventricular tachycardia, and still faster ventricular tachycardia or ventricular fibrillation is treated aggressively with a high-energy shock. In addition, current ICDs provide bradycardia support, as single- or dual-chamber devices. The zones, detection rates of the different zones, specifics of the different therapies, and bradycardia pacing options are all programmable, and programming flexibility varies significantly from device to device. Implant Procedure

When the ICD is placed transvenously with the pulse generator in the prepectoral position, the implantation technique and related complications are the same as those for pacemaker implantation, with the exception that complications can arise as a result of determining the defibrillation threshold (DFT). (DFT can be defined as the minimal energy that terminates ventricular fibrillation.[119] ) Risks associated with both procedures include lead dislodgment, pneumothorax and other potential complications of subclavian puncture if this venous approach is used, infection, and perforation. Most ICD implantations are now performed with conscious sedation and local anesthesia. During DFT testing, the patient is placed under deep anesthesia with mask-supported ventilation. When DFT determination is completed, the patient can be allowed to recover from deeper anesthesia as the pocket is closed. An acceptable DFT is a value that ensures an adequate safety margin for defibrillation, usually at least 10 J less than the maximum output of the ICD. The maximum output of current ICDs is in the range of 26 to 38 J. It is difficult to state an "ideal" DFT because it is ideally the lowest achievable DFT with an adequate safety margin. It is generally best to implant the ICD in the left pectoral region because of a more favorable vector for delivery of the shock. Although successful defibrillation can usually be accomplished with a right-sided implant, the shocking vector is less optimal and may have an effect on achievable DFT.[131] Regardless of whether the ICD is placed on the right or the left, in a small percentage of patients adequate DFT cannot be achieved with standard lead placement. In this situation, options include 1. Repositioning the ventricular lead. If the lead was not initially placed in a right ventricular apical position, such a position should be sought. If the right ventricular apical position resulted in unacceptable DFT, repositioning the lead slightly

superior to the apex or in a septal position may be successful. 2. Adding a second lead in the superior vena cava (Fig. 24-29) . 3. Adding a subcutaneous array (Fig. 24-30) . Follow-Up

Follow-up of the patient with an ICD must include periodic visits at which specific information is collected and assessed. In addition, patients may require interim assessment if there are concerns about the appropriateness of delivered therapy or other changes in the patient's medical status or drug regimen that could affect ICD therapy. The electrophysiologist or an allied professional with ICD expertise and immediate access to the electrophysiologist should perform follow-up procedures. Aspects of follow-up are history with specific emphasis on awareness of delivered therapy and any tachyarrhythmic events, device interrogation, assessment of battery status and charge time, retrieval and assessment of stored diagnostic data, periodic radiographic assessment, and periodic arrhythmic induction in the electrophysiology laboratory to assess defibrillation thresholds and efficacy. Diagnostic information that can be retrieved varies with different ICDs. All ICDs provide information about the cycle length, or rate, of the detected tachyarrhythmias (Fig. 24-31) , and most current devices provide stored electrograms of detected arrhythmias (Fig. 24-32) . Follow-up protocols for patients with ICDs vary. Some manufacturers have recommended follow-up every 3 months, but some institutions are comfortable with follow-up every 6 months for the first 3 to 4 years, after which the follow-up frequency increases. Complications

Exposure of the patient with an ICD to sources of EMI can result in the concerns expressed for pacemaker recipients.[119] EMI can interfere with bradycardia support and with detection of or response to tachyarrhythmias. Possible adverse effects of EMI are inappropriate delivery of anti-tachycardia therapy, reprogramming of the ICD parameters, and failure to deliver antibradycardia pacing. After any known or potential EMI exposure, the ICD, like a permanent pacemaker, should be reinterrogated, and programmed parameters should be compared with records obtained before the EMI exposure to be certain that EMI has not inappropriately reprogrammed the device.

Figure 24-32 Stored electrogram from a patient with an episode of ventricular fibrillation and a dual-chamber pacemaker and implantable cardioverter-defibrillator. The upper tracing is the atrial electrogram, the middle tracing is the ventricular electrogram, and the bottom tracing is the surface

electrocardiogram.

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TABLE 24-20 -- DIFFERENTIAL DIAGNOSIS AND MANAGEMENT OF MULTIPLE IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR (ICD) SHOCKS CLINICAL FINDING MANAGEMENT Frequent ventricular tachycardia or ventricular fibrillation (electrical storm)

Reassess antiarrhythmic therapy and programmed ICD therapy

Unsuccessful ICD therapy due to inappropriately low output shock or elevation of defibrillation threshold

Reprogram ICD

Assess potential causes of defibrillation threshold increase (e.g., drugs) Lead fracture

Replace fractured lead

Lead dislodgement

Reposition lead

Sensing supraventricular rhythms

Reassess antiarrhythmic therapy Reprogram ICD parameters Ablate supraventricular arrhythmic focus

Oversensing separate pacing system

Reprogram pacemaker or ICD (or both) Reposition pacemaker or ICD leads (or both) Remove pacemaker and replace ICD with another ICD with more sophisticated bradycardia support

Oversensing electromagnetic interference

Avoid source Reprogram ICD

Oversensing intracardiac signals

Reprogram ICD Reposition sensing lead

Modified from Pinsky SL, Fahy GJ: Implantable cardioverter-defibrillators. Am J Med 106:446, 1999. By permission of Excerpta Medica.

Specific EMI sources and their potential effect on ICDs should be mentioned. In the hospital, magnetic resonance imaging is still considered contraindicated in the patient with an ICD, although there are scattered case reports of it being successfully done. Lithotripsy is contraindicated if the ICD is in the lithotripsy field.[132] Concerns have also been raised about transcutaneous nerve stimulation when an ICD is present.[133] Outside

the hospital, welding has generally been considered a contraindication. However, some data suggest that some patients can be allowed to carry out this activity if they are evaluated in their work environment. It appears that cellular phones can be used safely by the patient with an ICD so long as the same guidelines noted for pacemaker patients are followed.[134] When using a cellular phone, the patient should avoid having the phone in close contact with the ICD and should not carry an activated phone in a pocket that is near the device. Theft detector devices are not a problem unless there is prolonged exposure.[135] Changes in drug therapy must be monitored closely in the patient with an ICD.[136] Certain drugs have the potential for interaction by altering the detection of ventricular tachycardia, altering the pacing threshold (as previously discussed), increasing defibrillation thresholds, and producing proarrhythmic effects. Drug alteration of the rate of ventricular tachycardia may result in inadequate detection of the arrhythmia. Elevation of the DFT may occur as the result of amiodarone administration.[137] Other drugs can theoretically increase the DFT or have been reported to do so in single-case reports, but a clinically significant change does not often result.[136] Frequent ICD discharges may represent a clinical emergency. These discharges may be appropriate or inappropriate (Table 24-20) . Appropriate discharges represent frequently occurring ventricular tachycardia or fibrillation or electrical storm. If the device is discharging frequently because the defibrillation is unsuccessful, the device may be programmed to an inappropriately low shock output or an alteration in the DFT may have occurred that resulted in inadequate programmed therapy. Inappropriate discharges are usually the result of inappropriate detection of a supraventricular tachyarrhythmia, most commonly atrial fibrillation (see Table 24-20 ). Inappropriate discharge can also be the result of device failure, for example, lead fracture. Before the incorporation of sophisticated bradycardia support within the ICD, many patients had separate pacing and ICD systems. Numerous types of interactions between pacemakers and ICDs have been described.[138] Pacemaker output preventing proper detection of ventricular tachycardia or ventricular fibrillation by the ICD is one of the more serious. Asynchronous pacemaker activity during ventricular arrhythmias may be caused by either undersensing of the arrhythmia or noise reversion. Conditions favoring noise reversion are specific pacemaker models, arrhythmia cycle lengths in the range causing noise reversion of the individual pacemaker model, long noise sampling periods, and the VVI pacing mode. Noise reversion can be diagnosed by telemetering the pacemaker marker channel during ventricular arrhythmias as a part of routine evaluation of pacemaker-ICD interaction.

REFERENCES

PACEMAKER NOMENCLATURE AND INDICATIONS Bernstein AD, Camm AJ, Fletcher RD, et al: The NASPE/BPEG generic pacemaker code for antibradyarrhythmia and adaptive-rate pacing and antitachyarrhythmia devices. Pacing Clin Electrophysiol 10:794, 1987. 1.

Gregoratos G, Cheitlin MD, Conill A, et al: ACC/AHA guidelines for implantation of cardiac pacemakers and antiarrhythmia devices: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Pacemaker Implantation). J Am Coll Cardiol 31:1175, 1998. 2.

Hayes DL, Barold SS, Camm AJ, et al: Evolving indications for permanent cardiac pacing: an appraisal of the 1998 American College of Cardiology/American Heart Association Guidelines. Am J Cardiol 82:1082, 1998. 3.

Michaelsson M, Jonzon A, Riesenfeld T: Isolated congenital complete atrioventricular block in adult life. A prospective study. Circulation 92:442, 1995. 4.

Serwer GA, Dorostkar PC: Pediatric pacing. In Ellenbogen K, Kay GN, Wilkoff BL (eds): Clinical Cardiac Pacing, p 706. Philadelphia, WB Saunders Co, 1995. 5.

5A.

Sheldon R: Pacing to prevent vasovagal syncope. Cardiol Clin 18:81, 2000.

Richardson DA, Bexton RS, Shaw FE, et al: Prevalence of cardioinhibitory carotid sinus hypersensitivity in patients 50 years or over presenting to the accident and emergency department with "unexplained" or "recurrent" falls. Pacing Clin Electrophysiol 20:820, 1997. 6.

Maloney JD, Jaeger FJ, Rizo-Patron C, et al: The role of pacing for the management of neurally mediated syncope: carotid sinus syndrome and vasovagal syncope. Am Heart J 127:1030, 1994. 7.

Fitzpatrick A, Theodorakis G, Ahmed R, et al: Dual chamber pacing aborts vasovagal syncope induced by head-up 60 degrees tilt. Pacing Clin Electrophysiol 14:13, 1991. 8.

Sra JS, Jazayeri MR, Avitall B, et al: Comparison of cardiac pacing with drug therapy in the treatment of neurocardiogenic (vasovagal) syncope with bradycardia or asystole. N Engl J Med 328:1085, 1993. 9.

Connolly SJ, Sheldon R, Roberts RS, et al: The North American Vasovagal Pacemaker Study (VPS). A randomized trial of permanent cardiac pacing for the prevention of vasovagal syncope. J Am Coll Cardiol 33:16, 1999. 10.

Brignole M, Menozzi C, Lolli G, et al: Long-term outcome of paced and nonpaced patients with severe carotid sinus syndrome. Am J Cardiol 69:1039, 1992. 11.

Vasovagal Syncope International Study: Is dual-chamber pacing efficacious in treatment of neurally-mediated tilt positive cardioinhibitory syncope? Pacemaker vs no therapy: a multicenter randomised study. Eur JCPE 3:169, 1993. 12.

Kenny RA, Seifer C: SAFE PACE 2: Syncope and Falls in the Elderly Pacing and Carotid Sinus Evaluation: a randomized control trial of cardiac pacing in older patients with falls and carotid sinus hypersensitivity. Am J Geriatr Cardiol 8:87, 1999. 13.

808

Ammirati F, Colivicchi S, Toscano R, et al: The SYDIT (Syncope: Diagnosis and Treatment) study: preliminary data (abstract). Eur Heart J 20 (Abstract Suppl):455, 1999. 14.

SELECTION OF THE APPROPRIATE PACING MODE Rosenqvist M, Brandt J, Schuller H: Long-term pacing in sinus node disease: effects of stimulation mode on cardiovascular morbidity and mortality. Am Heart J 116:16, 1988. 15.

Barold SS, Santini M: Natural history of sick sinus syndrome after pacemaker implantation. In Barold SS, Mugica J (eds): New Perspectives in Cardiac Pacing, 3, p 169. Mount Kisco, New York, Futura Publishing Co, 1993. 16.

Lamas GA, Pashos CL, Normand SL, et al: Permanent pacemaker selection and subsequent survival in elderly Medicare pacemaker recipients. Circulation 91:1063, 1995. 17.

17A. Tang

CY, Kerr CR, Connolly SJ: Clinical trials of pacing mode selection. Cardiol Clin 18:1, 2000.

Andersen HR, Nielsen JC, Thomsen PE, et al: Long-term follow-up of patients from a randomised trial of atrial versus ventricular pacing for sick-sinus syndrome. Lancet 350:1210, 1997. 18.

Lamas GA, Orav EJ, Stambler BS, et al. for the Pacemaker Selection in the Elderly Investigators: Quality of life and clinical outcomes in elderly patients treated with ventricular pacing as compared with dual-chamber pacing. N Engl J Med 338:1097, 1998. 19.

Connolly SJ, Kerr CR, Gent M, et al: Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes. N Engl J Med 342:1385, 2000. 20.

Lamas GA: Pacemaker mode selection and survival: a plea to apply the principles of evidence based medicine to cardiac pacing practice. Heart 78:218, 1997. 21.

Toff WD, Skehan JD, De Bono DP, et al: The United Kingdom Pacing and Cardiovascular Events (UKPACE) trial. United Kingdom Pacing and Cardiovascular Events. Heart 78:221, 1997. 22.

Andersen HR, Nielsen JC: Pacing in sick sinus syndrome--need for a prospective, randomized trial comparing atrial with dual chamber pacing. Pacing Clin Electrophysiol 21:1175, 1998. 23.

Andersen HR, Thuesen L, Bagger JP, et al: Prospective randomised trial of atrial versus ventricular pacing in sick-sinus syndrome. Lancet 344:1523, 1994. 24.

Schrepf R, Koller B, Pache J, et al: Results of the randomized prospective DDD vs. VVI trial in patients with paroxysmal atrial fibrillation (abstract). Pacing Clin Electrophysiol 20:1152, 1997. 25.

Wharton JM, Sorrentino RA, Campbell P, et al: Effect of pacing modality on atrial tachyarrhythmia recurrence in the tachycardia-bradycardia syndrome: preliminary results of the pacemaker atrial tachycardia trial (abstract). Circulation 98 Suppl:I-494, 1998. 26.

27.

Ausubel K, Furman S: The pacemaker syndrome. Ann Intern Med 103:420, 1985.

Benditt DG, Petersen M, Lurie KG, et al: Cardiac pacing for prevention of recurrent vasovagal syncope. Ann Intern Med 122:204, 1995. 28.

Heldman D, Mulvihill D, Nguyen H, et al: True incidence of pacemaker syndrome. Pacing Clin Electrophysiol 13:1742, 1990. 29.

Hayes DL, Furman S: Stability of AV conduction in sick sinus node syndrome patients with implanted atrial pacemakers. Am Heart J 107:644, 1984. 30.

Irwin M, Harris L, Cameron D, et al: DDI pacing: indications, expectations, and follow-up. Pacing Clin Electrophysiol 17:274, 1994. 31.

Lau CP, Tai YT, Leung SK, et al: Long-term stability of P wave sensing in single lead VDDR pacing: clinical versus subclinical atrial undersensing. Pacing Clin Electrophysiol 17:1849, 1994. 32.

Hayes DL: Endless-loop tachycardia: the problem has been solved? In Barold SS, Mugica J (eds): New Perspectives in Cardiac Pacing, p 375. Mount Kisco, New York, Futura Publishing Co, 1988. 33.

RATE-ADAPTIVE PACING Rossi P: Rate-responsive pacing: biosensor reliability and physiological sensitivity. Pacing Clin Electrophysiol 10:454, 1987. 34.

34A. Leung

SK, Lau CP: Developments in sensor-driven pacing. Cardiol Clin 18:113, 2000.

Alt E, Millerhagen JO, Heemels J-P: Accelerometers. In Ellenbogen KA, Kay GN, Wilkoff BL (eds): Clinical Cardiac Pacing, p 267. Philadelphia, WB Saunders Co, 1995. 35.

Benditt DG, Duncan JL: Activity-sensing, rate-adaptive pacemakers. In Ellenbogen KA, Kay GN, Wilkoff BL (eds): Clinical Cardiac Pacing, p 167. Philadelphia, WB Saunders Co, 1995. 36.

Alt E, Combs W, Willhaus R, et al: A comparative study of activity and dual sensor: activity and minute ventilation pacing responses to ascending and descending stairs. Pacing Clin Electrophysiol 21:1862, 1998. 37.

Bongiorni MG, Soldati E, Arena G, et al: Multicenter clinical evaluation of a new SSIR pacemaker. Pacing Clin Electrophysiol 15:1798, 1992. 38.

Faerastrand S, Ohm OJ: Clinical study of a new activity sensor for rate adaptive pacing controlled by electrical signals generated by the kinetic energy of a moving magnetic ball. Pacing Clin Electrophysiol 17:1944, 1994. 39.

Nappholtz T, Valenta H, Maloney J, et al: Electrode configurations for a respiratory impedance measurement suitable for rate responsive pacing. Pacing Clin Electrophysiol 9:960, 1986. 40.

Soucie LP, Carey C, Woodend AK, et al: Correlation of the heart rate-minute ventilation relationship with clinical data: relevance to rate-adaptive pacing. Pacing Clin Electrophysiol 20:1913, 1997. 41.

Connelly DT, Rickards AF: The evoked QT interval. In Ellenbogen KA, Kay GN, Wilkoff BL (eds): Clinical Cardiac Pacing, p 250. Philadelphia, WB Saunders Co, 1995. 42.

Lau CP: The combination of sensors and algorithms. In Lau CP (ed): Rate Adaptive Cardiac Pacing: Single and Dual Chamber, p 213. Mount Kisco, New York, Futura Publishing Co, 1993. 43.

Leung SK, Lau CP, Tang MO: Cardiac output is a sensitive indicator of difference in exercise performance between single and dual sensor pacemakers. Pacing Clin Electrophysiol 21:35, 1998. 44.

Fananapazir L, Cannon RO III, Tripodi D, et al: Impact of dual-chamber permanent pacing in patients with obstructive hypertrophic cardiomyopathy with symptoms refractory to verapamil and beta-adrenergic blocker therapy. Circulation 85:2149, 1992. 45.

45A. Sorajja

P, Elliott PM, McKenna WJ: Pacing in hypertrophic cardiomyopathy. Cardiol Clin 18:67, 2000.

45B. Erwin

JP III, Nishimura RA, Lloyd MA, et al: Dual chamber pacing for patients with hypertrophic obstructive cardiomyopathy: A clinical perspective in 2000. Mayo Clinic Proc 75:173, 2000. Jeanrenaud X, Goy JJ, Kappenberger L: Effects of dual-chamber pacing in hypertrophic obstructive cardiomyopathy. Lancet 339:1318, 1992. 46.

Fananapazir L, Epstein ND, Curiel RV, et al: Long-term results of dual-chamber (DDD) pacing in obstructive hypertrophic cardiomyopathy. Evidence for progressive symptomatic and hemodynamic improvement and reduction of left ventricular hypertrophy. Circulation 90:2731, 1994. 47.

Nishimura RA, Hayes DL, Ilstrup DM, et al: Effect of dual-chamber pacing on systolic and diastolic function in patients with hypertrophic cardiomyopathy. Acute Doppler echocardiographic and catheterization hemodynamic study. J Am Coll Cardiol 27:421, 1996. 48.

Kappenberger L, Linde C, Daubert C, et al., and the PIC Study Group: Pacing in hypertrophic obstructive cardiomyopathy. A randomized crossover study. Eur Heart J 18:1249, 1997. 49.

Maron BJ, Nishimura RA, McKenna WJ, et al: Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy. A randomized, double-blind, crossover study (M-PATHY). Circulation 99:2927, 1990. 50.

Hochleitner M, Hortnagl H, Ng CK, et al: Usefulness of physiologic dual-chamber pacing in drug-resistant idiopathic dilated cardiomyopathy. Am J Cardiol 66:198, 1990. 51.

Hochleitner M, Hortnagl H, Hortnagl H, et al: Long-term efficacy of physiologic dual-chamber pacing in the treatment of end-stage idiopathic dilated cardiomyopathy. Am J Cardiol 70:1320, 1992. 52.

Brecker SJ, Xiao HB, Sparrow J, et al: Effects of dual-chamber pacing with short atrioventricular delay in dilated cardiomyopathy. Lancet 340:1308, 1992. 53.

Gold MR, Feliciano Z, Gottlieb SS, et al: Dual-chamber pacing with a short atrioventricular delay in congestive heart failure: a randomized study. J Am Coll Cardiol 26:967, 1995. 54.

Linde C, Gadler F, Edner M, et al: Results of atrioventricular synchronous pacing with optimized delay in patients with severe congestive heart failure. Am J Cardiol 75:919, 1995. 55.

Innes D, Leitch JW, Fletcher PJ: VDD pacing at short atrioventricular intervals does not improve cardiac output in patients with dilated heart failure. Pacing Clin Electrophysiol 17:959, 1994. 56.

Nishimura RA, Hayes DL, Holmes DR Jr, et al: Mechanism of hemodynamic improvement by dual-chamber pacing for severe left ventricular dysfunction: an acute Doppler and catheterization hemodynamic study. J Am Coll Cardiol 25:281, 1995. 57.

Aaronson KD, Schwartz JS, Chen TM, et al: Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 95:2660, 1997. 58.

Schoeller R, Andresen D, Buttner P, et al: First- or second-degree atrioventricular block as a risk factor in idiopathic dilated cardiomyopathy. Am J Cardiol 71:720, 1993. 59.

59A. Peters

RW, Gold MR: Pacing for patients with congestive heart failure and dilated cardiomyopathy. Cardiol Clin 18:55, 2000. Bakker P, Chin A, Sen K, et al: Biventricular pacing improves functional capacity in patients with end-stage congestive heart failure (abstract). Pacing Clin Electrophysiol 18:825, 1995. 60.

Gras D, Mabo P, Tang T, et al: Multisite pacing as a supplemental treatment of congestive heart failure: preliminary results of the Medtronic Inc. InSync Study. Pacing Clin Electrophysiol 21:2249, 1998. 61.

Auricchio A, Stellbrink C, Block M, et al., for the Pacing Therapies for Congestive Heart Failure Study Group and the Guidant Congestive Heart Failure Research Group: Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. Circulation 99:2993, 1999. 62.

Daubert C, Linde C, Caseau S, et al., on behalf of the MUSTIC Study Group: Protocol design of the MUSTIC (Multisite Stimulation in Cardiomyopathy) study (abstract). Arch Mal Coeur Vaiss 91 Suppl III:154, 1998. 63.

Auricchio A, Stellbrink C, Sack S, et al., for the PATH-CHF Study Group: The Pacing Therapies for Congestive Heart Failure (PATH-CHF) study: rationale, design, and endpoints of a prospective randomized multicenter study. Am J Cardiol 83:130D, 1999. 64.

809

Saxon LA, Boehmer JP, Hummel J, et al., for the VIGOR CHF and VENTAK CHF Investigators: Biventricular pacing in patients with congestive heart failure: two prospective randomized trials. Am J Cardiol 83:120D, 1999. 65.

65A. Gillis

AM: Packing to prevent atrial fibrillation. Cardiol Clin 18:25, 2000.

Daubert C, Mabo P, Berder V, et al: Atrial tachyarrhythmias associated with high degree interatrial conduction block: prevention by permanent atrial resynchronisation. Eur JCPE 4(1 Suppl 3):35, 1994. 66.

Mabo P, Paul V, Jung W, et al., on behalf of the SYNBIAPACE Study Group: Biatrial synchronous pacing for atrial arrhythmia prevention: the SYNBIAPACE Study (abstract). Eur Heart J 20(Abstr Suppl):4, 1999. 67.

68.

Saksena S, Prakash A, Hill M, et al: Prevention of recurrent atrial fibrillation with chronic dual-site right

atrial pacing. J Am Coll Cardiol 28:687, 1996. Delfaut P, Saksena S, Prakash A, et al: Long-term outcome of patients with drug-refractory atrial flutter and fibrillation after single- and dual-site right atrial pacing for arrhythmia prevention. J Am Coll Cardiol 32:1900, 1998. 69.

Spencer WH III, Zhu DW, Markowitz T, et al: Atrial septal pacing: a method for pacing both atria simultaneously. Pacing Clin Electrophysiol 20:2739, 1997. 70.

Bailin SJ, Johnson WB, Hoyt R: A prospective randomized trial of Bachmann's bundle pacing for the prevention of atrial fibrillation (abstract). J Am Coll Cardiol 29:74A, 1997. 71.

Gillis AM, Wyse DG, Connolly SJ, et al: Atrial pacing periablation for prevention of paroxysmal atrial fibrillation. Circulation 99:2553, 1999. 72.

Fitts SM, Hill MRS, Mehra R, et al., for the DAPPAF Phase I Investigators: Design and implementation of the Dual Site Atrial Pacing to Prevent Atrial Fibrillation (DAPPAF) clinical trial. J Interventional Cardiac Electrophysiol 2:139, 1998. 73.

Charles RG, McComb JM: Systematic Trial of Pacing to Prevent Atrial Fibrillation (STOP-AF). Heart 78:224, 1997. 74.

75.

Sopher SM, Camm AJ: New trials in atrial fibrillation. J Cardiovasc Electrophysiol 9 Suppl:S211, 1998.

Garson A Jr, Dick M II, Fournier A, et al: The long QT syndrome in children. An international study of 287 patients. Circulation 87:1866, 1993. 76.

PULSE GENERATOR IMPLANTATION Hayes DL, Naccarelli GV, Furman S, et al., and the NASPE Pacemaker Training Policy Conference Group: Report of the NASPE Policy Conference training requirements for permanent pacemaker selection, implantation, and follow-up. Pacing Clin Electrophysiol 17:6, 1994. 77.

Josephson ME, Maloney JD, Barold SS, et al: Guidelines for training in adult cardiovascular medicine. Core Cardiology Training Symposium (COCATS). Task Force 6: training in specialized electrophysiology, cardiac pacing and arrhythmia management. J Am Coll Cardiol 25:23, 1995. 78.

Hayes DL, Holmes DR Jr, Furman S: Permanent pacemaker implantation. In Furman S, Hayes DL, Holmes DR Jr. A Practice of Cardiac Pacing, 3rd edition, p 261. Mount Kisco, New York, Futura Publishing Co, 1993. 79.

Crossley GH, Gayle DD, Simmons TW, et al: Reprogramming pacemakers enhances longevity and is cost-effective. Circulation 1996; 94 (Suppl 2):II-245, 1995. 80.

80A. Wood

MA: Automated pacemaker function. Cardiol Clin 18:177, 2000.

Janosik DL, Pearson AC, Buckingham TA, et al: The hemodynamic benefit of differential atrioventricular delay intervals for sensed and paced atrial events during physiologic pacing. J Am Coll Cardiol 14:499, 1989. 81.

Rees M, Haennel RG, Black WR, et al: Effect of rate-adapting atrioventricular delay on stroke volume and cardiac output during atrial synchronous pacing. Can J Cardiol 6:445, 1990. 82.

Sutton R, Stack Z, Heaven D, et al: Mode switching for atrial tachyarrhythmias. Am J Cardiol 83:202D, 1999. 83.

83A. Fu

EY, Ellenbogen KA: Management of atrial tachyarrhythmias in patients with implantable devices. Cardiol Clin 18:37, 2000. 83B. Wood

MA, Brown-Mahoney C, Kay GN, et al: Clinical outcomes after ablation and pacing therapy for atrial fibrillation: A meta-analysis. Circulation 101:1138, 2000. 83C.

Strobel JS, Kay GN: Programming of sensor driven pacemakers. Cardiol Clin 18:157, 2000.

Wilkoff BL: Cardiac chronotropic responsiveness. In Ellenbogen KA, Kay GN, Wilkoff BL (eds): Clinical Cardiac Pacing, p 432. Philadelphia, WB Saunders Co, 1995. 84.

Wilkoff BL, Corey J, Blackburn G: A mathematical model of the cardiac chronotropic response to exercise. J Electrophysiol 3:176, 1989. 85.

Hayes DL: Pacemaker complications. In Furman S, Hayes DL, Holmes DR Jr (eds): A Practice of Cardiac Pacing, 3rd edition, p 537. Mount Kisco, New York, Futura Publishing Co, 1993. 86.

Parsonnet V, Bernstein AD, Lindsay B: Pacemaker-implantation complication rates: an analysis of some contributing factors. J Am Coll Cardiol 13:917, 1989. 87.

Parsonnet V, Roelke M: The cephalic vein cutdown versus subclavian puncture for pacemaker/ICD lead implantation. Pacing Clin Electrophysiol 22:695, 1999. 88.

Spittell PC, Hayes DL: Venous complications after insertion of a transvenous pacemaker. Mayo Clin Proc 67:258, 1992. 89.

Mond HG, Helland JR: Engineering and clinical aspects of pacing leads. In Ellenbogen KA, Kay GN, Wilkoff BL (eds): Clinical Cardiac Pacing, p 69. Philadelphia, WB Saunders Co, 1995. 90.

Souliman SK, Christie J: Pacemaker failure induced by radiotherapy. Pacing Clin Electrophysiol 17:270, 1994. 91.

Lewis AB, Hayes DL, Holmes DR Jr, et al: Update on infections involving permanent pacemakers. Characterization and management. J Thorac Cardiovasc Surg 89:758, 1985. 92.

Mounsey JP, Griffith MJ, Tynan M, et al: Antibiotic prophylaxis in permanent pacemaker implantation: a prospective randomised trial. Br Heart J 72:339, 1994. 93.

Love CJ, Wilkoff BL, Byrd CL, et al: Recommendations for extraction of chronically implanted transvenous pacing and defibrillator leads: Indications, facilities, training. North American Society of Pacing and Electrophysiology Lead Extraction Conference Faculty. Pacing Clin Electrophysiol 23:544, 2000. 94.

94A. Love

CJ: Current concepts in extraction of transvenous pacing and ICD leads. Cardiol Clin 18:193,

2000. Smith HJ, Fearnot NE, Byrd CL, et al: Five-years experience with intravascular lead extraction. U.S. Lead Extraction Database. Pacing Clin Electrophysiol 17:2016, 1994. 95.

Wilkoff BL, Byrd CL, Love CJ, et al: Pacemaker lead extraction with the laser sheath: results of the Pacing Lead Extraction with the Excimer Sheath (PLEXES) trial. J Am Coll Cardiol 33:1671, 1999. 96.

Furman S, Behrens M, Andrews C, et al: Retained pacemaker leads. J Thorac Cardiovasc Surg 94:770, 1987. 97.

Love CJ, Hayes DL: Evaluation of pacemaker malfunction. In Ellenbogen KA, Kay GN, Wilkoff BL (eds): Clinical Cardiac Pacing, p 656. Philadelphia, WB Saunders Co, 1995. 98.

ELECTROMAGNETIC INTERFERENCE Hayes DL: Pacemaker electrocardiography. In Furman S, Hayes DL, Holmes DR Jr (eds): A Practice of Cardiac Pacing, 2nd edition, p 289. Mount Kisco, New York, Futura Publishing Co, 1989. 99.

Levine PA: Differential diagnosis, evaluation, and management of pacing system malfunction. In Ellenbogen KA (ed): Cardiac Pacing, p 309. Boston, Blackwell Scientific Publications, 1992. 100.

Marco D, Eisinger G, Hayes DL: Testing of work environments for electromagnetic interference. Pacing Clin Electrophysiol 15:2016, 1992. 101.

101A.

Pinski SL, Trohman RG: Interference with cardiac pacing. Cardiol Clin 18:219, 2000.

Hayes DL, Carrillo RG, Findlay GK, et al: State of the science: pacemaker and defibrillator interference from wireless communication devices. Pacing Clin Electrophysiol 19:1419, 1996. 102.

Hayes DL, Wang PJ, Reynolds DW, et al: Interference with cardiac pacemakers by cellular telephones. N Engl J Med 336:1473, 1997. 103.

McIvor ME: Electronic article surveillance systems and pacemakers: a perspective on advising patients. Cardiovasc Rev Rep 20:216, 1999. 104.

Santucci PA, Haw J, Trohman RG, et al: Interference with an implantable defibrillator by an electronic antitheft-surveillance device. N Engl J Med 339:1371, 1998. 105.

MED-MANUAL, MED-GUIDE ¶27,201, Coverage Issue Manual §50-1 Cardiac Pacemaker Evaluation Services (effective date: October 1, 1984). 106.

The Antiarrhythmics Versus Implantable Defibrillators (AVID) Investigators: A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med 337:1576, 1997. 107.

Siebels J, Cappato R, Ruppel R, et al: Preliminary results of the Cardiac Arrest Study Hamburg (CASH). Am J Cardiol 72:109F, 1993. 108.

Pathmanathan RK, Lau EW, Cooper J, et al: Potential impact of antiarrhythmic drugs versus implantable defibrillators on the management of ventricular arrhythmias: the Midlands trial of empirical amiodarone versus electrophysiologically guided intervention and cardioverter implant registry data. Heart 80:68, 1998. 109.

Dorian P, Newman D, Thibault B, et al: A randomized clinical trial of a standardized protocol for the prevention of inappropriate therapy using a dual chamber implantable cardioverter defibrillator (abstract). 110.

Circulation 100 Suppl:I-786, 1999. Moss AJ: Background, outcome, and clinical implications of the Multicenter Automatic Defibrillator Implantation Trial. Am J Cardiol 80:28F, 1997. 111.

Moss AJ, Hall WJ, Cannom DS, et al, for the Multicenter Automatic Defibrillator Implantation Trial Investigators: Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med 335:1933, 1996. 112.

Bigger JT Jr, for the Coronary Artery Bypass Graft (CABG) Patch Trial Investigators: Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary-artery bypass graft surgery. N Engl J Med 337:1569, 1997. 113.

Buxton AE, Fisher JD, Josephson ME, et al., and the MUSTT Investigators: Prevention of sudden death in patients with coronary artery disease: the Multicenter Unsustained Tachycardia Trial (MUSTT). Prog Cardiovasc Dis 36:215, 1993. 114.

The German Dilated CardioMyopathy Study Investigators: Prospective studies assessing prophylactic therapy in high risk patients: the German Dilated CardioMyopathy Study (GDCMS)--study design. Pacing Clin Electrophysiol 15:697, 1992. 115.

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IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR THERAPY Raviele A, Bongiorni MG, Brignole M, et al: Which strategy is "best" after myocardial infarction? The Beta-blocker Strategy plus Implantable Cardioverter Defibrillator Trial: rationale and study design. Am J Cardiol 83:104D, 1999. 116.

Moss AJ, Cannom DS, Daubert JP, et al: Multicenter Automatic Defibrillator Implantation Trial II (MADIT II): design and clinical protocol. Ann Noninvasive Electrocardiol 4:83, 1999. 117.

Bardy GH, Lee KL, Mark DB, et al., and the SCD-HeFT Pilot investigators: Sudden Cardiac Death in Heart Failure Trial: pilot study (abstract). Pacing Clin Electrophysiol 20:1148, 1997. 118.

119.

Pinski SL, Fahy GJ: Implantable cardioverter-defibrillators. Am J Med 106:446, 1999.

Bigger JT Jr, Whang W, Rottman JN, et al: Mechanisms of death in the CABG Patch trial: a randomized trial of implantable cardiac defibrillator prophylaxis in patients at high risk of death after coronary artery bypass graft surgery. Circulation 99:1416, 1999. 120.

Sarter BH, Finkle JK, Gerszten RE, et al: What is the risk of sudden cardiac death in patients presenting with hemodynamically stable sustained ventricular tachycardia after myocardial infarction? J Am Coll Cardiol 28:122, 1996. 121.

Caruso AC, Marcus FI, Hahn EA, et al, and the ESVEM Investigators: Predictors of arrhythmic death and cardiac arrest in the ESVEM trial. Circulation 96:1888, 1997. 122.

123.

Fogoros RN, Elson JJ, Bonnet CA, et al: Efficacy of the automatic implantable

cardioverter-defibrillator in prolonging survival in patients with severe underlying cardiac disease. J Am Coll Cardiol 16:381, 1990. Groh WJ, Silka MJ, Oliver RP, et al: Use of implantable cardioverter-defibrillators in the congenital long QT syndrome. Am J Cardiol 78:703, 1996. 124.

Hamilton RM, Dorian P, Gow RM, et al: Five-year experience with implantable defibrillators in children. Am J Cardiol 77:524, 1996. 125.

Maron BJ, Shen WK, Link MS, et al: Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med 342:365, 2000. 125A.

McKenna WJ, Franklin RC, Nihoyannopoulos P, et al: Arrhythmia and prognosis in infants, children and adolescents with hypertrophic cardiomyopathy. J Am Coll Cardiol 11:147, 1988. 126.

Wellens HJ, Lemery R, Smeets JL, et al: Sudden arrhythmic death without overt heart disease. Circulation 85 (Suppl 1):I-92, 1992. 127.

Klein LS, Shih HT, Hackett FK, et al: Radiofrequency catheter ablation of ventricular tachycardia in patients without structural heart disease. Circulation 85:1666, 1992. 128.

Kroll MW, Lehmann MH (eds): Implantable Cardioverter Defibrillator Therapy: the Engineering-Clinical Interface. Norwell, Massachusetts, Kluwer Academic Publishers, 1996. 129.

Jones GK, Bardy GH: Considerations for ventricular fibrillation detection by implantable cardioverter defibrillators. Am Heart J 127:1107, 1994. 130.

Higgins SL, Pak JP, Barone J, et al: The first-year experience with the dual chamber ICD. PACE 23:18, 2000. 130A.

Friedman PA, Rasmussen MJ, Grice S, et al: Defibrillation thresholds are increased by right-sided implantation of totally transvenous implantable cardioverter defibrillators. Pacing Clin Electrophysiol 22:1186, 1999. 131.

Chung MK, Streem SB, Ching E, et al: Effects of extracorporeal shock wave lithotripsy on tiered therapy implantable cardioverter defibrillators. Pacing Clin Electrophysiol 22:738, 1999. 132.

Stamato NJ, Eddy SL, Rawoof SA, et al: Sensing of a transcutaneous nerve stimulator by an ICD device. HeartWeb October 1996; http://www.heartweb.org/ 133.

Fetter JG, Ivans V, Benditt DG, et al: Digital cellular telephone interaction with implantable cardioverter-defibrillators. J Am Coll Cardiol 31:623, 1998. 134.

Groh WJ, Boschee SA, Engelstein ED, et al: Interactions between electronic article surveillance systems and implantable cardioverter-defibrillators. Circulation 100:387, 1999. 135.

Carnes CA, Mehdirad AA, Nelson SD: Drug and defibrillator interactions. Pharmacotherapy 18:516, 1998. 136.

Kopp D, Kall J, Kinder C, et al: Effect of amiodarone and left ventricular mass on defibrillation energy requirements: monophasic vs biphasic shocks. Pacing Clin Electrophysiol 18:872, 1995. 137.

Glikson M, Trusty JM, Grice SK, et al: Importance of pacemaker noise reversion as a potential mechanism of pacemaker-ICD interactions. Pacing Clin Electrophysiol 21:1111, 1998. 138.




GUIDELINES USE OF CARDIAC PACEMAKERS AND ANTIARRHYTHMIA DEVICES Thomas H. Lee An American College of Cardiology/American Heart Association (ACC/AHA) task force updated guidelines for the implantation of cardiac pacemakers and antiarrhythmia devices in 1998.[1] These guidelines evaluate potential indications for the implantation of pacemakers and antiarrhythmic devices. The guidelines use the same system as other guidelines from these organizations; i.e., they divide them into classes according to their appropriateness. Class I signifies general agreement that the device or therapy is indicated. Class II indicates a divergence of opinion with respect to their usefulness, with Class IIa favoring and Class IIb not favoring usefulness. The level of evidence to support each position is rated on a scale from A to C (see Guidelines to Chap. 5 ), in which "A" indicates that data were derived from multiple randomized trials involving a large number of individuals, "B" indicates that data were derived from a limited number of trials involving a relatively small number of patients or from well-designed observational studies, and "C" indicates that expert consensus was the primary source of the recommendation.

Indications for Permanent Pacing (Table 24-G-1) ACQUIRED ATRIOVENTRICULAR BLOCK. For patients with acquired atrioventricular (AV) block, bifascicular or trifascicular block, or sinus node dysfunction, permanent pacing was considered appropriate when the abnormality caused complications and was not precipitated by a drug that could be discontinued. Examples of complications include symptomatic bradycardia, congestive

heart failure, and confusional states. Permanent pacing was also deemed appropriate for asymptomatic patients with a high risk for the subsequent development of complications, such as patients with complete heart block and periods of asystole of 3 seconds or more or a slow escape rate or patients with bifascicular or trifascicular block with intermittent third-degree AV block. For patients with first-degree AV block who have symptoms suggestive of pacemaker syndrome, these guidelines include a new indication for permanent pacing that is considered equivocal but supported by some data (Class IIa). Patients with pacemaker syndrome need a dual-chamber pacemaker to restore normal AV synchrony. A Class IIb indication for permanent pacing was described for patients with a prolonged PR interval and drug-refractory dilated cardiomyopathy if acute hemodynamic studies demonstrate the benefit of pacing. Indications for permanent pacing for patients who do not have symptoms or complications are less certain. In asymptomatic patients, complete heart block with a ventricular escape rate of 40 or more beats/min or type II second-degree AV block was considered an equivocal (Class IIa) indication for permanent pacing. Bifascicular or trifascicular block in patients with syncope was also not a clear indication for permanent pacing but was regarded as acceptable if other possible causes of syncope cannot be identified. Pacemakers were explicitly discouraged for patients with mild asymptomatic conduction abnormalities, such as type I second-degree AV block at the supra-His level, fascicular block with no or only a first-degree AV block, and sinus node dysfunction. Symptoms do not play as important a role in determination of the appropriateness of permanent pacing in patients with acute myocardial infarction because of the poor prognosis and high incidence of sudden death in postinfarction patients with conduction system disturbances. The ACC/AHA task force emphasized that the requirement for temporary pacing after acute myocardial infarction is not in itself an indication for permanent pacing (see Guidelines to Chap. 35 for guidelines on temporary pacing in acute myocardial infarction). However, permanent pacemakers were considered appropriate for patients with persistent advanced-degree AV block or transient infranodal AV block and associated bundle branch block. The usefulness of electrophysiology study to determine the site of block was acknowledged. The usefulness of permanent pacemakers for patients with advanced

811

TABLE 24--G-1 -- ACC/AHA GUIDELINES FOR PERMANENT PACING* Issue

Class

Recommendation

Level of Evidence

Permanent pacing in acquired AV block

I

Third-degree AV block at any anatomical level associated with any one of the following conditions: Bradycardia with symptoms presumed to be C due to AV block Arrhythmias and other medical conditions that require drugs that result in symptomatic bradycardia

C

Documented periods of asystole of B, C 3.0 sec or any escape rate of < 40 beats/min in awake, symptom-free patients After catheter ablation of the AV junction

B, C

Postoperative AV block that is not expected C to resolve

IIa

Neuromuscular diseases with AV block such as myotonic muscular dystrophy, Kearns-Sayre syndrome, Erb's dystrophy (limb-girdle), and peroneal muscular atrophy

B

Second-degree AV block, regardless of the type or site of block, with associated symptomatic bradycardia

B

Asymptomatic third-degree AV block at any anatomical site with average awake ventricular rates of 40 beats/min or faster

B, C

Asymptomatic type II second-degree AV block

B

Asymptomatic type I second-degree AV block at the intra- or infra-His levels found incidentally at electrophysiological study performed for other indications

B

First-degree AV block with symptoms suggestive of pacemaker syndrome and documented alleviation of symptoms with temporary AV pacing

B

IIb

Marked first-degree AV block (> 0.30 sec) in C patients with LV dysfunction and symptoms of congestive heart failure in whom a shorter AV interval results in hemodynamic improvement, presumably by decreasing left atrial filling pressure

III

Asymptomatic first-degree AV block

B

Asymptomatic type 1 second-degree AV block at the supra-His (AV node) level or not known to be intra- or infra-Hisian

B, C

III

Permanent pacing in chronic bifascicular and trifascicular block

I IIa

Asymptomatic type 1 second-degree AV block at the supra-His (AV node) level or not known to be intra- or infra-Hisian

B, C

AV block expected to resolve and unlikely to recur (e.g., drug toxicity, Lyme disease)

B

Intermittent third-degree AV block

B

Type II second-degree AV block

B

Syncope not proved to be due to AV block when other likely causes have been excluded, specifically VT

B

Incidental finding at electrophysiological study of markedly prolonged H-V interval (> 100 msec) in asymptomatic patients

B

Incidental finding at electrophysiological B study of a pacing-induced infra-His block that is not physiological III

Permanent pacing after the acute phase of myocardial infarction

I

Fascicular block without AV block or symptoms

B

Fascicular block with first-degree AV block without symptoms

B

Persistent second-degree AV block in the His-Purkinje system with a bilateral bundle branch block or third-degree AV block within or below the His-Purkinje system after acute MI

B

Transient advanced (second- or third-degree) B infranodal AV block and associated bundle branch block. If the site of block is uncertain, an electrophysiological study may be necessary Persistent and symptomatic second- or third-degree AV block

C

IIb

Persistent second- or third-degree AV block at the AV node level

B

III

Transient AV block in the absence of intraventricular conduction defects

B

Transient AV block in the presence of isolated left anterior fascicular block

B

Acquired left anterior block in the absence of B AV block Persistent first-degree AV block in the B presence of a bundle branch block that is old or age indeterminate

Permanent pacing in sinus node dysfunction

I

Sinus node dysfunction with documented symptomatic bradycardia, including frequent sinus pauses that produce symptoms

C

Symptomatic chronotropic incompetence

C

IIa

Sinus node dysfunction occurring spontaneously or as a result of necessary drug therapy, with a heart rate of or = 65 years. Am J Cardiol 74:560-564, 1994. 535.

Lee MA, Dae MW, Langberg JJ, et al: Effects of long-term right ventricular apical pacing on left ventricular perfusion, innervation, function and histology. J Am Coll Cardiol 24:225-232, 1994. 536.

OTHER ELECTYROPHYSIOLOGICAL ABNORMALITIES LEADING TO ARRHYTHMIAS Oreto G, Smeets JL, Rodriguez LM, et al: Supernormal conduction in the left bundle branch. J Cardiovasc Electrophysiol 5:345-349, 1994. 537.

Centurion OA, Isomoto S, Shimizu A, et al: Supernormal atrial conduction and its relation to atrial vulnerability and atrial fibrillation in patients with sick sinus syndrome and paroxysmal atrial fibrillation. Am Heart J 128:88-95, 1994. 538.

Moore EN, Spear JF, Fisch C: "Supernormal" conduction and excitability. J Cardiovasc Electrophysiol 4:320-337, 1993. 539.

Chen PS, Wolf PL, Cha YM, et al: Effects of subendocardial ablation on anodal supernormal excitation and ventricular vulnerability in open-chest dogs. Circulation 87:216-219, 1993. 540.

Liu Y, Zeng W, Delmar M, Jalife J: Ionic mechanisms of electronic inhibition and concealed conduction in rabbit atrioventricular nodal myocytes. Circulation 88:1634-1646, 1993. 541.

Fisch C: Electrocardiographic manifestations of exit block, concealed conduction and "supernormal" conduction. In Zipes DP, Jalife J (eds): Cardiac Electrophysiology: From Cell to Bedside. 3rd ed. Philadelphia, WB Saunders, 2000, pp 955-976. 542.

Fujiki A, Mizumaki K, Tani M: Effects of diltiazem on concealed atrioventricular nodal conduction in relation to ventricular response during atrial fibrillation in anesthetized dogs. Am Heart J 125:1284-1289, 1993. 543.

Martinez-Alday JD, Almendral J, Arenal A, et al: Identification of concealed posteroseptal Kent pathways by comparison of ventriculoatrial intervals from apical and posterobasal right ventricular sites. Circulation 89:1060-1067, 1994. 544.

Castellanos A, Saoudi N, Moleiro F: Parasystole. In Zipes DP, Jalife J (eds): Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia, WB Saunders, 1994, pp 942-954. 545.




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Chapter 26 - Cardiac Arrest and Sudden Cardiac Death ROBERT J. MYERBURG AGUSTIN CASTELLANOS

Definition Sudden cardiac death (SCD) is natural death due to cardiac causes, heralded by abrupt loss of consciousness within 1 hour of the onset of acute symptoms. Preexisting heart disease may or may not have been known to be present, but the time and mode of death are unexpected. This definition incorporates the key elements of "natural," "rapid," and "unexpected." It consolidates previous definitions that have conflicted,[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] largely because the most useful operational definition of SCD in the past differed for the clinician, the cardiovascular epidemiologist, the pathologist, and the scientist attempting to define pathophysiological mechanisms. As causes and mechanisms began to be understood, these differences disappeared. Four elements must be considered in the construction of a definition of SCD to satisfy medical, scientific, legal, and social considerations: (1) prodromes, (2) onset, (3) cardiac arrest, and (4) biological death (Fig. 26-1) . Because the proximate cause of SCD is a disturbance of cardiovascular function, which is incompatible with maintaining consciousness because of abrupt loss of cerebral blood flow, any definition must

recognize the brief time interval between the onset of the mechanism directly responsible for cardiac arrest and the consequent loss of consciousness ( Fig. 26-1 C). The 1-hour definition, however, refers to the duration of the "terminal event" (Fig. 26-1 B), which defines the interval between the onset of symptoms signaling the pathophysiological disturbance leading to cardiac arrest and the onset of the cardiac arrest itself (Fig. 26-1 B and C).

Figure 26-1 Sudden cardiac death is viewed from four temporal perspectives: (A) prodromes, (B) onset of the terminal event, (C) cardiac arrest, and (D) progression to biological death. Individual variability of the components influence clinical expression: some victims experience no prodromes, with onset leading almost instantaneously to cardiac arrest; others may have an onset that lasts up to 1 hour before clinical arrest; some patients may live weeks after the cardiac arrest before progression to biological death if there has been irreversible brain damage and life-support systems are used. These modifying factors influence interpretation of the 1-hour definition. From the perspective of the clinician, the two most relevant factors are the onset of the terminal event (B) and the clinical cardiac arrest itself (C). In contrast, legal and social considerations focus on the time of biological death (D).

891

TABLE 26-1 -- DEFINITION OF TERMS RELATED TO SUDDEN CARDIAC DEATH TERM DEFINITION QUALIFIERS OR EXCEPTIONS Death

Irreversible cessation of all biological functions

None

Cardiac arrest

Abrupt cessation of cardiac pump function, which may be reversible but will lead to death in the absence of prompt intervention

Rare spontaneous reversions; likelihood of successful intervention relates to mechanism of arrest, clinical setting, and time to intervention

Cardiovascular collapse

A (sudden) loss of effective blood flow due to cardiac and/or peripheral vascular factors that may revert spontaneously (e.g., vasodepressor or cardioinhibitory syncope) or only with interventions (e.g., cardiac arrest)

Nonspecific term that includes cardiac arrest and its consequences and also events that characteristically revert spontaneously

Premonitory signs and symptoms, which may occur during the days or weeks before a cardiac arrest,[13] tend to be nonspecific for the impending event.[8] Prodromes (Fig. 26-1 A), which may be more specific for an imminent cardiac arrest, are relatively abrupt changes that begin during an arbitrarily defined period of up to 24 hours before the

onset of cardiac arrest.[4] [16] The fourth element, biological death (Fig. 26-1 D), was an immediate consequence of the clinical cardiac arrest in the past, usually occurring within minutes. However, since the development of community-based intervention systems, and life support systems, patients may now remain biologically alive for a long period of time after the onset of a pathophysiological process that has caused irreversible damage and will ultimately lead to death.[15] [17] [18] [19] In this circumstance, the causative pathophysiological and clinical event is the cardiac arrest itself, rather than the factors responsible for the delayed biological death. However, for legal, forensic, and certain social considerations, biological death must continue to be used as the absolute definition of death. Finally, the forensic pathologist studying unwitnessed deaths may use the definition of sudden death for a person known to be alive and functioning normally 24 hours before,[4] and this remains appropriate within obvious limits.[20] The generally accepted clinical-pathophysiological definition of up to 1 hour between onset of the terminal event and biological death requires qualifications for specific circumstances. The development of community-based intervention systems also has led to inconsistencies in the use of terms considered absolute. Death is defined biologically, legally, and literally as an absolute and irreversible event. Thus SCD may be aborted, or a patient may survive cardiac arrest or cardiovascular collapse; however, survival after (sudden) death is a contradiction in terms. Table 26-1 provides definitions for events and terms related to the concept of SCD--death, cardiac arrest, and cardiovascular collapse.




Epidemiology and Causes of Sudden Death EPIDEMIOLOGY The worldwide incidence of SCD is difficult to estimate because it varies largely as a function of coronary heart disease prevalence in different countries. [21] Estimates for the United States range from 250,000 to nearly 400,000 SCDs annually,[22] [23] [24] the variation based in part on the definition of sudden death used in individual studies.[13] The most widely used estimate is 300,000 SCDs annually,[25] a figure that represents 50 percent or more of all cardiovascular deaths in the United States. The influence of the temporal definition of SCD on epidemiological data is demonstrated by a retrospective death certificate study in a large metropolitan area in the United States reported by Kuller and colleagues. When the temporal definition was restricted to death less than 2 hours after the onset of symptoms, 12 percent of all natural deaths were sudden and 88 percent of the sudden natural deaths were due to cardiac causes. This estimate is similar to observations in a large prospective cohort study--the Framingham Study--in which 13 percent of all deaths observed during a 26-year period were "sudden," defined as death within 1 hour of the onset of symptoms.[28] [29] In contrast to deaths occurring less than 2 hours after the onset of symptoms, the application of the 24-hour definition of sudden death to the data from Kuller and colleagues increased the fraction of all natural deaths falling into the "sudden" category to 32 percent but reduced the proportion of all sudden natural deaths that were cardiac deaths to 75 percent. Prospective studies demonstrate that about 50 percent of all coronary heart disease deaths are sudden and unexpected, occurring shortly (instantaneous to 1 hour) after the onset of symptoms. In the prospective combined Albany-Framingham Study of 4120

males, sudden deaths within 1 hour of an observed collapse were analyzed for a population of men dying between 45 and 74 years of age.[9] During a 16-year follow-up, there were 234 total coronary deaths/1000 population observed, of which 109 (47 percent) were sudden and unexpected. Because coronary heart disease is the dominant cause of both sudden and nonsudden cardiac deaths in the United States, the fraction of total cardiac deaths that are sudden is similar to the fraction of coronary heart disease deaths that are sudden, although there does appear to be a geographical variation in the fraction of coronary deaths that are sudden. [30] This 50 percent fraction may not apply to other nations or to subcultures that have a lower prevalence of coronary heart disease. It also is of interest that the recent decline in coronary heart disease mortality in the United States[31] has not changed the fraction of coronary deaths that are sudden and unexpected,[32] even though there may be a decline in out-of-hospital deaths compared with emergency department death,[26] and the number of sudden deaths from coronary heart disease that occur in victims' homes may be lower than previously thought.[23] POPULATION POOLS AND TIME-DEPENDENCE OF RISK Two factors are of primary importance for identifying populations at risk and when considering strategies for primary prevention of SCD: (1) the size of denominators of population subgroups (Fig. 26-2 A), and (2) time-dependence of risk (Fig. 26-2 B). POPULATION SUBGROUPS AND SCD.

The more than 300,000 adult SCDs that occur annually in the United States can be expressed as the global incidence in an unselected adult population. Viewed this way, the overall incidence is 1 to 2/1000 population (0.1-0.2 percent) per year. This large population base includes those victims whose SCDs occur as a first cardiac event, as well as those whose SCDs can be predicted with greater accuracy because they are included in higher-risk subgroups. Any intervention designed for the general population must, therefore, be applied to the 999/1000 who will not have an event, in order

892

Figure 26-2 Impact of population pools and time-from-events on the clinical epidemiology of sudden cardiac death. The top panel (A) compares incidence and total numbers of sudden cardiac deaths in different subgroups; the lower panel (B) demonstrates time-dependence of risk for sudden death after major cardiovascular events. In the top panel (A), estimates of incidence figures (percent/year) and the total number of events/year are shown for the overall adult population in the United States, and for increasingly higher-risk subgroups. The overall adult population has an estimated sudden death incidence of 0.1 to 0.2 percent/year, accounting for a total number of events of more than 300,000/year. With the identification of increasingly powerful risk factors, the incidence increases progressively, but it is accomplished by a progressive decrease in the total number of patients identified. The inverse relation between incidence and total number of events occurs because of the progressively smaller denominator pool in the highest subgroup categories. Successful interventions among larger population subgroups will require identification of specific markers to increase the ability to identify specific patients who will be at

particularly high risk for a future event. (Note: The horizontal axis for the incidence figures is not linear and should be interpreted accordingly.) In the lower panel (B), idealized curves of survival from sudden death are shown for a population of patients with known cardiovascular disease but at low risk because of freedom from major cardiovascular (CV) events (top curve) and for populations of patients who have survived a major cardiovascular event (bottom curve). Attrition over time is accelerated in both absolute and relative terms for the initial 6 to 18 months after the major cardiovascular event. After the initial attrition, the slopes of the curves for the high-risk and low-risk populations parallel each other, highlighting both the early attrition and the attenuation of risk after 18 to 24 months. These relations have been observed in diverse high-risk subgroups (cardiac arrest survivors, post-myocardial infarction patients with high-risk markers, recent onset of heart failure), and highlight the changing risk pattern as a function of time and the importance of the time dimension for recognition and intervention in strategies designed to alter outcome. (Modified from Myerburg RJ, et al: Sudden cardiac death: Structure, function and time-dependence of risk. Circulation 85[Suppl 1]:1-2, 1992. Copyright 1992 American Heart Association.)

to reach and possibly influence the 1/1000 who will. The cost and risk-to-benefit uncertainties limit the nature of such broad-based interventions and demand a higher resolution of risk identification. Figure 26-2 A highlights this problem by expressing the incidence (percent/year) of SCD among various subgroups and comparing the incidence figures to the total number of events that occur annually in each subgroup. By moving from the total adult population to a subgroup with high risk because of the presence of selected coronary risk factors, there may be a 10-fold or greater increase in the incidence of events annually, with the magnitude of increase dependent on the number of risk factors operating in the subgroup. The size of the denominator pool, however, remains very large, and implementation of interventions remains problematic, even at this heightened level of risk. Higher resolution is desirable and can be achieved by identification of more specific subgroups. However, the corresponding absolute number of deaths becomes progressively smaller as the subgroups become more focused (Fig. 26-2 A), limiting the potential benefit of interventions to a much smaller fraction of the total number of patients at risk. TIME-DEPENDENCE OF RISK.

Risk of SCD is not linear as a function of time after a change in cardiovascular status.[25] [32] [33] Survival curves after major cardiovascular events, which identify populations at high risk for both sudden and total cardiac death, usually demonstrate that the most rapid rate of attrition occurs during the first 6 to 18 months (Fig. 26-2 B). Thus there is a time-dependence of risk that focuses the opportunity for maximum efficacy of an intervention during the early period after a conditioning event. Curves that have these characteristics have been generated from among survivors of out-of-hospital cardiac arrest, new onset of heart failure, and unstable angina, and from high-risk subgroups of patients having recent myocardial infarction. Even though attrition rates decrease over time, an effective intervention can still cause late diversion of treated versus control risk curves, indicating continuing benefit. The addition of time as a dimension for measuring risk may increase the resolution within subgroups. AGE, HEREDITY, GENDER, AND RACE

AGE.

There are two ages of peak incidence of sudden death: between birth and 6 months of

age (the sudden infant death syndrome) and between 45 and 75 years of age.[3] In the adult population the incidence of sudden death due to coronary heart disease increases as a function of advancing age,[31] [34] [35] [36] [346A] in parallel with the age-related increase in incidence of total coronary heart disease deaths. The incidence is 100-fold less in adolescents and adults younger than the age of 30 years (1 in 100,000 per year) than in adults older than age of 35 years (1 in 1,000 per year)[37] [38] [39] (Fig. 26-3) . However, in contrast to incidence, the proportion of deaths caused by coronary heart diseases that are sudden and unexpected decreases with advancing age.[31] [34] [35] [36] [346A] Kuller and colleagues[40] reported that 76 percent of coronary heart disease deaths in the 20- to 39 year age group were sudden and unexpected, and the Framingham study data demonstrated that 62 percent of all coronary heart disease deaths were sudden in the 45 to 54-year age group in men. The proportion fell progressively to 58 percent in the 55- to 64-year age group and to 42 percent in the 65- to 74-year age group.[35] [36] Age also influences the proportion of cardiovascular causes among all causes of natural sudden death in that the proportion of coronary deaths and of all cardiac causes of death that are sudden is highest in the younger age groups, whereas the fraction of total sudden natural deaths that are due to any cardiovascular cause is higher in the older age groups. In their study of sudden death in children and young adults, Neuspiel and Kuller[41] reported that only 19 percent of sudden natural deaths in children between 1 and 13 years of age were cardiac deaths; the proportion increased to 30 percent in the 14- to 21-year age group. All of these studies of age factors used a 24-hour definition of sudden death. HEREDITY.

To the extent that SCD is an expression of underlying coronary heart disease, hereditary factors that contribute to coronary heart disease risk have been thought to operate nonspecifically for the SCD syndrome.[42] In addition, however, two population studies suggest that SCD, as an expression of coronary heart disease, clusters in specific families.[43] [44] Whether this familial pattern is genetically or environmentally determined, or both, awaits clarifications. Among the less common causes of SCD, hereditary patterns have been reported for specific syndromes[45] such as the congenital long QT interval syndromes,[46] [47] [48] [49] [50] [51] [52] [52A] [53] [54] [55] [56] [57] [58] hypertrophic cardiomyopathy, [54] [55] [56] right ventricular dysplasia,[57] [58] the Brugada syndrome,[59] [60] [61] [62] and yet-to-be-defined

893

Figure 26-3 Age-specific risk of sudden cardiac death (SCD). For the general population age 35 years and older, the risk of SCD is 0.1 to 0.2 percent per year (1 per 500 to 1,000 population). Among the general population of adolescents and adults younger than the age of 30 years, the overall risk of SCD is 1 per 100,000 population, or 0.001 percent per year. The risk of SCD increases dramatically beyond the age of 35 years and continues to increase past the age of 70 years (curve A). The greatest rate of increase is between 40 and 65 years (note that the vertical axis is discontinuous). Among patients older

than 30 years of age, with advanced structural heart disease and markers of high risk for cardiac arrest, the event rate may exceed 25 percent per year (curve B). This magnitude of the risk is determined to a greater extent by the nature of the established disease, rather than by age. Among adolescents and young adults at risk for SCD because of specific identified causes, it is difficult to ascertain risk for individual patient because of variable expression of the disease state and the influences of interventions. However, for many of these conditions (e.g., long QT interval syndromes, Brugada syndrome, right ventricular dysplasia, idiopathic ventricular fibrillation [VF]), the major risk is electrical; and the competing risk of mechanical dysfunction of the heart as in advanced ischemic heart disease or dilated cardiomyopathy does not contribute significantly to risk. Therefore, effective electrical interventions are expected to have a better total mortality benefit than in the latter case (see text for details).

patterns of familial SCD in children and young adults.[63] [63A] Although stable congenital conducting system abnormalities have a good prognosis,[64] progressive familial conducting system disease, which appears to have a hereditary pattern, carry an increased risk of SCD.[65] Familial sudden death associated with cardiac ganglionitis has been reported,[66] but an inheritance pattern has not been demonstrated in the reports to date. Identification of multiple specific gene abnormalities in loci on at least four chromosomes (chromosomes 3, 7, 11, and 21), and linkage analysis suggesting a locus on chromosome 4, in families with long QT interval syndromes have provided a major advance in the understanding of a genetic basis for this cause of sudden death (see Chaps. 23 and 25) . This observation may provide a screening tool for individuals at risk, as well as the potential for specific therapeutic strategies. GENDER.

The SCD syndrome has a huge preponderance in males compared with females because of the protection females enjoy from coronary atherosclerosis before menopause.[28] [29] [35] During the first 14 years of follow-up in the Framingham Study, 59 of 66 (89 percent) sudden unexpected coronary deaths (3-second pause); (2) the vasodepressor type, characterized by a 50-mm Hg fall in the systolic blood pressure in the absence of bradycardia; and (3) the mixed response. Carotid sinus hypersensitivity is commonly detected in patients with syncope. One study reported the presence of carotid sinus hypersensitivity in 65 of 279 patients (23 percent) who presented to the emergency department with falls. [21] It is important to recognize that carotid sinus hypersensitivity is also commonly observed in asymptomatic elderly patients, with carotid sinus hypersensitivity identified in one study in more than one third of asymptomatic patients undergoing cardiac catheterization for coronary artery disease. Because of this, the diagnosis of carotid sinus hypersensitivity should be approached cautiously after excluding alternative causes of syncope. Cardiac Causes of Syncope

Cardiac causes of syncope, particularly tachyarrhythmias and bradyarrhythmias, are the second most common causes, accounting for 10 to 20 percent of syncopal episodes.

Ventricular tachycardia is the most common tachyarrhythmia that can cause syncope. Supraventricular arrhythmias can also cause syncope, although the great majority of patients with supraventricular arrhythmias present with less severe symptoms such as palpitations, dyspnea, and lightheadedness. Bradyarrhythmias that can result in syncope include sick sinus syndrome as well as AV block. Anatomical causes of syncope result from obstruction to blood flow, such as a massive pulmonary embolus, an atrial myxoma, and/or aortic stenosis. Neurological Causes of Syncope

Neurological causes of syncope, including migraines, seizures, Arnold Chiari malformations, and transient ischemic attacks, are surprisingly uncommon causes of syncope, accounting for less than 10 percent of all cases of syncope. The majority of patients in whom a "neurological" cause of syncope is established are found in fact to have had a seizure rather than true syncope.[5] Metabolic/Miscellaneous Causes of Syncope

Metabolic causes of syncope are rare, accounting for less than 5 percent of syncopal episodes. The most common metabolic causes of syncope are hypoglycemia, hypoxia, and hyperventilation. The establishment of hypoglycemia as the cause of syncope requires demonstration of hypoglycemia during the syncopal episode. Although the mechanism of hyperventilation-induced syncope has been generally considered to be due to a reduction in cerebral blood flow, a recent study demonstrated that hyperventilation alone was not sufficient to cause syncope. This suggests that hyperventilation-induced syncope may also have a psychological component.[22] Psychiatric disorders may also cause syncope. It has been reported that up to 25 percent of patients with syncope of unknown origin may have psychiatric disorders for which syncope is one of the presenting symptoms.[23] Cerebral syncope is a rare, recently described cause of syncope resulting from cerebral vasoconstriction induced by orthostatic stress.[24] Relationship Between Prognoses and the Cause of Syncope

The prognosis of patients with syncope varies greatly with diagnosis. Syncope of unknown origin or syncope due to a noncardiac etiology (including reflex mediated syncope) is generally associated with a benign prognosis. In contrast, syncope due to a cardiac cause is associated with a 30 percent mortality at 1 year. DIAGNOSTIC TESTS Identification of the precise cause of syncope is often challenging. Because syncope usually occurs sporadically and infrequently, it is extremely difficult to either examine a patient or obtain an electrocardiogram (ECG) during an episode of syncope. For this reason, the primary goal in the evaluation of a patient with syncope is to arrive at a presumptive determination of the cause of syncope.

History and Physical Examination

The history and physical examination is the most important component of the evaluation of a patient with syncope.[5] [25] [26] [27] In one prospective series of 433 patients a diagnosis was established based on the history and physical examination in 144 patients, representing 58 percent of those patients in whom a diagnosis was established.[5] When taking a clinical history, particular attention should then be focused on (1) determining if the patient experienced true syncope as compared with a transient alteration in consciousness without loss of postural tone; (2) determining if the patient has a history of cardiac disease or if a family history of cardiac disease, syncope, or sudden death exists;

935

TABLE 27-3 -- DIFFERENTIATING SYNCOPE DUE TO NEURALLY MEDIATED HYPOTENSION, ARRHYTHMIAS, AND SEIZURES NEURALLY MEDIATED ARRHYTHMIAS SEIZURE HYPOTENSION Demographics/Clinical Setting

Premonitory Symptoms

Female>male gender Younger age (2) Standing, warm room, emotional upset

Longer duration (>5 sec) Palpitations Blurred vision Nausea Warmth Diaphoresis Lightheadedness

Male>female gender Older age (>54 yr) Fewer episodes (3 gm/day) and beta-blocker therapy. If ineffective, treatment with fludrocortisone, midodrine, or a serotonin reuptake inhibitor such as paroxetine can be considered. Although pacemakers have also been demonstrated to be valuable in the treatment of some patients with neurally mediated syncope, they are generally considered in patients who fail attempts at pharmacologic therapy and have demonstrated a predominantly cardioinhibitory response during tilt-table testing.[62] Because of the profound implications of pacemaker implantation, particular restraint should be exercised when considering the implantation of a pacemaker in a young person. The development of asystole during tilt-table testing is not considered to be an absolute indication for pacemaker implantation.[63]

GENERAL REFERENCES Atiga WL, Rowe P, Calkins H: Management of vasovagal syncope. J Cardiovasc Electrophysiol 10:874-886, 1999. Grubb BP, Olshansky B (eds): Syncope: Mechanisms and Management. Armonk, NY, Futura Publishing Co, 1998. Kapoor WN, Karpf M, Wieand S, et al: A prospective evaluation and follow-up of patients with syncope. N Engl J Med 309:197-204, 1983. Linzer M, Yang EH, Estes M III, et al: Diagnosing syncope: II. Unexplained syncope. Ann Intern Med 127:76-86, 1997. Linzer M, Yang EH, Estes M III, et al: Diagnosing syncope: I. Value of history, physical examination, and electrocardiography. Ann Intern Med 126:989-996, 1997. Wayne HH: Syncope, physiological considerations and an analysis of the clinical characteristics in 510 patients. Am J Med 30:418-438, 1961.




REFERENCES CAUSES OF SYNCOPE 1.

Kapoor W: Evaluation and management of syncope. JAMA 268:2553-2560, 1992.

Nyman JA, Krahn AD, Bland PC, et al: The costs of recurrent syncope of unknown origin in elderly patients. Pacing Clin Electrophysiol 22:1386-1394, 1999. 2.

Linzer M, Pontinen M, Gold DT, et al: Impairment of psychosocial function in recurrent syncope. J Clin Epidemiol 44:1037-1043, 1991. 3.

Calkins H, Byrne M, El-Atassi R, et al: The economic burden of unrecognized vasodepressor syncope. Am J Med 95:473-479, 1993. 4.

5.

Kapoor WN: Evaluation and outcome of patients with syncope. Medicine 69:160-175, 1990.

Sra JS, Anderson AJ, Sheikh SH, et al: Unexplained syncope evaluated by electrophysiologic studies and head-up tilt testing. Ann Intern Med 114:1013-1019, 1991. 6.

Wieling W, van Lieshout JJ: Maintenance of postural normotension in humans. In Low P (ed): Clinical Autonomic Disorders. Boston: Little, Brown, 1993, pp 69-75. 7.

The Consensus Committee of the American Autonomic Society and the American Academy of Neurology. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. Neurology 46:1470-1471, 1996. 8.

9.

Vaitkevicius PV, Esserwein DM, Maynard AK, et al: Frequency and importance of postprandial blood

pressure reduction in elderly nursing-home patients. Ann Intern Med 115:865, 1991. 10.

Kapoor WN: Syncope in the older person. J Am Geriatr Soc 42:426, 1994.

Mathias CJ: The classification and nomenclature of autonomic disorders: Ending chaos, resolving conflict and hopefully achieving clarity. Clin Auton Res 5:307-310, 1995. 11.

Low P, McLeod J: The autonomic neuropathies. In Low P (ed): Clinical Autonomic Disorders. Boston: Little, Brown, 1993, pp 395-421. 12.

Schondorf R, Low PA: Idiopathic postural orthostatic tachycardia syndrome: An attenuated form of acute pandysautonomia? Neurology 43:132, 1993. 13.

Low P, Opfer-Gehrking T, Textor S, et al: Postural tachycardia syndrome (POTS). Neurology 45:519-525, 1995. 14.

940

14A. Shannon

JR, Flattem NL, Jordan J, et al: Orthostatic intolerance andtachycardia associated with norepinephrine-transporter deficiency. N Engl J Med 342:541-549, 2000. Smith ML, Carlson MD, Thames MD: Reflex control of the heart and circulation: Implications for cardiovascular electrophysiology. J Cardiovasc Electrophysiol 2:441-449, 1991. 15.

Benarroch E: The central autonomic network: Functional organization, dysfunction, and perspective. Mayo Clin Proc 68:998-1001, 1993. 16.

Rea R, Thames M: Neural control mechanisms and vasovagal syncope. J Cardiovasc Electrophysiol 4:587-595, 1993. 17.

18.

Abboud FM: Neurocardiogenic syncope. N Engl J Med 328:1117-1119, 1993.

Morillo CA, Eckberg DL, Ellenbogen KA, et al: Vagal and sympathetic mechanisms in patients with orthostatic vasovagal syncope. Circ 96:2509-2513, 1997. 19.

Hjorth S: Penbutolol as a blocker of central 5HT1A receptor-mediated responses. Eur J Pharmacol 222:121-127, 1992. 20.

Richardson DA, Beston RS, Shaw FE, Kenny RA: Prevalence of cardioinhibitory carotid sinus hypersensitivity in patients 50 years or over presenting to the accident and emergency department with "unexplained" or "recurrent" falls. PACE 20:820-823, 1997. 21.

21A. Morillo

CA, Camacho ME, Wood MA, et al: Diagnostic utility of mechanical, pharmacological and orthostatic stimulation of the carotid sinus in patients with unexplained syncope. J Am Coll Cardiol 34:1587-1594, 1999. 21B. Parry

SW, Richardson DA, O'Shea D, Kenny RA: Diagnosis of carotid sinus hypersensitivity in older adults: Carotid sinus massage in the upright position is essential. Heart 83:22-23, 2000.

Racco F, Sconocchini C, Reginelli R: La sincope in una popolazone generale: Diagnosi ezilogoca e follow-up. Min Med 84:249-261, 1993. 22.

Kapoor WN, Fortunato M, Hanusa BH, Schulberg HC: Psychiatric illnesses in patients with syncope. Am J Med 99:505-512, 1995. 23.

Grubb, BP, Samoil D, Kosinski D, et al: Cerebral syncope: Loss of consciousness associated with cerebral vasoconstriction in the absence of systemic hypotension. Pacing Clin Electrophysiol 21(4 Pt 1):652-658, 1998. 24.

DIAGNOSTIC TESTS Calkins H, Shyr Y, Frumin H, et al: The value of the clinical history in the differentiation of syncope due to ventricular tachycardia, atrioventricular block, and neurocardiogenic syncope. Am J Med 98:365-373, 1995. 25.

Hoefnagels WAJ, Padberg GW, Overweg J, et al: Transient loss of consciousness: The value of the history for distinguishing seizure from syncope. J Neurol 238:39-43, 1991. 26.

Benbadis SR, Wolgamuth BR, Goren H, et al: Value of tongue biting in the diagnosis of seizures. Arch Intern Med 155:2346-2349, 1995. 27.

Benditt DG, Ferguson DW, Grubb BP, et al: Tilt table testing for assessing syncope. J Am Coll Cardiol 28:263-275, 1996. 28.

28A. Foglia-Manzillo

G, Giada F, Beretta S, et al: Reproducibility of head-up tilt testing potentiated with sublingual nitroglycerin in patients with unexplained syncope. Am J Cardiol 84:284-288, 1999. Natale A, Akhtar M, Jazayeri M, et al: Provocation of hypotension during head-up tilt testing in subjects with no history of syncope or presyncope. Circulation 92:54-58, 1995. 29.

Ammirati F, Colivicchi F, Biffi A, et al: Head-up tilt testing potentiated with low-dose sublingual isosorbide dinitrate: A simplified time-saving approach for the evaluation of unexplained syncope. Am Heart J 135:671-676, 1998. 30.

Sutton R, Peterson MEV: The clinical spectrum of neurocardiogenic syncope. J Cardiovasc Electrophysiol 6:569, 1995. 31.

Sumiyoshi M, Nakata Y, Yoriaki M, et al: Response to head-up tilt testing in patients with situational syncope. Am J Cardiol 82:1117-1118, 1998. 32.

Ewy GA, Appleton CP, DeMaria AN, et al: ACC/AHA guidelines for the clinical application of echocardiography. Circulation 82:2323-2345, 1990. 33.

Krumholz HM, Douglas PS, Goldman L, Waksmonski C: Clinical utility of transthoracic two-dimensional and Doppler echocardiography. J Am Coll Cardiol 24:125-131, 1994. 34.

Panther R, Mahmood S, Gal R: Echocardiography in the diagnostic evaluation of syncope. J Am Soc Echocardiogr 11:294-298, 1998. 35.

36.

Recchia D, Barzilai B: Echocardiography in the evaluation of patients with syncope. J Gen Intern Med

10:649-655, 1995. Brugada J, Brugada P: Further characterization of the syndrome of right bundle branch block, ST segment elevation, and sudden cardiac death. J Cardiovasc Electrophysiol 8:325-331, 1997. 37.

Alings M, Wilde A: "Brugada" syndrome: Clinical data and suggested pathophysiological mechanism. Circulation 99:666-673, 1999. 38.

Steinberg JS, Prystowsky E, Freedman RA, et al: Use of the signal-averaged electrocardiogram for predicting inducible ventricular tachycardia in patients with unexplained syncope: Relation to clinical variables in a multivariate analysis. J Am Coll Cardiol 23:99-106, 1994. 39.

Linzer M, Pritchett ELC, Pontinen M, et al: Incremental diagnostic yield of loop electrocardiographic recorders in unexplained syncope. Am J Cardiol 66:214-219, 1990. 40.

Fogel RI, Evans JJ, Prystowsky EN: Utility and cost of event recorders in the diagnosis of palpitations, presyncope, and syncope. Am J Cardiol 79:207-208, 1997. 41.

Krahn AD, Klein GJ, Yee R, et al: Use of an extended monitoring strategy in patients with problematic syncope. Circulation 99:406-410, 1999. 42.

Zipes DP, DiMarco JP, Gillette PC, et al: Guidelines for clinical intracardiac electrophysiological and catheter ablation procedures. J Am Coll Cardiol 26:555-573, 1995. 43.

Bachinsky WB, Linzer M, Weld L, Estes NAM III: Usefulness of clinical characteristics in predicting the outcome of electrophysiologic studies in unexplained syncope. Am J Cardiol 69:1044-1049, 1992. 44.

Moazez F, Peter T, Simonson J, et al: Syncope of unknown origin: Clinical, noninvasive, and electrophysiologic determinants of arrhythmia induction and symptom recurrence during long-term follow-up. Am Heart J 121:81-88, 1991. 45.

Petrac D, Radic B, Birtic K, Gjurovic J: Prospective evaluation of infrahisal second-degree block induced by atrial pacing in the presence of chronic bundle branch block and syncope. PACE 19:784-792, 1996. 46.

Leitch JW, Klein GJ, Yee R, et al: Syncope associated with supraventricular tachycardia. Circulation 85:1064-1071, 1992. 47.

Krahn AD, Llein GJ, Norris C, et al: The etiology of syncope in patients with negative tilt table and electrophysiologic testing. Circulation 92:1819-1824, 1995. 48.

Middlekauf HB, Stevenson WG, Saxon LA: Prognosis after syncope: Impact of left ventricular function. Am Heart J 125:121-127, 1993. 49.

Middlekauff HR, Stevenson WG, Stevenson LW: Prognostic significance of atrial fibrillation in advanced heart failure: A study of 390 patients. Circulation 84:40, 1991. 50.

Knight BP, Goyal R, Pelosi F, et al: Outcome of patients with nonischemic dilated cardiomyopathy and unexplained syncope treated with an implantable defibrillator. J Am Coll Cardiol 33:1964-1970, 1999. 51.

Davis TL, Freemon FR: Electroencephalography should not be routine in the evaluation of syncope in adults. Arch Intern Med 150:2027-2029, 1990. 52.

Zaidi A, Crampton S, Clough P, et al: Misdiagnosis of epilepsy--many seizure-like episodes have a cardiovascular cause. PACE 22(2):815, 1999 (abstract). 53.

APPROACH TO THE EVALUATION OF PATIENTS WITH SYNCOPE AND MANAGEMENT Epstein AE, Miles WM, Benditt DG: Personal and public safety issues related to arrhythmias that may affect consciousness: Implications for regulation and physician recommendations: An AHA/NASPE Medical Scientific Statement. Circulation 94:1147-1166, 1996. 54.

Consensus Conference, Canadian Cardiovascular Society: Assessment of the cardiac patient for fitness to drive. Can J Cardiol 8:406-412, 1992. 55.

Mahanonda N, Bhuripanyo K, Kangkagate C, et al: Randomized double-blind, placebo-controlled trial of oral atenolol in patients with unexplained syncope and positive upright tilt table test results. Am Heart J 130:1250-1253, 1995. 56.

Scott WA, Giacomo P, Bromberg BI, et al: Randomized comparison of atenolol and fludrocortisone acetate in the treatment of pediatric neurally mediated syncope. Am J Cardiol 76:400-402, 1995. 57.

Girolamo ED, Iorio CD, Sabatini P, et al: Effects of paroxetine hydrochloride, a selective serotonin reuptake inhibitor, or refractory vasovagal syncope: A randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 33:1227-1230, 1999. 58.

Ward CR, Gray JC, Gilroy JJ, et al: Midodrine: A role in the management of neurocardiogenic syncope. Heart 79:45-49, 1998. 59.

Sra J, Maglio C, Biehl M, et al: Efficacy of midodrine hydrochloride in neurocardiogenic syncope refractory to standard therapy. J Cardiovasc Electrophysiol 8:42-46, 1997. 60.

Atiga W, Rowe P, Calkins H: Management of vasovagal syncope. J Cardiovasc Electrophysiol 10:874-886, 1999. 61.

61A. Mitro

P, Trejbal D, Rybar R: Midodrine hydrochloride in the treatment of vasovagal syncope. PACE 22:1620-1624, 1999. 61B. Girolamo

ED, Iorio CD, Leonzio L, et al: Usefulness of a tilt training program for the prevention of refractory neurocardiogenic syncope in adolescents: A controlled study. Circulation 100:1798-1801, 1999.

Connolly SJ, Sheldon R, Roberts RS, Gent M: The North American Vasovagal Pacemaker Study: A randomized trial of permanent cardiac pacing for the prevention of vasovagal syncope. J Am Coll Cardiol 33:16-20, 1999. 62.

Sra JS, Jazayeri MR, Avitall B, et al: Comparison of cardiac pacing with drug therapy in the treatment of neurocardiogenic (vasovagal) syncope with bradycardia or asystole. N Engl J Med 328(15):1085-1090, 1993. 63.




Part IV - HYPERTENSIVE AND ATHEROSCLEROTIC CARDIOVASCULAR DISEASE

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Chapter 28 - Systemic Hypertension: Mechanisms and Diagnosis NORMAN M. KAPLAN

Definitions, Prevalence, and Consequences of Hypertension Hypertension, despite its widely recognized high prevalence and associated danger, remains inadequately treated in the majority of patients. In the representative sample of the U.S. population examined in the 1991-1994 National Health and Nutrition Examination Survey (NHANES III), only 27 percent of hypertensives had their blood pressure well controlled, as defined by a reading below 140/90 mm Hg[1] (Fig. 28-1) . Although most cases of hypertension had been identified previously, only about half of

hypertensives were currently being treated. Similarly inadequate rates of control have been noted among patients managed in health maintenance organizations[2] and Veterans Affairs clinics.[3] Moreover, cardiovascular mortality remains higher even in presumably well treated hypertensives than in nonhypertensives.[4] Despite these disturbing figures, management of hypertension is now the leading indication for both visits to physicians and the use of prescription drugs in the United States. According to the National Ambulatory Care Survey, over 100 million office visits related to hypertension were made in 1997.[5] Clearly, more attention is being directed toward hypertension, but adequate hypertension control remains elusive, in large part because of the asymptomatic nature of the disease for the first 15 to 20 years, even as it progressively damages the cardiovascular system.[6] Asymptomatic patients are often unwilling to alter life style or take medication to forestall some far-off, poorly perceived danger, particularly when they are made uncomfortable in the process. In view of these built-in barriers to effective control of the individual patient, population-wide application of preventive measures becomes inherently more attractive. Although the specific mechanisms for most hypertension remain unknown, it is highly likely that the process could be slowed, if not prevented, by the prevention of obesity, moderate reduction in sodium intake, higher levels of physical activity, and avoidance of excessive alcohol consumption.[6] Since hypertension will eventually develop in most people during their lifetime, the need for more widespread adoption of potentially effective and totally safe preventive measures is obvious. In the meantime, better management

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Figure 28-1 Percentages of U.S. adult men and women aged 18 to 74 years identified in the National Health and Nutrition Examination Survey (NHANES), 1991-1994, with hypertension diagnosed (left-hand bars), treated (middle), and controlled (right). Hypertension was defined as blood pressure of 140/90 or above. (Adapted from Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure: The Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Arch Intern Med 157:2413, 1997. Copyright 1997, American Medical Association.)

of those already afflicted must be practiced, starting with careful documentation of the diagnosis. DEFINITION OF HYPERTENSION Blood pressure is distributed in a typical bell-shaped curve within the overall population (Fig. 28-2) . As seen in the 12-year experience of the almost 350,000 men screened for the Multiple Risk Factor Intervention Trial (MRFIT), the long-term risks for cardiovascular mortality associated with various levels of pressure rise progressively over the entire range of blood pressure, with no threshold that clearly identifies potential

danger. Therefore, the definition of hypertension is somewhat arbitrary and usually taken as that level of pressure associated with a doubling of long-term risk. Perhaps the best operational definition is "the level at which the benefits (minus the risks and costs) of action exceed the risks and costs (minus the benefits) of inaction." The issue of what blood pressure level should be taken to signify hypertension is further complicated by its typically marked variability. Such variability is seldom recognized by the relatively few office readings taken by most practitioners but can easily be identified by automatically recorded measurements taken throughout the day and night (Fig. 28-3) . This variability can often be attributed to physical activity or emotional stress but is frequently without obvious cause. In a few patients, markedly elevated levels clearly indicate serious disease requiring immediate treatment. However, in most cases, initial readings are not high enough to indicate immediate danger, and the diagnosis of hypertension should be substantiated by repeated readings. The reason for such caution is obvious: The diagnosis of hypertension imposes psychological and socioeconomic burdens on an individual and usually implies the need for commitment to lifelong therapy. Both transient and persistent elevations in pressure are common when it is taken in the physician's office or hospital. To identify "white coat" hypertension, more widespread use of out-of-the-office readings, either with semiautomatic inexpensive devices or with automatic ambulatory recorders, is encouraged both to establish the diagnosis and to monitor the patient's response to therapy. [1] A large body of data provides normal ranges for both home self-recorded[7] and automatic ambulatory measurements. [8] Both average about 10/5 mm Hg lower than the average of multiple office readings. A closer correlation between the presence of various types of target organ damage, specifically, left ventricular hypertrophy (LVH), carotid wall thickness, proteinuria, and retinopathy, has been noted with ambulatory levels than with office levels.[9] However, in the absence of adequate long-term follow-up evidence of the risks associated with either home or ambulatory monitoring, office readings should continue to be the basis for the diagnosis and management of hypertension. OUT-OF-THE-OFFICE MEASUREMENTS.

Whenever possible, office readings should be supplemented by out-of-the-office measurements, particularly when there is an apparent

Figure 28-2 Left, Percent distribution of systolic blood pressure (SBP) for men screened for the Multiple Risk Factor Intervention Trial who were 35 to 57 years old and had no history of myocardial infarction (n = 347,978) (shaded bars) and corresponding 12-year rates of cardiovascular mortality by SBP level adjusted for age, race, total serum cholesterol level, cigarettes smoked per day, reported use of medications for diabetes mellitus, and estimated household income (using census tract of residence). Right, Same as at the left, except distribution of diastolic blood pressure (DBP) (n = 356,222). (From National High Blood Pressure Education Program Working Group: National High Blood Pressure Education Program Working Group report on primary prevention of hypertension. Arch Intern Med

153:186, 1993. Copyright 1993, American Medical Association.)

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Figure 28-3 Computer printout of blood pressure readings obtained by ambulatory blood pressure monitoring over a 24-hour period beginning at 9 A.M. in a 50-year-old man with hypertension receiving no therapy. The patient slept from midnight until 6 A.M.Solid circles = heart rate. (From Zachariah PK, Sheps SG, Smith RL: Defining the roles of home and ambulatory monitoring. Diagnosis 10:39, 1988. © Medical Economics Publishing Company, Inc., Pradell, NJ. All rights reserved.)

discrepancy between the level of blood pressure and the degree of target organ damage, in which case white coat hypertension should be suspected. Pickering has provided a scheme for the use of home and ambulatory monitoring in such a circumstance[10] (Fig. 28-4) . In as many as half of patients with office readings that remain elevated despite the use of three or more drugs, hypertension in as many as half is found to be well controlled by out-of-the-office readings. [11] Purely white coat hypertension, that is, persistently elevated office readings but persistently normal out-of-the-office readings, is found in 20 to 30 percent of patients. Most are found to be free of the target organ damage and metabolic abnormalities (dyslipidemia, hyperinsulinemia) that are often found in patients with sustained hypertension,[12] and follow-up for up to 10 years has found no increase in cardiovascular events. [13] Therefore, close observation and life style modifications but not antihypertensive drug therapy seem appropriate management for such patients.

Figure 28-4 Schema for evaluation of hypertensive patients by use of clinic, home, and ambulatory monitoring of blood pressure. (From Pickering TG: Blood pressure measurement and detection of hypertension. Lancet 344:31, 1994. © by The Lancet Ltd., 1994.)

In addition to their role in the recognition of white coat hypertension, out-of-the-office readings are essential for the recognition of persistently elevated pressures soon after awakening, when the largest proportion of sudden deaths, myocardial infarctions, and strokes occur.[14] Increased awareness of the role of the abrupt and marked rise in pressure after awakening in the etiology of these early morning cardiovascular catastrophes has prompted therapeutic strategies to ensure control of hypertension at that time, including late evening dosing with currently available medications and the development of tablets that are delayed in releasing active drug so that they can be taken at bedtime but not become active until the hours before awakening. [15] In view of the usual nocturnal fall in pressure (see Fig. 28-3) , addition of the maximal antihypertensive effect of medication taken before bedtime could incite myocardial and cerebral ischemia during sleep. Therefore, the best way to blunt the early morning surge in pressure is to use formulations that provide full 24-hour coverage and to take them as

early in the morning as possible. Although a nocturnal fall in pressure is usual, various groups of hypertensives who have a more serious degree of target organ damage or subsequent major cardiovascular events have been noted to have little or no nocturnal fall.[16] These groups include patients with LVH, diabetes, or renal damage and blacks. Recognition of abnormal nocturnal patterns of blood pressure, presumably adding an additional stress to the cardiovascular system, is a potential indication for more widespread use of automatic recordings. BLOOD PRESSURE RESPONSE TO EXERCISE.

Another source of potentially useful prognostic information is the blood pressure response to exercise, usually ascertained by treadmill testing. An exaggerated response in normotensive adults, defined as a systolic pressure rise of more than 60 mm Hg at 5 minutes of exercise (6.3 METs) or more than 70 mm Hg at 10 minutes (8.1 METs) or a diastolic rise of more than 10 mm Hg at any time, was associated with a 3-fold greater likelihood of hypertension developing over the next 5 to 15 years.[17] Such patients had a 3.6 times greater risk ratio for major cardiovascular events over an 8-year follow-up than did those without an exaggerated response during exercise.[18] DOCUMENTATION OF HYPERTENSION.

For most patients who are in no immediate danger from markedly elevated pressure, i.e., below approximately 170/110 mm Hg, the following guidelines are offered:

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TABLE 28-1 -- GUIDELINES IN MEASURING BLOOD PRESSURE Conditions for the Patient Posture For patients who are older than 65 yr, diabetic, or receiving antihypertensive therapy, check for postural changes by taking readings immediately and 2 min after patient stands Sitting pressures are usually adequate for routine follow-up. Patient should sit quietly with back supported for 5 min and arm supported at level of heart Circumstances No caffeine for preceding hour No smoking for preceding 15 min No exogenous adrenergic stimulants, e.g., phenylephrine in nasal decongestants or eyedrops for pupillary dilation

Quiet, warm setting Home readings taken under varying circumstances and 24-hr ambulatory recordings may be preferable and more accurate in predicting subsequent cardiovascular disease Equipment Cuff size: The bladder should encircle and cover two-thirds of the length of the arm; if not, place the bladder over the brachial artery; if bladder is too small, spuriously high readings may result Manometer: Aneroid gauges should be calibrated every 6 mo against a mercury manometer For infants, use ultrasound equipment, e.g., the Doppler method Technique Number of readings On each occasion, take at least 2 readings separated by as much time as practical. If readings vary by more than 5 mm Hg, take additional readings until 2 are close For diagnosis, obtain at least 3 sets of readings at least a week apart Initially, take pressure in both arms; if pressure differs, use arm with higher pressure If arm pressure is elevated, take pressure in one leg, particularly in patients younger than 30 yr Performance Inflate the bladder quickly to a pressure 20 mm Hg above the systolic, as recognized by disappearance of the radial pulse Deflate the bladder 3 mm Hg every second Record the Korotkoff phase V (disappearance) except in little children, in whom use of phase IV (muffling) may be preferable If Korotkoff sounds are weak, have the patient raise the arm and open and close the hand 5-10 times, after which the bladder should be inflated quickly Recordings Note the pressure, patient position, which arm, and cuff size (e.g., 140/90, seated, right arm, large adult cuff)

1. Multiple readings should be obtained with appropriate technique (Table 28-1) . If possible, the readings should be taken under varying conditions and at various times for at least 4 to 6 weeks with a semiautomatic home device. If the diagnosis must be established more rapidly, a set of readings obtained by an automatic monitor over a single 24-hour period will be adequate. 2. Although the logical approach would be to calculate the average values from multiple readings when deciding whether hypertension is present, even a single high measurement should not be disregarded. In large populations, a single set of casual measurements has been found to predict a greater likelihood of

subsequent cardiovascular disease.[19] However, such elevated measurements do not necessarily predict either fixed hypertension or increased risk for each individual. For example, in one study only 10.8 percent of 719 men aged 18 to 30 with initial systolic values of 140 to 170 began to exhibit systolic pressures persistently above 140 over the next 12 to 15 years. [20] Nonetheless, persistently elevated pressures were found 2.3 times more often among those with initially high readings, obviously placing them at higher risk. 3. Systolic elevations pose a risk that is equal to or greater than that posed by diastolic elevations, and a wide pulse pressure is the most potent predictor of cardiovascular risk.[21] isolated systolic hypertension, as commonly seen among the elderly, presents a risk for both stroke and myocardial infarction.[19] 4. The elderly often have sclerotic brachial arteries that may not become occluded until very high pressures are exerted by the balloon; therefore, cuff diastolic levels may be considerably higher than those measured intraarterially. In patients with high cuff readings but little or no hypertensive retinopathy, cardiac hypertrophy, or other evidence of longstanding hypertension, "pseudohypertension" should be suspected and ruled out before treatment is begun. 5. Elderly persons with elevated systolic pressure should be monitored carefully for significant falls in pressure either with sudden upright posture or after meals.[22] These changes probably reflect a progressive loss of baroreceptor responsiveness with age. This condition makes the elderly particularly susceptible to marked orthostatic hypotension after even small decreases in vascular volume. For the individual patient, hypertension can be definitively diagnosed when most readings are at a level known to be associated with a significantly higher cardiovascular risk without treatment. The recommendations of the Sixth Joint National Committee (JNC/6) are shown in Table 28-2 .[1] Note that systolic levels of 130 to 139 mm Hg and diastolic levels of 85 to 89 mm Hg are classified as high normal blood pressure, a recommendation stemming from prospective observations of over 420,000 people for 6 to 25 years wherein a doubling of the risk for stroke was seen among those with mean diastolic blood pressure of 85 mm Hg when compared with those with a mean of 76 mm Hg.[23] Therefore, persons with relatively high systolic or diastolic pressures should be advised that they may be at increased risk and counseled to follow better health habits in the hope of slowing the progression toward definite hypertension. The criteria shown in Table 28-2 are based on at least three sets of measurements taken over at least a 3-month interval. Even more readings may be needed to establish a patient's usual level. Even though they are diagnosed as hypertensive, not all persons with usual levels above 140/90 mm Hg need be treated with drugs, although all should be advised to use the various life style modifications described in Chapter 29 . As recommended in both the 1997 JNC-6 report[1] and the 1999 World Health Organization-International Society of Hypertension (WHO-ISH) guidelines,[24] the threshold for institution TABLE 28-2 -- CLASSIFICATION OF BLOOD PRESSURE FOR ADULTS AGED 18 YEARS AND OLDER* BLOOD PRESSURE (mm Hg)

CATEGORY

Systolic

Diastolic

Optimal

180/110 mm Hg Organ damage Funduscopic findings of grade 2 or higher Serum creatinine >1.5 mg/100 ml Cardiomegaly (on radiograph) or left ventricular hypertrophy (on electrocardiogram) Features indicative of secondary causes Unprovoked hypokalemia Abdominal bruit Variable pressures with tachycardia, sweating, tremor Family history of renal disease Poor response to therapy that is usually effective

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value of an IVP or isotopic renogram suggestive of this diagnosis is only 10 percent, and an abnormal IVP or renogram is more likely to be a false-positive result than be true-positive and indicate a specific diagnosis.[32] NATURAL HISTORY OF UNTREATED HYPERTENSION

A meta-analysis of nine major prospective observational studies involving 420,000 individuals free of known coronary or cerebral vascular disease at baseline who were monitored for 6 to 25 years (mean of 10 years) shows a "direct, continuous and apparently independent association" of diastolic blood pressure with both stroke and coronary heart disease[23] (Fig. 28-6) . The data indicate that prolonged increases in the usual diastolic pressure of 5 and 10 mm Hg were associated with at least 34 and 56 percent increases in stroke risk and with at least 21 and 37 percent increases in coronary heart disease risk, respectively. SYMPTOMS AND SIGNS.

Because uncomplicated hypertension is almost always asymptomatic, a person may be unaware of the consequent progressive cardiovascular damage for as long as 10 to 20 years. Only if blood pressure is measured frequently and people are made aware that hypertension may be harmful even if asymptomatic will the majority of people with unrecognized or inadequately treated hypertension be managed effectively. Symptoms often attributed to hypertension--headache, tinnitus, dizziness, and fainting--may be observed just as commonly in the normotensive population. Moreover, many symptoms attributed to the elevated blood pressure are psychogenic in origin, often reflecting hyperventilation induced by anxiety over the diagnosis of a lifelong, insidious disease that threatens well-being and survival.[33] Even headache, long considered a frequent symptom of hypertension, is poorly related to the level of blood pressure, as noted in 10 to 20 percent of those with diastolic blood pressure levels from below 90 to above 120

mm Hg.[34] COURSE OF UNTREATED HYPERTENSION.

As noted in Figure 28-6 , even minimal hypertension is accompanied by significant increases in coronary disease and stroke. However, these figures may be misleading since they seem to imply that most hypertensives, including those with minimally elevated pressure, will experience adverse consequences of hypertension, and rather quickly. The issue is well identified in the data from the Pooling Project,[35] which includes multiple prospective follow-up studies, including the Framingham cohort. These data indicate that white men with diastolic pressures of 80 to 87 mm Hg had a 52 percent greater relative risk of having a major coronary event over an 8.6-year period than did those with diastolic pressures below 80. However, this large increased relative risk translates to an absolute excess risk of only 3.5 men per 100 over the 8.6-year interval. Obviously, the majority of those with even higher diastolic pressures did not suffer a major coronary event. Nonetheless, because so many persons have hypertension, the fact that even a minority of them will suffer a premature cardiovascular event in the course of their disease makes hypertension a major societal problem. In fact, when the death rates for various levels of diastolic blood pressure are multiplied by the proportion of people in the population who have these various levels, the majority of excess deaths attributable to hypertension are found to occur among those with minimally elevated pressure (see Fig. 28-2 ). As the public and the medical profession have become aware of the overall societal consequences of even mild hypertension, enthusiasm for early recognition and aggressive treatment of hypertension has continued to mount. A closer look at the issue of deciding on the need for therapy is provided in Chapter 29 . However, further consideration of the natural course of hypertension, as it applies to the individual patient, is needed to answer a basic question: Are the blood pressure and the consequent risk high enough to justify medical intervention? Unless the risk is high enough to mandate some form of intervention, there seems to be no need to identify and label the person as hypertensive since psychological and socioeconomic burdens accompany this label; unless risks clearly outweigh these burdens, caution is obviously advised. A cogent view of this issue has been offered by Rose.[36] In reality the care of the symptomless hypertensive person is preventive medicine, not therapeutics. If a preventive measure exposes many people to a small risk, the harm it does may readily . . . outweigh the benefits, since these are received by relatively few. . . . We may thus be unable to identify that small level of harm to individuals from long-term intervention that would be sufficient to make that line of prevention unprofitable or even harmful. Consequently we cannot accept long-term mass preventive medication. We are thus left with a dilemma: For hypertensive individuals as a group, even those with the least elevated pressures, risk is increased; for the individual hypertensive, the

risk may not justify the labeling or treatment of the condition. ASSESSMENT OF INDIVIDUAL RISK Guidelines are available to help practitioners resolve this dilemma in dealing with the individual patient. These guidelines are based on the overall assessment of cardiovascular risk and the biological aggressiveness of the hypertension. They are intended to apply only to those with stage 1 (formerly referred to as mild) hypertension, that is, diastolic

Figure 28-6 The relative risks of stroke and coronary heart disease (CHD), estimated from the combined results of prospective observational studies, for each of five categories of diastolic blood pressure (DBP). (Estimates of the usual DBP in each baseline DBP category are taken from mean DBP values 4 years postbaseline in the Framingham Study.) The solid squares represent disease risks in each category relative to risk in the whole study population; the sizes of the squares are proportional to the number of events in each DBP category, and 95 percent confidence intervals for the estimates of relative risk are denoted by vertical lines. (From MacMahon S, Peto R, Cutler J, et al: Blood pressure and coronary heart disease: Part 1, prolonged differences in blood pressure: Prospective observational studies corrected for the regression dilution bias. Lancet 335:765, 1990. © by the Lancet Ltd., 1990.)

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Figure 28-7 Estimated 10-year risk of coronary artery disease in hypothetical 55-year-old men and women according to levels of various risk factors. Lipid units are milligrams per deciliter. (From O'Donnell CJ, Kannel WB: Cardiovascular risks of hypertension: Lessons from observational studies. J Hypertens 16(Suppl 6):3, 1998.)

pressure between 90 and 99 mm Hg; those with diastolic levels persistently at or above 100 mm Hg have been shown to be at high enough risk from the hypertension per se to justify immediate intervention. Recall, however, that most hypertensives are in the range between 90 and 99 mm Hg (see Fig. 28-2 ). On the other hand, patients at high overall cardiovascular risk even with high normal blood pressure are deemed to be in need of active drug therapy.[1] OVERALL CARDIOVASCULAR RISK.

The Framingham Study and other epidemiological surveys have clearly defined certain risk factors for premature cardiovascular disease in addition to hypertension (see Chap. 31 ). For varying levels of blood pressure, the Framingham data (available in the Coronary and Stroke Risk Handbooks published by the American Heart Association) show the increasing likelihood of a vascular event over the next 10 years for both men and women at various ages as more and more risk factors are added. [19] For example, a 55-year-old man with a systolic blood pressure of 160 mm Hg who is otherwise at low

risk would have a 13.7 percent chance of a vascular event in the next 10 years (Fig. 28-7) . A man of the same age with the same pressure but with all the additional risk factors (elevated serum total cholesterol, low high-density lipoprotein cholesterol, cigarette smoking, glucose intolerance, and LVH on the electrocardiogram) has a 59.5 percent chance. Obviously, the higher the overall risk, the more intensive the interventions should be. An interesting--and disturbing--connection between untreated hypertension and hypercholesterolemia has been noted in multiple populations.[37] This connection may be mediated through insulin resistance and hyperinsulinemia and is anticipated in those with upper body obesity[38] but may also be found in nonobese hypertensives. Clearly, through this association, hypertensives are often burdened with an even greater risk than that imposed by their blood pressure alone. Complications of Hypertension

The higher the level of blood pressure, the more likely that various cardiovascular diseases will develop prematurely through acceleration of atherosclerosis, the pathological hallmark of uncontrolled hypertension. If untreated, about 50 percent of hypertensive patients die of coronary heart disease or congestive failure, about 33 percent of stroke, and 10 to 15 percent of renal failure. Those with rapidly accelerating hypertension die more frequently of renal failure, as do those who are diabetic once proteinuria or other evidence of nephropathy develops. It is easy to underestimate the role of hypertension in producing the underlying vascular damage that leads to these cardiovascular catastrophes. Death is usually attributed to stroke or myocardial infarction instead of to the hypertension that was largely responsible. Moreover, hypertension may not persist after a myocardial infarction or stroke. In general, the vascular complications of hypertension can be considered as either "hypertensive" or "atherosclerotic" (Table 28-7) . The former are more directly caused by the increased blood pressure per se and can be prevented by lowering this level; the latter have more multiple causations. Although hypertension may represent the most significant of the known risk factors for atherosclerosis in quantitative terms, lowering blood pressure may not by itself halt the atherosclerotic process. The path from hypertension to vascular disease probably involves three interrelated processes: pulsatile flow, endothelial cell dysfunction, and smooth muscle cell hypertrophy. Higher systolic pressures are probably more responsible for these changes than are lower diastolic levels, which provides an explanation for the closer approximation of cardiovascular risk to systolic pressure and pulse pressure. These three interrelated processes are probably responsible for the arteriolar and arterial sclerosis that is the usual consequence of longstanding hypertension; the subsequent target organ damage (see below) should be included in the overall assessment of hypertension risk. Beyond damage to the eyes, heart, brain, and kidney, large vessels such as the aorta may be directly affected and be at risk for aneurysms and dissection.

Target Organ Damage

The biological aggressiveness of a given level of hypertension varies among individuals. This inherent propensity to induce vascular damage can best be ascertained by examination of the eyes, heart, and kidney. FUNDUSCOPIC EXAMINATION.

As described by Keith and associates in 1939, vascular changes in the fundus reflect both hypertensive retinopathy and arteriosclerotic retinopathy[39] (see Fig. 4-1 ). The two processes first induce TABLE 28-7 -- VASCULAR COMPLICATIONS OF HYPERTENSION HYPERTENSIVE

ATHEROSCLEROTIC

Accelerated-malignant phase

Coronary heart disease

Hemorrhagic stroke

Sudden death


Other arrhythmias

Nephrosclerosis

Atherothrombotic stroke

Aortic dissection

Peripheral vascular disease

Adapted from Smith WM: Treatment of mild hypertension. Results of a ten-year intervention trial. Circ Res 25(Suppl 1):98, 1977. By permission of the American Heart Association.

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narrowing of the arteriolar lumen (grade 1) and then sclerosis of the adventitia and/or thickening of the arteriolar wall, visible as arteriovenous nicking (grade 2). Progressive hypertension induces rupture of small vessels, seen as hemorrhage and exudate (grade 3) and eventually papilledema (grade 4). The grade 3 and 4 changes are clearly indicative of an accelerated-malignant form of hypertension, whereas the lesser changes have been correlated with other evidence of target organ damage. [40] CARDIAC INVOLVEMENT.

Hypertension places increased tension on the left ventricular myocardium that is manifested as stiffness and hypertrophy, which accelerates the development of atherosclerosis within the coronary vessels. The combination of increased demand and lessened supply increases the likelihood of myocardial ischemia and thereby leads to a higher incidence of myocardial infarction, sudden death, arrhythmias, and congestive failure in hypertensives (see Figs. 28-2 and Fig. 28-6 ).

Abnormalities in Left Ventricular Function.

Even before LVH develops, changes in both systolic and diastolic function may be seen. Those with minimally increased left ventricular muscle mass may have supernormal contractility as reflected by an increased inotropic state with a high percentage of fractional shortening and increased wall stress.[41] The earliest functional cardiac changes in hypertension are in left ventricular diastolic function, with prolongation and incoordination of isovolumic relaxation, a reduced rate of rapid filling, and an increase in the relative amplitude of the a wave, probably caused by increased passive stiffness[42] (see Chap. 15 ). With increasing hemodynamic load, either systolic or diastolic dysfunction may evolve and progress to different forms of congestive heart failure[43] (Fig. 28-8) . In addition, impaired coronary flow reserve and thallium perfusion defects may be observed in hypertensives without obstructive coronary disease.[44] The syndrome of severe concentric hypertrophy with a small ventricular cavity leading to dyspnea and pulmonary congestion has been most frequently

Figure 28-8 Consequences of systolic and diastolic dysfunction related to hypertension. A, Systolic dysfunction and congestive heart failure caused by impaired ventricular contraction may occur late in the evolution of hypertensive heart disease. B, Diastolic dysfunction is the most common manifestation of the effect of hypertension on cardiac function and can also lead to congestive heart failure from increased filling pressures. LV = left ventricular. (From Shepherd RFJ, Zachariah PK, Shub C: Hypertension and left ventricular diastolic function. Mayo Clin Proc 64:1521, 1989. By permission of the Mayo Foundation.)

Figure 28-9 Mean left ventricular mass by sex and by systolic pressure, including participants taking antihypertensive medications. These data were obtained by M-mode echocardiograms taken on 2226 men and 2746 women aged 17 to 90 years in the Framingham Study, cohort examination 16 and offspring cycle 2, 1979 to 1983. (From Savage DD, Levy D, Danneberg AL, et al,: Association of echocardiographic left ventricular mass with body size, blood pressure and physical activity [the Framingham Study]. Am J Cardiol 65:371, 1990.)

reported in black hypertensive women.[45] Moreover, blacks are at a higher risk for progression to heart failure and death from left ventricular dysfunction than are similarly treated whites.[46] Left Ventricular Hypertrophy.

Hypertrophy as a response to the increased afterload associated with elevated systemic vascular resistance can be viewed as necessary and protective up to a certain point. Beyond that point, a variety of dysfunctions accompany LVH. In the past, LVH was recognized on electrocardiography (see Chap. 5 ) by increased

voltage of QRS complexes, intrinsicoid deflection over lead V2 or V3 greater than 0.06 seconds, and ST segment depression greater than 0.5 mm. Increasingly, echocardiography is being used (see Chap. 7 ) because it is much more sensitive in recognizing early cardiac involvement. By echocardiography, left ventricular mass is shown to progressively increase with increases in blood pressure[47] (Fig. 28-9) . Left ventricular mass is greater in those whose pressure does not fall during sleep because of a more persistent pressure load. [48] The pathogenesis of LVH involves a number of variables other than the pressure load, one of which is hemodynamic volume load. Devereux and colleagues[48] found a closer correlation between left ventricular stroke volume and left ventricular mass with diastolic than with systolic blood pressure. Other determinants are obesity,[49] levels of sympathetic nervous system and renin-angiotensin activity, and whole blood viscosity, presumably by way of its influence on peripheral resistance. The correlation is much closer between LVH and pressure readings taken during the stress of work by ambulatory monitoring than between LVH and casual pressure readings.[50] Different patterns of hypertrophy may evolve, often starting with asymmetrical left ventricular remodeling from isolated septal thickening, which has been noted in 22 percent of untreated hypertensives with normal total left ventricular mass.[51] The pattern of LVH may have important prognostic implications. In a 10-year follow-up of 253 hypertensives, all-cause mortality was higher and cardiovascular events were most frequent in those with concentric LVH.[52] The degree of increased muscle mass is a strong and independent risk factor for cardiac mortality over and above the extent of coronary artery disease.[47] In addition, the risk of ventricular arrhythmias is increased at least twofold in the presence of LVH.[53] Since the presence of LVH may connote a number of deleterious effects of hypertension on cardiac function, a great deal of effort has been expended in showing that treatment of hypertension will cause LVH to regress. Treatment with all antihypertensive drugs except those that further activate sympathetic nervous system activity, e.g., direct vasodilators such as hydralazine when used alone, has been shown to cause LVH regression.[54] With regression, left ventricular function usually improves and cardiovascular morbidity decreases.[55]

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Features of Coronary Artery Disease.

As detailed elsewhere (see Chap. 31 ), hypertension is a major risk factor for myocardial ischemia and infarction. Moreover, in the Framingham cohort, the prevalence of silent myocardial infarction was significantly increased in hypertensive subjects, and they were also more susceptible to silent ischemia and sudden death,[56] as well as having a greater risk for mortality after an initial myocardial infarction. [57] Beyond these multiple additional risks associated with hypertension, a higher incidence of cardiovascular mortality has also been recognized when elevated diastolic blood pressures are

reduced to levels below 80 mm Hg.[58] This J-shaped curve probably reflects a reduction in perfusion pressure through coronary vessels either narrowed or having impaired vasodilatory reserve in the presence of hypertrophied myocardium. RENAL FUNCTION.

Renal dysfunction too subtle to be recognized may be responsible for the development of most cases of essential hypertension. As discussed on p. 952 , increased renal retention of salt and water may be a mechanism initiating primary hypertension, but the retention is so small that it escapes detection. With detailed study, both structural damage and functional derangements reflecting intraglomerular hypertension often reflected by microalbuminuria can be found in most hypertensive persons. Microalbuminuria in hypertensives has been correlated with both insulin resistance[59] and evidence of endothelial cell dysfunction.[60] As hypertension-induced nephrosclerosis proceeds, the plasma creatinine level begins to rise, and eventually, renal insufficiency with uremia may develop, thus making hypertension a leading cause of end-stage renal disease (ESRD), particularly in blacks.[61] CEREBRAL INVOLVEMENT.

Hypertension may accelerate cognitive decline with age.[62] Hypertension, particularly systolic, is a major risk factor for initial and recurrent stroke and for transient ischemic attacks caused by extracranial atherosclerosis.[63] Usually with, but sometimes without, hypertension, increasing left ventricular mass on echocardiography is associated with a progressively higher risk for stroke.[64] Blood pressure usually rises further during the acute phases of a stroke, and caution is advised in lowering blood pressure during this crucial period. On the basis of the aforementioned assessments of overall cardiovascular risk and severity of hypertension, it should be possible to determine the approximate risk status and prognosis for individual patients, which can most easily be accomplished with the Framingham data, as described on page 948 . SHORT-TERM COURSE OF LOW-RISK HYPERTENSION.

Data on the 4-year experiences of over 1600 "low-risk" hypertensives who served as controls in the Australian Therapeutic Trial document the validity of this assessment.[65] To enter this placebo-versus-drug trial, the patients had to be free of all identifiable cardiovascular disease, with the second set of diastolic pressures between 95 and 109 mm Hg. Thus, they could be considered "low-risk" hypertensives. Over the next 4 years, in the majority of these patients, who were given placebo tablets but neither nondrug nor drug therapy, blood pressures dropped progressively from an average of 157/102 to 144/91 mm Hg. Diastolic pressure was below 95 mm Hg in 47.5 percent at the end of the trial. The fall in blood pressure was not related to any recognizable change in the patients' status; similar decreases occurred independent of changes in or stability of body weight. Of great interest was the lack of excess morbidity and mortality among

those whose diastolic pressure remained below 100 mm Hg. These results strongly support the view that certain patients can be characterized as being at relatively low risk and can therefore safely do without drug therapy long enough for the clinician to monitor both their blood pressure levels over time and the effectiveness of nondrug measures, if indicated. The large number of patients whose pressure fell and the high average degree of fall may seem surprising, but none of these patients started with any identifiable cardiovascular disease or complications of hypertension. Moreover, placebo may be more effective than no therapy. THE POTENTIAL FOR PROGRESSION.

Although these data reflect the benign nature of "low-risk" hypertension over the short term, it should be noted that diastolic blood pressure rose above 110 mm TABLE 28-8 -- COMPONENTS OF CARDIOVASCULAR RISK STRATIFICATION IN PATIENTS WITH HYPERTENSION Major Risk Factors Smoking Dyslipidemia Diabetes mellitus Age >60 yr Sex (men and postmenopausal women) Family history of cardiovascular disease: Women 55 yr Target Organ Damage/Clinical Cardiovascular Disease Heart diseases Left ventricular hypertrophy Angina or prior myocardial infarction Prior coronary revascularization Heart failure Stroke or transient ischemic attack Nephropathy Peripheral arterial disease Retinopathy From The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 157:2413. 1997. Copyright 1997, American Medical Association. Hg in 12 percent of the non-drug-treated patients in the Australian trial. Therefore, continued monitoring of blood pressure levels is obviously needed for all patients with even the mildest "low-risk" hypertension. A SYNTHESIS OF RISK.

As first clearly articulated by a group of New Zealand physicians,[66] the degree of risk from hypertension can be categorized with reasonable accuracy by taking into account (1) the level of blood pressure, (2) the biological nature of the hypertension based on the degree of target organ damage, and (3) the coexistence of other risks. The JNC-6 report provides a stratification of risk into three groups based on known components of risk (Table 28-8) and levels of blood pressure, which are, in turn, used as the basis for deciding upon initial treatment (Table 28-9) . According to this stratification, active drug therapy is recommended for high-risk patients even if blood pressure is only high normal, whereas life style modifications are recommended for low-risk patients even if blood pressure is as high as 159/99 mm Hg. Similar recommendations have been made in the 1999 WHO-ISH guidelines.[24] It is obvious that since the course of the blood pressure cannot be predicted with certainty, even hypertensives who are not treated should be monitored, and recognition of their hypertension should motivate them to follow good health habits. In this way, no harm should be done, and the potential benefit may be considerable if progression of the disease can be slowed by life style modifications. MECHANISMS OF PRIMARY (ESSENTIAL) HYPERTENSION No single or specific cause is known for most hypertension, and the condition is referred to as primary in preference to essential. Since persistent hypertension can develop only in response to an increase in cardiac output or a rise in peripheral resistance, defects may be present in one or more of the multiple factors that affect these two forces (Fig. 28-10) . The interplay of various derangements in factors affecting cardiac output and peripheral resistance may precipitate the disease, and these abnormalities may differ in both type and degree in different patients.

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TABLE 28-9 -- RISK STRATIFICATION AND TREATMENT* BLOOD RISK GROUP A RISK GROUP B (AT RISK GROUP C PRESSURE (NO RISK LEAST 1 RISK (TOD/CCD AND/OR STAGES (mm Hg) FACTORS: NO FACTOR, NOT DIABETES, WITH OR TOD/CCD) INCLUDING WITHOUT OTHER DIABETES: NO RISK FACTORS) TOD/CCD) High normal (130-139/85-89)

Life style modification

Life style modification

Drug therapy

Stage 1 (140-159/90-99)

Life style modification (up to 12 mo)

Life style modification (up to 6 mo)

Drug therapy

Stages 2 and 3 (>160/>100)

Drug therapy

Drug therapy

Drug therapy

CCD=clinical cardiovascular disease; TOD=target organ disease.From The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 157:2413. 1997. Copyright 1997, American Medical Association. *Note: For example, a patient with diabetes and a blood pressure of 142/94 mm Hg plus left ventricular hypertrophy should be classified as having stage 1 hypertension with target organ disease (left ventricular hypertrophy) and with another major risk factor (diabetes). This patient would be categorized as "stage 1, risk group C," and recommended for immediate initiation of pharmacological treatment. Life style modification should be adjunctive therapy for all patients recommended for pharmacological therapy.

Hemodynamic Patterns

Before describing specific abnormalities in the various factors shown in Figure 28-10 to affect the basic equation blood pressure = cardiac output × peripheral resistance (BP = CO × PR), the hemodynamic patterns that have been measured in patients with hypertension will be considered. One cautionary factor should be kept in mind: Development of the disease is slow and gradual. By the time that blood pressure becomes elevated, the initiating factors may no longer be apparent because they may have been "normalized" by multiple compensatory interactions. Nonetheless, when a group of untreated young hypertensive patients was studied initially, cardiac output was normal or slightly increased and peripheral resistance was normal.[67] Over the next 20 years, cardiac output fell progressively while peripheral resistance rose. In a much larger study involving over 2600 subjects in Framingham who were monitored for 4 years by echocardiography, an increased cardiac index and end-systolic wall stress were related to the development of hypertension,[68] and in a 10-year follow-up of 4700 young people, an increased heart rate, presumably associated with a reflection of increased cardiac output, has been found to be a predictor of future hypertension.[69] Regardless of how hypertension begins, the eventual primacy of increased resistance can be shown even in models of hypertension that feature an initial increase in fluid volume and cardiac output.[6] Genetic Predisposition

As discussed in Chapter 56 and shown in Fig. 28-10 , genetic alterations may initiate the cascade to permanent hypertension. In studies of twins and family members in which the degree of familial aggregation of blood pressure levels is compared with the closeness of genetic sharing, the genetic contributions have been estimated to range from 30 to 60 percent. [70] Unquestionably, environment plays some role, and Harrap[70] offers as a working model an interaction between genes and environment "in which the average population pressure is determined by environment, but blood pressure rank

within the distribution is decided largely by genes." Three rare forms of hypertension have been found to be

Figure 28-10 Some of the factors involved in the control of blood pressure that affect the basic equation Blood pressure = cardiac output (CO) × peripheral resistance (PR). Cellular hyperplasia may be seen along with hypertrophy. (From Kaplan NM: Clinical Hypertension. 7th ed. Baltimore, Williams & Wilkins, 1998, p 45.)

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caused by a monogenic abnormality: glucocorticoid-remediable aldosteronism, Liddle syndrome, and apparent mineralocorticoid excess.[71] In addition, polymorphism of genes involving the renin-angiotensin system,[72] aldosterone synthesis,[73] and adrenergic receptors[74] has been noted to be more common in hypertensive than normotensive patients. If genetic markers of a predisposition for the development of hypertension are found, specific environmental manipulations could then be directed toward susceptible subjects.[75] For now, children and siblings of hypertensives should be more carefully screened. They should be vigorously advised to avoid environmental factors known to aggravate hypertension and increase cardiovascular risk (e.g., smoking, inactivity, and excess sodium). The Fetal Environment

Environmental factors may come into play very early. Low birth weight as a consequence of fetal undernutrition is followed by an increased incidence of high blood pressure later in life.[76] Brenner and Chertow hypothesized that a decreased number of nephrons from intrauterine growth retardation could very well serve as this permanent, irreparable defect that eventuates in hypertension [77] (Fig. 28-11) . In their words: This hypothesis draws on observations suggesting (1) a direct relationship between birth weight and nephron number, (2) an inverse relationship between birth weight and childhood, adolescent, and adult blood pressures, and (3) an inverse relationship between nephron number and blood pressure, irrespective of whether nephron number is reduced congenitally or in postnatal life (as from partial renal ablation or acquired renal disease). This hypothesis fits nicely with Brenner's explanation for the inexorable progression of renal damage once it begins and the concept that hypertension may begin by renal sodium retention induced by the decreased filtration surface area.[78]

Renal Retention of Excess Dietary Sodium

A considerable amount of circumstantial evidence supports a role for sodium in the genesis of hypertension (Table 28-10) . To induce hypertension, some of that excess sodium must be retained by the kidneys. Such retention could arise in a number of ways, including

Figure 28-11 The risk of essential hypertension and progressive renal injury developing in adult life is increased as a result of congenital oligonephropathy, an inborn deficit of filtration surface area (FSA) caused by impaired renal development. Low birth weight resulting from intrauterine growth retardation or prematurity contributes to this oligonephropathy. Systemic and glomerular hypertension in later life results in progressive glomerular sclerosis, further reducing FSA and thereby perpetuating a vicious cycle that leads, in the extreme, to end-stage renal failure. (From Brenner BM, Chertow GM: Congenital oligonephropathy: An inborn cause of adult hypertension and progressive renal injury? Curr Opin Nephrol Hypertens 2:691, 1993.)

TABLE 28-10 -- EVIDENCE FOR A ROLE OF SODIUM IN PRIMARY (ESSENTIAL) HYPERTENSION In multiple populations, the rise in blood pressure with age is directly correlated with increasing levels of sodium intake. Multiple, scattered groups who consume little sodium (less than 50 mmol/d) have little or no hypertension. When they consume more sodium, hypertension appears. Hypertension develops in animals given sodium loads, if genetically predisposed. In some people, large sodium loads given over short periods cause an increase in vascular resistance and blood pressure. An increased concentration of sodium is present in the vascular tissue and blood cells of most hypertensives. Sodium restriction to a level below 100 mmol/d will lower blood pressure in most people. The antihypertensive action in diuretics requires an initial natriuresis.

A decrease in filtration surface by a congenital or acquired deficiency in nephron number or function.[78] A resetting of the normal pressure-natriuresis relationship wherein a rise in pressure invokes an immediate increase in renal sodium excretion, thereby shrinking fluid volume and returning the pressure to normal. Guyton has long argued for a resetting of this relationship as a fundamental defect that must be present to explain the persistence of elevated pressure.[79] Nephron heterogeneity, which is hypothesized by Sealey and coworkers[80] as the presence of "a subpopulation of nephrons that is ischemic either from afferent arteriolar vasoconstriction or from an intrinsic narrowing of the lumen. Renin

secretion from this subgroup of nephrons is tonically elevated. This increased renin secretion then interferes with the compensatory capacity of intermingled normal nephrons to adaptively excrete sodium and, consequently, perturbs overall blood pressure homeostasis." An acquired inhibitor of the sodium pump[81] or other abnormalities in sodium transport.[82] Deficient responsiveness to atrial natriuretic hormone.[83] Thus, more than enough ways are available to incite renal retention of even a very small bit of the excess sodium typically ingested that could eventually expand body fluid volume. Variations in sensitivity to sodium have also been noted and may explain why only some people respond to excess sodium and others do not.[84] Those who are more sodium sensitive have been found to have more markers of endothelial damage,[85] nondipping of nocturnal blood pressure, [86] and increased mortality[87] than do those who are less sodium sensitive. Sodium sensitivity is more common among normotensive blacks and is associated with sodium-induced renal vasoconstriction.[88] Both the pressor sensitivity and renal vasoconstriction were reversed by increased intake of potassium bicarbonate, thus supporting a role for reduced potassium intake as a contributor to the excess number of cases of hypertension found in people of low-socioeconomic status.[89] Vascular Hypertrophy

Both excess sodium intake and renal sodium retention would presumably work primarily on increasing fluid volume and cardiac output. A number of other factors may work primarily on the second part of the equation BP = CO × PR (see Fig. 28-10 ). Most of these factors can cause both functional contraction and structural remodeling and hypertrophy. Multiple vasoactive substances act as growth factors for vascular hypertrophy. These pressor-growth promoters may result in both vascular contraction and hypertrophy simultaneously,

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but perpetuation of hypertension involves hypertrophy. Various hormonal mediators may serve as the initiator of what eventuates as increased peripheral resistance. From the study of certain "pure" forms of hormonally induced hypertension, Lever and Harrap[90] have postulated that Most forms of secondary hypertension have two pressor mechanisms: a primary cause, e.g., renal clip, and a second process, which is slow to develop, capable of maintaining hypertension after removal of the primary

cause, and probably self-perpetuating in nature. We suggest that essential hypertension also has two mechanisms, both based upon cardiovascular hypertrophy: (1) a growth-promoting process in children (equivalent to the primary cause in secondary hypertension) and (2) a self-perpetuating mechanism in adults. These investigators have built on the original proposal of Folkow[91] of a "positive feedback interaction" wherein even mild functional pressor influences, if repeatedly exerted, may lead to structural hypertrophy, which in turn reinforces and perpetuates the elevated pressure (Fig. 28-12) . Lever and Harrap[90] have added two hypotheses to Folkow's first: a reinforcement of the hypertrophic response to stimuli that initially raise the pressure, e.g., defects in the vascular cell membrane, and the action of various trophic mechanisms that may cause vascular hypertrophy directly (the "slow pressor mechanism"). This scheme to explain an immediate pressor action and a slow hypertrophic effect is thought to be common to the action of pressor-growth promoters. When present in high concentrations over long periods, as with angiotensin II in renal artery stenosis, each of these pressor-growth promoters causes hypertension. Moreover, when the source of the excess pressor-growth promoter is removed, hypertension may recede slowly, presumably reflecting the time needed to reverse vascular hypertrophy. No marked excess of any known pressor hormone is identifiable in the majority of hypertensive patients. Nonetheless, a lesser excess of one or more may have been responsible for initiation of a process sustained by the positive feedback postulated by Folkow[91] and the trophic effects emphasized by Lever and Harrap. [90] This sequence encompasses a variety of specific initiating mechanisms that accentuate and maintain the hypertension by a nonspecific feedback-trophic mechanism (Fig. 28-12) . If this double process is fundamental to the pathogenesis of primary hypertension, the difficulty in recognizing the initiating causal factor is easily explained. As formulated by Lever[92] The primary cause of hypertension will be most apparent in the early stages; in the later stages, the cause will be concealed by an increasing contribution from hypertrophy... A particular form of hypertension may wrongly be judged to have "no known cause" because each mechanism considered is insufficiently abnormal by itself to have produced the hypertension. The cause of essential hypertension may have been considered already but rejected for this reason.

Figure 28-12 Hypotheses for the initiation and maintenance of hypertension. A, Folkow's first proposal that minor overactivity of a pressor mechanism (A) raises blood pressure slightly, which initiates positive feedback (BCB) and a progressive rise in blood pressure. B, As in A with two additional signals: D, an abnormal or "reinforced" hypertrophic response to pressure; and E, increase in a humoral agent causing hypertrophy directly. (From Lever AF and Harrap SB: Essential hypertension: A disorder of growth with origins in childhood? J Hypertens 10:101, 1992.)

Neurohumoral Causes of Primary Hypertension

A large number of circulating hormones and locally acting substances may be involved in the development of hypertension. Support exists for each of those shown as potential instigators in Figure 28-10 . They will be considered in the order shown without attempting to prioritize their role. In addition to these hypertrophic changes, capillary rarefaction[93] and impaired microvascular dilation [94] may also be involved in the pathogenesis of hypertension. Sympathetic Nervous Hyperactivity

Young hypertensives tend to have increased levels of circulating catecholamines, augmented sympathetic nerve traffic in muscles, faster heart rate,[69] and heightened vascular reactivity to alpha-adrenergic agonists.[95] These changes could raise blood pressure in a number of ways--either alone or in concert with stimulation of renin release by catecholamines--by causing arteriolar and venous constriction, by increasing cardiac output, or by altering the normal renal pressure-volume relationship. In addition to cardiac stimulation by sympathetic activity, vagal inhibitory responses to baroreceptors and other stimuli may also be important. In humans with denervated transplanted hearts, both pulse and blood pressure fail to display the usual nocturnal fall, and hypertension is frequent.[96] The transient increase in epinephrine during stress reactions may invoke a more prolonged pressor response by facilitating the release of norepinephrine from sympathetic neurons but this mechanism could not be demonstrated in humans.[97] Repetitive stress or an accentuated, exaggerated response to stress is the logical means by which sympathetic activation would arise. Young hypertensives tend to be hyperresponsive,[95] and at least among middle-aged men in Framingham, the development of hypertension over an 18- to 20-year period was associated with heightened anxiety and anger intensity and suppressed expression of anger at baseline.[98] Moreover, in the 29-year-old normotensives in the Tecumseh Blood Pressure study, increased sympathetic activity was closely correlated with higher hematocrit levels, presumably reflecting a decrease in plasma volume from vasoconstriction[99] The Tecumseh subjects with higher plasma catecholamine levels also tended to have higher plasma renin activity (PRA). Other investigators have noted that hypertensives with high PRA had more anxiety, suppressed anger, and susceptibility to emotional distress.[100] Obviously, the sympathetic and renin mechanisms may be connected in various ways. Sympathetic nervous activity could be activated from the brain without the mediation of stress or emotional distress. Hypertension has been induced in animals by various neurogenic defects. An intriguing association has been reported but not documented between essential hypertension and compression of the ventrolateral medulla by loops of the posterior inferior cerebellar artery or an ectatic vertebral artery seen by magnetic

resonance tomography.[101] Whatever the specific role of sympathetic activity in the pathogenesis of hypertension, it appears to be involved in the increased cardiovascular morbidity and mortality that affect hypertensive patients during the early morning hours. Increased alpha-sympathetic activity occurs in the early morning in association with the preawakening increase in rapid eye movement (REM) sleep and the assumption of upright posture after overnight recumbency.[102] As a consequence of the increased sympathetic activity, blood pressure rises abruptly and markedly. This rise must be at least partly responsible for the increase in cardiovascular catastrophes in the early morning hours.[14] Renin-Angiotensin System

Both as a direct pressor and as a growth promoter, the renin-angiotensin mechanism may also be involved in the pathogenesis of hypertension. All functions of renin are mediated through the synthesis of angiotensin II. This system is the primary stimulus for the secretion of aldosterone and hence mediates mineralocorticoid responses to varying sodium intake and volume load. When sodium intake is reduced or effective plasma volume shrinks, the increase in renin-angiotensin II stimulates aldosterone secretion, which in turn is responsible for a portion of the enhanced

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Figure 28-13 Overall scheme of the renin-angiotensin mechanism indicating the site of action of angiotensin II type I receptor antagonist.

renal retention of sodium and water (Fig. 28-13) . As noted elsewhere (see Chap. 64 ), aldosterone may have additional roles including a contribution to myocardial fibrosis and to baroreceptor dysfunction.[103] According to the feedback shown in Fig. 26-13 , any rise in blood pressure inhibits release of renin from the renal juxtaglomerular cells. Therefore, primary (essential) hypertension would be expected to be accompanied by low, suppressed levels of PRA. However, when large populations of hypertensives are surveyed, only about 30 percent have low PRA, whereas 50 percent have normal levels and the remaining 20 percent have high levels.[104] NORMAL- AND HIGH-RENIN HYPERTENSION

A number of explanations have been offered for these "inappropriately normal" or high levels, beyond the proportion expected in a normal gaussian distribution curve. One of the more attractive is the concept of "nephron heterogeneity" described by Sealey and colleagues,[80] which assumes a mixture of normal and ischemic nephrons caused by

afferent arteriolar narrowing. Excess renin from the ischemic nephrons could raise the total blood renin level to varying degrees and cause some persons to have normal- or high-renin hypertension. This hypothesis is similar to that proposed by Goldblatt, who believed that "the primary cause of essential hypertension in man is intrarenal obliterative vascular disease, from any cause, usually arterial and arteriolar sclerosis, or any other condition which brings about the same disturbance of intrarenal hemodynamics."[105] When Goldblatt placed the clamp on the main renal arteries in canine studies, he was trying to explain the pathogenesis of primary (essential) hypertension rather than what he ended up explaining: the pathogenesis of renovascular hypertension. Nonetheless, his experimental concept is the basis for the more modern model of Sealey and colleagues. The elevated renin from the ischemic population of nephrons, although diluted in the systemic circulation, provides the "normal" renin levels that are usual in patients with primary hypertension who would otherwise be expected to shut down renin secretion and in whom levels would be low. These diluted levels are still high enough to impair sodium excretion in the nonischemic hyperfiltering nephrons but are too low to support efferent tone in the ischemic nephrons, thereby reducing sodium excretion in them as well. Sealey and associates' concept of nephron heterogeneity differs from Brunner and associates' concept of nephron scarcity previously noted.[105] Nevertheless, Sealey and colleagues agree that "a reduction in nephron number related to either age or ischemia could amplify the impaired sodium excretion and promote hypertension."[80] The renin-angiotensin system is active in multiple organs, either from in situ synthesis of various components or by transport from renal juxtaglomerular cells through the circulation. Most of the important pathophysiological effects are mediated through the angiotensin II type I receptor,[106] but some effects may involve the type II receptor [107] (Fig. 28-13) . The presence of the complete system in endothelial cells, the brain, the heart, and the adrenal cortex[108] broadens the potential roles of this mechanism far beyond its previously accepted boundaries. Hyperinsulinemia/Insulin Resistance

An association between hypertension and hyperinsulinemia has been recognized for many years, particularly with accompanying obesity but also in nonobese hypertensives.[37] The association does not apply to some ethnic groups such as Pima Indians, but it has been found in blacks and Asians, as well as whites. All obese people are hyperinsulinemic secondary to insulin resistance and even more so if the obesity is predominantly visceral, i.e., abdominal or upper body, wherein decreased hepatic uptake of insulin contributes to the hyperinsulinemia. The hyperinsulinemia of hypertension also arises as a consequence of resistance to the effects of insulin on peripheral glucose utilization.[109] The cause of the insulin resistance is unknown. It could reflect a simple inability of insulin to reach skeletal muscle cells, wherein its major peripheral actions on glucose metabolism occur. This impairment may in turn result from a defect in the usual vasodilatory effect of insulin mediated through

increased synthesis of nitric oxide (NO), which normally counters the multiple pressor effects of insulin[110] (Fig. 28-14) . These pressor effects, in addition to activation of sympathetic activity, include a trophic action on vascular hypertrophy, increased renal sodium reabsorption, and structural changes in the myocardium. [111]

Figure 28-14 Left, Insulin's actions in normal humans. Although insulin causes a marked increase in sympathetic neural outflow, which would be expected to increase blood pressure, it also causes vasodilation, which would decrease blood pressure. The net effect of these two opposing influences is no change or a slight decrease in blood pressure. There may be an imbalance between the sympathetic and vascular actions of insulin in conditions such as obesity or hypertension. Right, Insulin may cause potentiated sympathetic activation or attenuated vasodilation. An imbalance between these pressor and depressor actions of insulin may result in elevated blood pressure. (From Anderson EA, Mark AL: Cardiovascular and sympathetic actions of insulin: The insulin hypothesis of hypertension revisited. Cardiovasc Risk Factors 3:159, 1993.)

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Figure 28-15 Endothelium-derived vasoactive substances. Various blood- and platelet-derived substances can activate specific receptors (open circles) on the endothelial membrane to release relaxing factors such as nitric oxide (NO), prostacyclin (PGI 2 ), and an endothelium-derived hyperpolarizing factor (EDHF). Other contracting factors are released, such as endothelin-1 (ET-1), angiotensin (A), and thromboxane A2 (TXA 2 ), as well as prostaglandin H 2 (PGH2 ). ACE = angiotensin-converting enzyme; Ach = acetylcholine; 5HT = 5-hydroxytryptamine, or serotonin; BK = bradykinin; ECE = endothelin-converting enzyme; L -Arg = L - arginine; NOS = nitric oxide synthase; O2 - = superoxide; TGF-beta = transforming growth factor-beta; Thr = thrombin. (From Ruschitzka F, Corti R, Noll G, Luscher TF: A rationale for treatment of endothelial dysfunction in hypertension. J Hyperten 17(Suppl 1):25-35, 1999.)

The failure of vasodilation to antagonize the multiple pressor effects of insulin presumably eventuates in a rise in blood pressure that may be either a primary cause of hypertension or, at least, a secondary potentiator. In addition, the underlying insulin resistance is often associated with a full syndrome, including dyslipidemia and diabetes along with hypertension, which combine to be a major risk factor for premature coronary disease.[37] Endothelial Cell Dysfunction

The impairment of normal vasodilation seen in the insulin resistance syndrome has been shown to involve failure to synthesize the normal endothelium-derived relaxing factor NO.[112] Lack of NO synthesis is one of the rapidly increasing pieces of evidence for an active role for endothelial cells, now known to be the source of multiple relaxing and constricting substances, most having a local, paracrine influence on underlying smooth muscle cells (Fig. 28-15) .

NITRIC OXIDE (see Chap. 34 ).

Hypertensive patients have been shown to have a reduced vasodilatory response to various stimuli of NO release that appears to be independent of the etiology of the hypertension and the degree of gross vascular structural alteration. [113] [114] Impaired NOmediated vasodilation may promote abnormal vascular remodeling[115] and may be involved in the greater propensity for vascular damage in blacks than in white.[116] NO-mediated forearm responsiveness has been restored by normalization of blood pressure by antihypertensive drugs with different modes of action. [117] ENDOTHELIN.

A number of endothelium-derived constricting factors are shown in the middle portion of Fig. 28-15 . Of these, endothelin-1 appears to be of particular importance because it causes pronounced and prolonged vasoconstriction and because inhibitors of its synthesis or binding cause significant vasodilation.[118] Its role in human hypertension, however, remains uncertain. OTHER POSSIBLE MECHANISMS

The preceding description of the possible roles of the various mechanisms portrayed in Figure 28-10 does not exhaust the list of putative contributors to the pathogenesis of primary hypertension. The role of other pressor hormones in human hypertension remains unknown. Similarly, a number of vasodepressor hormones are known, but their function, too, remains uncertain. These hormones include kallikrein,[119] medullipin, a renomedullary lipid,[120] and adrenomedullin.[121] Contributions from excesses of various minerals, particularly lead,[122] and changing ratios among dietary sodium, potassium, calcium, and magnesium have also been postulated.[123] Support for these and other proposed mechanisms is meager, and the overall schemes involving intracellular sodium and calcium and the pressor-growth promoter mechanisms for vascular hypertrophy seem more than adequate to explain the pathogenesis of primary hypertension. However, a number of associations between hypertension and other conditions have been noted and may offer additional insight into the potential causes and possible prevention of the disease. ASSOCIATION OF HYPERTENSION WITH OTHER CONDITIONS OBESITY.

Hypertension is more common among obese individuals and adds to their increased risk for ischemic heart disease, particularly if it is abdominal or visceral in location.[124] In the Framingham offspring study, adiposity, as measured by subscapular skinfold thickness,

was the major controllable contributor to hypertension.[125] Even small amounts of weight gain are associated with a marked increase in the incidence of hypertension[126] and coronary mortality.[127] Unfortunately, there is a worldwide epidemic of obesity, perhaps most widespread in the United States, where the prevalence of obesity, defined as a body mass index above 30, increased by 50 percent from 1980 to 1995. [128] Obesity is rapidly increasing among U.S. children, and children seem particularly vulnerable to the hypertensive effects of weight gain.[26] Therefore, avoidance of childhood obesity in the hope of avoiding subsequent hypertension is important. The evidence that weight reduction will lower established hypertension is discussed on p. 976 . SLEEP APNEA.

One of the contributors to the hypertension in obese persons is sleep apnea. Snoring and sleep apnea are often associated with hypertension, which may in turn be induced by increased sympathetic activity and

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endothelin release in response to hypoxemia during apnea.[129] PHYSICAL INACTIVITY.

Physical fitness may help prevent hypertension, and persons who are already hypertensive may lower their blood pressure by means of regular isotonic exercise. The relationship may involve insulin resistance because increased resistance was coupled with low physical fitness in normotensive men with a family history of hypertension.[130] Regular exercise may prevent hypertension and thereby protect against the development of cardiovascular disease. Among 16,936 Harvard male alumni monitored for 16 to 50 years, those who did not engage in vigorous sports play were at 35 percent greater risk for the development of hypertension regardless of whether they had higher blood pressures while at Harvard, a family history of hypertension, or obesity--factors that also increased the risk of hypertension.[131] ALCOHOL INTAKE.

Alcohol in small amounts (less than two usual portions a day) provides protection from coronary disease, stroke, and atherosclerosis[132] but in larger amounts (more than two portions a day and even more so when drunk in binges), alcohol increases blood pressure.[133] The reduction in coronary disease in persons who ingest small amounts of alcohol may reflect an improvement in lipid profile, a reduction in factors that encourage thrombosis, and an improvement in insulin sensitivity.[134] The pressor effect of larger amounts of alcohol primarily reflects an increase in cardiac output and heart rate, possibly a consequence of increased sympathetic nerve activity.[135] Alcohol also alters cell membranes and allows more calcium to enter,

perhaps by inhibition of sodium transport.[136] SMOKING (see also p. 976).

Cigarette smoking raises blood pressure, probably through the nicotine-induced release of norepinephrine from adrenergic nerve endings. In addition, smoking causes an acute and marked reduction in radial artery compliance independent of the increase in blood pressure.[137] When smokers quit, a trivial rise in blood pressure may occur, probably reflecting a gain in weight. HEMATOLOGICAL FINDINGS.

Polycythemia vera is frequently associated with hypertension (see Chap. 69 ). More common is a "pseudo-" or "stress" polycythemia with a high hematocrit [99] and increased blood viscosity but contracted plasma volume, as well as normal red cell mass and serum erythropoietin levels. High white blood cell counts are predictive of the development of hypertension.[138] HYPERURICEMIA.

Hyperuricemia is present in 25 to 50 percent of individuals with untreated primary hypertension, about five times the frequency found in normotensive persons. Hyperuricemia probably reflects decreased renal blood flow, presumably a reflection of nephrosclerosis. In addition to these conditions often associated with hypertension, distinctive features of hypertension may be important in various special groups of people. HYPERTENSION IN SPECIAL GROUPS Blacks

Although, on average, blood pressure in blacks is not higher than that in whites during adolescence,[26] adult blacks have hypertension more frequently, with higher rates of morbidity and mortality. These higher rates may reflect a higher incidence of low birth weight from intrauterine growth retardation[76] a lesser tendency for the pressure to fall during sleep,[139] greater degrees of LVH, [46] and impaired NO-induced vasodilation,[116] but the lower socioeconomic status and lesser access to adequate, health care of blacks as a group are probably more important. [28] In particular, blacks suffer more renal damage, even with effective blood pressure control, which leads to a significantly greater prevalence of end-stage disease.[61] When given a high-sodium diet, most blacks but not whites tend to have renal vasoconstriction[88] and an increase in the glomerular filtration rate (GFR),[140] thus providing a possible mechanism for increased glomerular sclerosis.[140] Hypertension in blacks has been characterized as having a relatively greater component of fluid volume excess, including a higher prevalence of low PRA and greater responsiveness to diuretic therapy.[84]

Perhaps blacks evolved the physiological machinery that would offer protection in their ancestral habitat, i.e., hot, arid climates in which avid sodium conservation was necessary for survival because the diet was relatively low in sodium. When they migrate to areas where sodium intake is excessive, they are then more susceptible to "sodium overload." In addition, blacks may also be more susceptible to hypertension because as a group they tend to ingest less potassium.[89] Women

In general, women suffer less cardiovascular morbidity and mortality than men do for any degree of hypertension.[19] Moreover, before menopause, hypertension is less common in women than in men, perhaps reflecting the lower blood volume afforded women by menses. Eventually, however, more women than men have a hypertension-related cardiovascular complication because there are more elderly women than elderly men and hypertension is both more common and more dangerous in the elderly.[141] Children and Adolescents (see also Chap. 45 )

As in adults, care is needed in establishing the presence of persistently elevated blood pressure in children when using the upper limits of normal shown in Table 28-3 . Recall that these are the averages of the first blood pressure value obtained; since the pressure usually falls on repeated measurements, levels below those shown in Table 28-3 may be abnormally high for a given child. In addition, the recent inclusion of height along with age and weight to the nomograms for children and adolescents probably improves their diagnostic accuracy.[1] The significance of readings above the 95th percentile in an asymptomatic child remains uncertain since tracking of blood pressure as children grow older does not tend to be persistent; the positive predictive value of a blood pressure reading above the 95th percentile in a 10-year-old boy being at a hypertensive level at age 20 is only 0.44.[142] Moreover, the sensitivity of this high blood pressure in a 10-year-old to detect hypertension 10 years later is only 0.17. Nonetheless, most authorities[26] agree that children with "significant" hypertension (levels above the 95th percentile) should be given a limited work-up for target organ damage and secondary causes (perhaps including an echocardiogram and probably including a renal isotopic scan); if these tests are negative, the children should be carefully monitored and given nonpharmacological therapy. Those with "severe" hypertension (levels above the 99th percentile) should be more rapidly and completely evaluated and given appropriate pharmacological therapy. EPIDEMIOLOGY.

The older the child, the more likely the hypertension is of unknown cause, i.e., primary or essential. In prepubertal children, chronic hypertension is more likely caused by congenital or acquired renal parenchymal or vascular disease[143] (Table 28-11) .

In adolescents, primary hypertension is the most likely diagnosis. Factors that increase the likelihood for early onset of hypertension include a positive family history of hypertension, obesity, poor physical fitness, and an increase in thickness of the interventricular septum during systole on echocardiography. Among black children, a greater blood pressure reactivity to stress may also be predictive.[144]

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TABLE 28-11 -- MOST COMMON CAUSES OF CHRONIC HYPERTENSION IN CHILDHOOD Newborn Renal artery stenosis or thrombosis Congenital renal structural abnormalities Coarctation of the aorta Bronchopulmonary dysplasia Infancy to 6 yr Renal structural and inflammatory diseases Coarctation of the aorta Renal artery stenosis Wilms tumor 6-10 yr Renal structural and inflammatory diseases Renal artery stenosis Essential (primary) hypertension Renal parenchymal diseases Adolescence Primary hypertension Renal parenchymal diseases From Loggie JMH: Hypertension in children. Heart Dis Stroke May/June:147, 1994.

MANAGEMENT.

Once persistently elevated blood pressure is identified in children and adolescents and an appropriate work-up has been performed, weight reduction if the patient is overweight, regular dynamic exercise, and moderate restriction of dietary sodium should be encouraged. Those deemed to be in need of drug therapy are usually treated in the way adults are managed, as described in the next chapter and in Chapter 45 .

The Elderly

As more people live longer, more hypertension, particularly systolic, will be seen. By the usual criteria of the average of three blood pressure measurements on one occasion at or above 140 mm Hg systolic and/or 90 mm Hg diastolic or the taking of antihypertensive medication, 54 percent of men and women aged 65 to 74 have hypertension; among blacks, the prevalence is 72 percent.[27] In elderly patients with significant hypertension of recent onset, chronic renal disease or atherosclerotic renovascular disease is more likely to be found. The risks of both pure systolic and combined systolic and diastolic hypertension at every level are greater in the elderly than in younger patients as a result of the adverse effects of age-related atherosclerosis and concomitant conditions. It comes as no surprise that the elderly achieved even greater reductions in coronary disease and heart failure by effective therapy than did younger hypertensives in multiple clinical trials.[1] The elderly may display two features that reflect age-related cardiovascular changes. The first is pseudohypertension from markedly sclerotic arteries that do not collapse under the blood pressure cuff and therefore result in much higher cuff pressures than present within the vessels. If the arteries feel rigid but the patient has few retinal or cardiac findings to go along with marked hypertension, direct intraarterial measurements may be needed before therapy is begun to avoid inordinate lowering of a blood pressure that is not in fact elevated. The second feature, seen in 20 to 30 percent of the elderly, is postural and postprandial hypotension, which usually reflects a progressive loss of baroreceptor responsiveness with age.[22] A standing blood pressure should always be taken in patients older than 65 years, particularly if seated or supine hypertension is noted; if postural hypotension is present, maneuvers to overcome the precipitous falls in pressure should be attempted before the seated and supine hypertension is cautiously treated. More about the special therapeutic challenges often found in the elderly is provided in the next chapter. Patients with Diabetes Mellitus (see also Chap. 63 )

Hypertension and diabetes coexist more commonly than predicted by chance. They act in a synergistic manner to markedly accelerate cardiovascular damage, which is in turn responsible for the premature disabilities and higher rates of mortality that afflict diabetics. Among some 1500 diabetics monitored by Danish investigators, 51 percent of the insulin-dependent diabetics and 80 percent of the noninsulin-dependent diabetics had blood pressures above 140/90 mm Hg.[145] In more than half of these hypertensive diabetics, isolated systolic hypertension was noted. Not only is hypertension more common in diabetics, but it also tends to be more persistent, with less of the usual nocturnal fall in pressure. The absence of a nocturnal fall in pressure may reflect autonomic neuropathy or incipient diabetic nephropathy. The presence of hypertension increases all of the microvascular and macrovascular

complications observes in diabetes. Even at the initial diagnosis of diabetes, the presence of hypertension is associated with about a doubling of the prevalence of microalbuminuria, LVH, and electrocardiographic signs of myocardial ischemia.[146] These newly diagnosed diabetics were monitored for about 5 years, and those with hypertension suffered almost a twofold greater incidence of cardiovascular morbidity and mortality than did the nonhypertensive diabetics. When hypertensive, patients with diabetes mellitus may confront some unusual problems. With progressive renal insufficiency, they may have few functional juxtaglomerular cells, and as a result, the syndrome of hyporeninemic hypoaldosteronism may appear, usually manifested by hyperkalemia. If hypoglycemia develops because of too much insulin or other drugs, severe hypertension may occur as a result of stimulated sympathetic nervous activity. Diabetics are also susceptible to special problems associated with antihypertensive therapy. High doses of both diuretics and beta blockers may worsen diabetic control, probably by inducing further insulin resistance.[146A] Those who are prone to hypoglycemia may have difficulties with beta-blocking agents since these drugs blunt their protective catecholamine response, and severe hypoglycemia may develop with sweating as the only warning. Diabetic neuropathy may add to the postural hypotension and impotence that frequently complicate antihypertensive therapy. Diabetic nephropathy will impair sodium excretion and diminish the effectiveness of diuretics. On the other hand, successful control of hyperglycemia and blood pressure reduction will protect such patients from the otherwise inexorable progress of diabetic nephropathy. As will be noted in the next chapter, diabetic hypertensives are provided even better protection against cardiovascular morbidity and mortality than are nondiabetics when their blood pressure is lowered with antihypertensive drugs.[147]




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Identifiable (Secondary) Forms of Hypertension (See Tables 28-4 and 28-5 , p. 946) Oral Contraceptive and Postmenopausal Estrogen Use

The use of estrogen-containing oral contraceptive pills is probably the most common cause of secondary hypertension in young women. Most women who take them experience a slight rise in blood pressure, and hypertension develops in about 5 percent (i.e., blood pressure above 140/90 mm Hg) within 5 years of oral contraceptive use. This incidence is more than twice that seen among women of the same age who do not use these agents. Although the hypertension is usually mild, it may persist after oral contraceptive use is discontinued, it may be severe, and it is almost certainly a factor in the increased cardiovascular mortality seen among young women who take these agents.[148] Despite these facts, these drugs have provided effective and safe birth control for millions of women, and the need for oral contraceptives remains. The dangers of oral contraceptives should be kept in proper perspective. While it is true that use of these drugs is associated with increased morbidity and mortality, the absolute numbers are quite small, and overall mortality from cardiovascular disease has been declining progressively among women in the United States at a rate equal to that noted among American men. Moreover, the risks appear to have been lessened by more careful selection of users and lower doses of hormones. [149] Most adverse effects occur in women who smoke and have other cardiovascular risk factors and who take formulations with more than 50 mug of estrogen. Thus, the currently used low-estrogen

and low-progesterone forms seem quite safe for the purposes of temporary birth control. INCIDENCE.

The best data on the incidence of oral contraceptive-induced hypertension came from a large study of the Royal College of General Practitioners. The incidence of hypertension was 2.6 times greater among 23,000 pill users than 23,000 nonusers, with pill users having a 5 percent incidence over 5 years of oral contraceptive use. [150] In addition, this incidence increased with longer duration of pill use, being only slightly higher than that in controls during the first year but rising to almost 3 times higher by the fifth year. In a much smaller, but more carefully performed, prospective study of 186 Scottish women, systolic pressure rose in 164 (by more than 25 mm Hg in 8) and diastolic pressure rose in 150 (by more than 20 mm Hg in 2) during the first 2 years of oral contraceptive use.[151] After 3 years, the mean rise in 83 of these women was 9.2 mm Hg. The current use of smaller amounts of estrogen (20 to 35 mug) than the 50 mug taken by most of these women may induce less hypertension. CLINICAL FEATURES.

The likelihood of hypertension developing among women using oral contraceptives is much greater in those who are older than 35 or obese or who drink large quantities of alcohol. The presence of hypertension during a prior pregnancy increases this likelihood, but not enough to preclude pill use in such women who require contraception. In most women the hypertension is mild; however, in some it may accelerate rapidly and cause severe renal damage. When use of the pill is discontinued, blood pressure falls to normal within 3 to 6 months in about half the patients. Whether the pill caused permanent hypertension in the other half or just uncovered primary hypertension at an earlier time is not clear. MECHANISMS OF HYPERTENSION.

Oral contraceptive use probably causes hypertension by volume expansion since both estrogens and the synthetic progestogens used in oral contraceptive pills cause sodium retention. Although plasma renin levels rise in response to increased levels of angiotensinogen, angiotensin-converting enzyme (ACE) inhibition did not alter blood pressure any more in women with oral contraceptive-induced hypertension than in women with essential hypertension.[152] In keeping with the probable role of hyperinsulinemia in other hypertensive states (see p. 954 ) hyperinsulinemia may be involved in oral contraceptive-induced hypertension as well because plasma insulin levels are increased after the start of oral contraceptive use, a finding reflective of peripheral insulin resistance.[153] MANAGEMENT.

The use of estrogen-containing oral contraceptives should be restricted in women older than 35, particularly if they also smoke or are hypertensive or obese. Women given the pill should be properly monitored as follows: (1) The supply should be limited initially to

3 months and thereafter to 6 months; (2) they should be required to return for a blood pressure check before an additional supply is provided; and (3) If blood pressure has risen, an alternative contraceptive should be offered. If the pill remains the only acceptable contraceptive, the elevated blood pressure can be reduced with appropriate therapy. In view of the possible role of aldosterone, use of a diuretic-spironolactone combination seems appropriate. In those who stop taking oral contraceptives, evaluation for secondary hypertensive diseases should be postponed for at least 3 months to allow changes in the renin-angiotensin-aldosterone system to remit. If the hypertension does not recede, additional work-up and therapy may be needed. POSTMENOPAUSAL ESTROGEN USE.

Millions of women use estrogen for its potential benefits after menopause. It does not appear to induce hypertension, even though it does induce the various changes in the renin-angiotensin-aldosterone system seen with oral contraceptive use.[154] Moreover, the majority of case-control studies have shown a significantly lower mortality rate from coronary artery disease among postmenopausal estrogen users than nonusers.[155] Such cardioprotection probably reflects improvement in endothelium-dependent, flow-mediated vasodilation, either from a direct effect on endothelial function or through changes in blood lipids.[156] Renal Parenchymal Disease

In the overall population, renal parenchymal disease is the most common cause of secondary hypertension and is responsible for 2 to 5 percent of cases (see Table 28-5 ). As chronic glomerulonephritis has become less common, hypertensive nephrosclerosis and diabetic nephropathy have become the most common causes of ESRD. [157] The higher prevalence of hypertension among U.S. blacks is probably responsible for their significantly higher rate of ESRD, with hypertension as the underlying cause in as many as half of these patients.[61] Not only does hypertension cause renal failure and renal failure cause hypertension, but also more subtle renal dysfunction may be involved in patients with primary hypertension. As discussed earlier (see p. 952 ), the kidneys may initiate the hemodynamic cascade eventuating in primary hypertension. As that disease progresses, some renal dysfunction is demonstrable in most patients; progressive renal damage is the end result and is the cause of death in perhaps 10 percent of hypertensives. Since early treatment of hypertension will probably protect against nephrosclerosis, there is hope that improved control of hypertension will slow the progression and reduce the frequency of ESRD. In hypertension with renal parenchymal disease the sequence of progressively worsening renal damage is (1) acute renal diseases that are often reversible, (2) unilateral and bilateral diseases without renal insufficiency, (3) chronic renal disease with renal insufficiency, and

959

(4) hypertension in the anephric state and after renal transplantation. ACUTE RENAL DISEASES.

Hypertension may appear with any sudden, severe insult to the kidneys that either markedly impairs excretion of salt and water, which leads to volume expansion, or reduces renal blood flow, which sets off the renin-angiotension-aldosterone mechanism. Bilateral ureteral obstruction is an example of the former; sudden bilateral renal artery occlusion, as by emboli, is an example of the latter. Relief of either may dramatically reverse severe hypertension. Such reversal of hypertension has been particularly striking in men with high-pressure chronic retention of urine, who may manifest both renal failure and severe hypertension, both of which may be ameliorated by relief of the obstruction.[158] Some of the collagen diseases may also produce rapidly progressive renal damage. The more common acute processes are glomerulonephritis and oliguric renal failure. ACUTE GLOMERULONEPHRITIS.

Although the classic syndrome of type-specific poststreptococcal nephritis has become much less common, glomerular lesions of various types may be associated with hypertension. Moreover, although the epidemic poststreptococcal disease is usually self-limited, the disease in some patients follows a progressive, smoldering course that may lead to renal insufficiency. Typically, hypertension accompanies the fluid retention of acute renal injury and is best relieved by sodium and fluid restriction and potent diuretics. Dialysis and parenteral antihypertensive drugs may be needed if encephalopathy supervenes. In milder cases, the hypertension recedes as the edema is relieved. ACUTE OLIGURIC RENAL FAILURE.

Acute renal failure may occur after hypotension, particularly in patients in whom renin levels are already high, such as those with cirrhosis and ascites or at the end of pregnancy. The release of even more renin by decreased blood pressure and effective circulating blood volume may flood the renal vasculature and cause such intense renal vasoconstriction that renal function shuts down. Hypertension in this setting is not usually an important problem and can be controlled by preventing volume overload. High doses of furosemide may be helpful, but dialysis is often needed. When acute renal failure occurs in the setting of accelerated or malignant hypertension, aggressive therapy (including dialysis) may be followed by sustained recovery of renal function.[159] The use of nonsteroidal antiinflammatory agents may cause acute renal failure, usually in the setting of chronic renal damage.[160]

VASCULITIS.

Rapidly progressive renal deterioration with severe hypertension occurs not infrequently during the course of scleroderma and other forms of vasculitis (see Chap. 67 ). Therapy with antihypertensives, particularly ACE inhibitors, may reverse the process.[161] EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY.

As this procedure has been increasingly used to treat nephrolithiasis, at least transient rises in blood pressure have been observed in 20 to 30 percent of patients, but persistent hypertension is unusual.[162] RENAL DISEASE WITHOUT RENAL INSUFFICIENCY.

Although an entire kidney may be removed without obvious effect and no rise in blood pressure, hypertension may be associated with unilateral and bilateral renal parenchymal diseases in the absence of significant renal insufficiency. Even though such hypertension may reflect other unrecognized processes, most likely it is caused by activation of the renin-angiotensin-aldosterone mechanism. However, in some patients whose hypertension has been relieved by correction of a renal defect, the levels of renin have not been high. UNILATERAL PARENCHYMAL RENAL DISEASE.

A number of unilateral kidney diseases may be associated with hypertension, and in some of these diseases the affected kidney is shrunken. Nonetheless, most small kidneys do not cause hypertension, and when they are indiscriminately removed from patients with hypertension, the condition is relieved in only about 25 percent. Of that 25 percent, most have arterial occlusive disease, either as the primary cause of the renal atrophy or secondary to irregular scarring of the parenchyma. POLYCYSTIC KIDNEY DISEASE.

Although patients with adult polycystic kidney disease usually progress to renal insufficiency, some retain reasonably normal GFRs and display no azotemia. Hypertension, although more common in those with renal failure, is present in perhaps half of those with a normal GFR and probably reflects variable degrees of both renin excess and fluid retention.[163] CHRONIC PYELONEPHRITIS.

The relationship between pyelonephritis and hypertension is multifaceted: Pyelonephritis, either unilateral or bilateral, may cause hypertension, and hypertensive individuals may be more susceptible to renal infection. In pyelonephritic patients with hypertension but fairly normal renal function, renin levels are high,[164] probably from

interstitial scarring with obstruction of intrarenal vessels. CHRONIC RENAL DISEASES WITH RENAL INSUFFICIENCY.

Because dialysis and transplantation prolong the lives of more patients with renal insufficiency, their hypertension must be dealt with over much longer periods. In most patients with renal insufficiency, hypertension is predominantly caused by volume overload resulting from an inability of the reduced functioning renal mass to handle the usual sodium and water intake. With proper attention to sodium and water intake and, if needed, adequate dialysis, control of blood pressure may not be particularly difficult. Unfortunately, some patients are much more fragile and alternate between low and high pressure, and some are much more resistant, presumably because of a greater contribution of high renin levels to the hypertension. Moreover, their pressures may not fall much during sleep, which poses an additional burden on the heart and vasculature. Nonetheless, with judicious use of available therapy, hypertension should not be a major problem for most patients with renal insufficiency. Three aspects of hypertension with ESRD should be recognized: (1) Hypertension contributes to the cardiovascular diseases that are the cause of death in about half of patients with ESRD; (2) renal damage may progress despite apparent control of hypertension, particularly among blacks;[165] and (3) a significant proportion of cases of ESRD may reflect bilateral renovascular disease that may be made worse by antihypertensive drug therapy but markedly improved by revascularization.[166] In view of increasing evidence that glomerular capillary hypertension is responsible for the progressive loss of renal function once renal damage begins (see Fig. 28-11 ), aggressive reduction of intraglomerular hypertension to prevent further renal loss is being actively pursued. ACE inhibitors maybe particularly effective in this regard.[165] Diabetic Nephropathy (see also Chap. 63 ).

Hypertension often accompanies diabetic nephropathy as a result of an inability to handle volume loads because of loss of nephrons secondary to progressive intercapillary glomerulosclerosis. As shown in Figure 28-16 , intrarenal hypertension accelerates the progress of the glomerulosclerosis, and antihypertensive therapy has been shown to slow the progression of renal damage.[167] Although more effective relief of glomerular capillary hypertension may be possible with ACE inhibitors, long-term protection has been obtained with traditional antihypertensive drugs, not including ACE inhibitors.[168] As common as it is, hypertension may not be as severe or as likely to progress to an accelerated-malignant phase in diabetics with nephropathy for two reasons: First, these patients often have diminished intravascular volume because of the hypoalbuminemia of the nephrotic syndrome, and second, they have low renin levels, presumably because of hyalinization of juxtaglomerular cells, which may be manifested as hyporeninemic hypoaldosteronism. Analgesic Nephropathy.

In addition to the acute renal insufficiency that may accompany the inhibition of renal prostaglandins by nonsteroidal antiinflammatory agents,[160] permanent interstitial renal damage may supervene after prolonged exposure to analgesics, particularly phenacetin and, to a lesser degree, acetaminophen.[169] Until late in their course, these patients have a greater propensity for salt wasting and may therefore have less severe hypertension. HYPERTENSION DURING CHRONIC DIALYSIS AND AFTER RENAL TRANSPLANTATION.

In patients with ESRD, blood pressure depends mainly on body fluid volume. Hypertension may be accentuated by the accumulation of endogenous inhibitors of nitric oxide (NO) synthase because of withdrawal of the vasodilation provided by NO. As these inhibitors are removed during dialysis, NO may contribute to hemodialysis-induced hypotension.[170] With neither the vasoconstrictor effects of renal renin nor the vasodepressor actions of various renal hormones, blood pressure may be particularly labile and sensitive to changes in adrenergic activity. Among patients receiving maintenance

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Figure 28-16 Pivotal role of glomerular hypertension in the initiation and progression of structural injury. (From Anderson S, Brenner BM: Progressive renal disease: A disorder of adaptation. QJM 70:185, 1989.)

hemodialysis every 48 hours, elevated blood pressures tend to fall progressively after dialysis is completed, remain depressed during the remainder of the first 24 hours, and rise again during the second day as a consequence of excessive fluid retention.[171] Thus, antihypertension therapy may be needed only on the days between dialysis. Although successful renal transplantation may cure primary hypertension, various problems may result, with about half of the recipients becoming hypertensive within 1 year.[172] These problems include stenosis of the renal artery at the site of anastomosis, rejection reactions, high doses of adrenal steroids and cyclosporine, and excess renin derived from the retained diseased kidneys. ACE inhibitor therapy may obviate the need to remove the native diseased kidneys to relieve hypertension caused by their persistent secretion of renin. The source of the donor kidney may also play a role in the subsequent development of hypertension in the recipient: More hypertension has been observed when donors had a family history of hypertension or when the donors had died of subarachnoid hemorrhage and had probably been hypertensive.[173] Renovascular Hypertension

Renovascular hypertension is among the most common secondary forms of hypertension and is not easily recognizable. Although no more than 1 percent of all

adults with hypertension have renovascular hypertension (see Table 28-5 ), the prevalence is much higher in those with sudden onset of severe hypertension and other suggestive features[174] (Table 28-12) . Mann and Pickering classified patients into those with a low, moderate, and high "clinical index of suspicion" as a guide to the selection of additional work-up for renovascular hypertension. Those with characteristics listed under moderate are considered to have a 5 to 15 percent likelihood of the diagnosis and are therefore in need of a noninvasive screening test. Those with characteristics listed under high are considered to have a greater than 25 percent likelihood of the diagnosis and renal arteriography should be the initial test. Renovascular disease is found less commonly in black hypertensives than in whites,[175] but it should be looked for when accompanied by the features described in Table 28-12 . CLASSIFICATION.

In adults, the two major types of renovascular disease tend to appear at different times and affect the sexes differently (Table 28-13) . Atherosclerotic disease affecting mainly the proximal third of the main renal artery is seen mostly in older men. Fibroplastic disease involving mainly the distal two-thirds and branches of the renal arteries appears most commonly in younger women. Overall, about two-thirds of cases are caused by atherosclerotic disease and one-third by fibroplastic disease. While the nonatherosclerotic stenoses involve all layers of the renal artery, the most common is medial fibroplasia. A number of other intrinsic and extrinsic causes of renovascular hypertension are known, including cholesterol emboli TABLE 28-12 -- TESTING FOR RENOVASCULAR HYPERTENSION: CLINICAL INDEX OF SUSPICION AS A GUIDE TO SELECTING PATIENTS FOR WORK-UP Low (Should Not Be Tested) Borderline, mild, or moderate hypertension, in the absence of clinical clues Moderate (Noninvasive Tests Recommended) Severe hypertension (diastolic blood pressure greater than 120 mm Hg) Hypertension refractory to standard therapy Abrupt onset of sustained, moderate to severe hypertension at age 50 Hypertension with a suggestive abdominal bruit (long, high pitched, and localized to the region of the renal artery) Moderate hypertension (diastolic blood pressure exceeding 105 mm Hg) in a smoker, in a patient with evidence of occlusive vascular disease (cerebrovascular, coronary, peripheral vascular), or in a patient with unexplained but stable elevation of serum creatinine Normalization of blood pressure by an angiotensin-converting enzyme inhibitor in a patient with moderate or severe hypertension (particularly a smoker or a patient with recent onset of hypertension)

High (May Consider Proceeding Directly to Arteriography) Severe hypertension (diastolic blood pressure greater than 120 mm Hg with either progressive renal insufficiency or refractoriness to aggressive treatment, particularly in a patient who has been a smoker or has other evidence of occlusive arterial disease) Accelerated or malignant hypertension (grade III or IV retinopathy) Hypertension with recent elevation of serum creatinine, either unexplained or reversibly induced by an angiotensin-converting enzyme inhibitor Moderate to severe hypertension with incidentally detected asymmetry of renal size Reproduced with permission from Mann SJ, Pickering TG: Detection of renovascular hypertension. State of the art: 1992. Ann Intern Med 117:845, 1992.

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TABLE 28-13 -- FEATURES OF THE TWO MAJOR FORMS OF RENAL ARTERY DISEASE CAUSE INCIDENCE AGE LOCATION OF NATURAL HISTORY (%) (yr) LESION IN RENAL ARTERY Atherosclerosis

65

>50

Proximal 2 cm; Progression in 50%, branch disease rare often to total occlusion

Intimal

1-2

Birth-25 Midportion of main renal artery and/or branches

Progression in most cases; dissection and/or thrombosis common

Medial

30

25-50

Distal segment of main renal artery and/or branches

Progression in 33%; dissection and/or thrombosis rare

Periarterial

1-2

15-30

Middle to distal segments of main renal artery or branches

Progression in most cases; dissection and/or thrombosis common

Fibromuscular dysplasias

From Kaplan NM: Clinical Hypertension. 7th ed. Baltimore, Williams & Wilkins, 1998, p 306. within the renal artery or compression of this vessel by nearby tumors. Most renovascular hypertension develops from partial obstruction of one main renal artery, but only a branch need be involved; segmental disease was found in 11 percent of cases in one large series.[176] On the other hand, if apparent complete occlusion of the

renal artery is slow in developing, enough collateral flow will become available to preserve viability of the kidney. In this way, the seemingly nonfunctioning kidney may be responsible for continued renin secretion and hypertension. If recognized, such totally occluded vessels can sometimes be repaired, with return of renal function and relief of hypertension. [177] Renovascular stenosis is often bilateral, although usually one side is clearly predominant. The possibility of bilateral disease should be suspected in those with renal insufficiency, particularly if rapidly progressive oliguric renal failure develops without evidence of obstructive uropathy and even more so if it develops after the start of ACE inhibitor therapy.[178] MECHANISMS.

After Goldblatt produced renovascular hypertension in the dog in 1934, confusion arose because of the use of one-kidney models, which are more appropriate to the study of renal parenchymal hypertension. The sequence of changes in the two-kidney (one-clip) model and in patients with renovascular hypertension almost certainly starts with the release of increased amounts of renin when sufficient ischemia is induced to diminish pulse pressure against the juxtaglomerular cells in the renal afferent arterioles. A reduction in renal perfusion pressure by 50 percent leads to an immediate and persistent increase in renin secretion from the ischemic kidney, along with suppression of secretion from the contralateral one. With time, renin levels fall (but not to the low level expected from the elevated blood pressure), accompanied by an expanded body fluid volume and increased cardiac output. DIAGNOSIS.

The presence of the clinical features listed under moderate suspicion for renovascular hypertension in Table 28-12 , found in perhaps 5 to 10 percent of all hypertensives, indicates the need for a screening test for renovascular hypertension. A positive screening test, or very strong clinical features, calls for more definitive confirmatory tests. Recurrent flash pulmonary edema has been associated with renovascular hypertension,[179] so this clinical manifestation should be added to the indication for diagnostic work-up. Some patients have renovascular hypertension but none of the clinical features listed in Table 28-12 , and they clinically resemble patients with mild primary hypertension. Nonetheless, these features should be used to exclude the majority of hypertensives from additional work-up and to identify the 10 percent or so who should undergo a work-up. Functional Diagnostic Tests.

Isotopic renography and plasma renin measurements after an oral captopril challenge are currently the best initial tests in patients with the suggestive clinical features listed under moderate in Table 28-12 , to be followed by renal arteriography and then renal

vein renin assays. The latter procedure may not be needed if isotopic renography after captopril indicates significant renal ischemia in the kidney with renal artery disease by arteriography. In some centers with facilities dedicated to the performance of renal artery duplex sonography, that procedure is being used for initial screening,[180] and in the future, intravascular ultrasound will probably be used.[181] In addition, contrast-enhanced magnetic resonance arteriography may be even more reliable, particularly for visualizing accessory renal arteries.[182] The captopril challenge test depends on abrupt inhibition of circulating angiotensin II by the ACE inhibitor, which removes the major support for perfusion through a stenotic renal artery to a kidney. The acutely ischemic kidney immediately releases more renin and undergoes a marked decrease in glomerular filtration and renal blood flow. Therefore, both plasma renin level and isotopic flow through the kidneys 1 hour after a single 50-mg dose of the ACE inhibitor should be measured. To measure the plasma renin response, the patient should have normal sodium dietary intake and not be taking diuretics and ACE inhibitors; if possible, other antihypertensive medications should be withdrawn for at least a week.[183] After the patient sits for 30 minutes, venous blood is obtained for basal PRA, and 50 mg of captopril is given orally. At 60 minutes, another blood sample for stimulated PRA is obtained. The authors have subsequently reported a high prevalence of false-positive responses in patients with high baseline renin levels.[183] Others report sensitivity ranging from 0.73 to 1.0 and specificity ranging from 0.73 to 0.95.[184] Performance of isotopic renography 1 hour after the oral captopril dose provides additional diagnostic information in most but not all series.[185] The renogram may use labeled hippurate, a measure of renal blood flow, or diethylenetriaminepentaacetic acid (DTPA) or mercaptoacetyltriglycine (MAG3), measures of the GFR. If the postcaptopril test shows a significant difference between the two kidneys, the procedure should be repeated without captopril to document the ischemic origin of the differences in blood flow or GFR. With captopril renography, renal vein renin measurements are needed less often to localize the affected side when renovascular disease is bilateral. MANAGEMENT

Medical.

The availability of ACE inhibitors may be considered a two-edged sword; one edge provides better control of renovascular hypertension than may be possible with other antihypertensive medications, while the other edge exposes the already ischemic kidney to further loss of blood flow by removing the high levels of angiotensin II that were supporting its circulation. Calcium entry blockers and other antihypertensive drugs may be almost as effective as ACE inhibitors and perhaps safer.[186]

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Angioplasty (see also Chap. 42 ).

Angioplasty has been shown to improve (at least transiently) 60 to 70 percent of patients, more with fibromuscular disease than with atherosclerosis, as is also the case for surgery. Ostial lesions may be successfully managed by placement of an arterial stent, which will probably be performed more frequently to improve the results of angioplasty.[187] Surgery.

Surgical repair has been shown to relieve renovascular hypertension in an increasing number of patients, including the elderly and those with renal insufficiency.[188] Most agree that surgery is indicated in patients whose hypertension is not well controlled or whose renal function deteriorates with medical therapy and in those with only a transient response to angioplasty or in whom lesions are not amenable to that procedure, more to preserve renal function than to relieve hypertension and before serum creatinine rises above 3 mg/dl.[189] RENIN-SECRETING TUMORS

Made up of juxtaglomerular cells or hemangiopericytomas, these tumors have been found mostly in young patients with severe hypertension, very high renin levels in both peripheral blood and the kidney harboring the tumor, and secondary aldosteronism manifested by hypokalemia.[190] The tumor can generally be recognized by selective renal angiography, usually performed for suspected renovascular hypertension, although a few are extrarenal. More commonly, children with Wilms tumors (nephroblastoma) may have hypertension and high plasma renin and prorenin levels that revert to normal after nephrectomy.[191] Adrenal Causes of Hypertension (see Chap. 64 )

Adrenal causes of hypertension include primary excesses of aldosterone, cortisol, and catecholamines; more rarely, excess deoxycorticosterone (DOC) is present along with congenital adrenal hyperplasia. Together, these conditions cause less than 1 percent of all hypertensive diseases, although as will be noted, primary aldosteronism may be more common than previously thought. Each can usually be recognized with relative ease, and patients suspected of having these disorders can be screened by readily available tests. More of a problem than the diagnosis of these adrenal disorders is the need to exclude their presence because of the increasing identification of incidental adrenal masses when abdominal computed tomography (CT) is done to diagnose intraabdominal pathology. Unsuspected adrenal tumors have been found in 1 to 2 percent of abdominal CT scans obtained for reasons unrelated to the adrenal gland. Most of these "incidentalomas" appear to be nonfunctional on the basis of normal basal adrenal hormone levels. However, when more detailed studies are done, a significant number show incomplete suppression of cortisol by dexamethasone, i.e., subclinical Cushing disease that does not appear to progress to overt hypercortisolism, and a few

have unsuspected catecholamine hypersecretion.[192] Nonfunctioning adenomas have significantly less lipid content than do functioning adenomas by chemical-shift magnetic resonance imaging (MRI),[193] so this procedure may have clinical usefulness. The threat of malignancy can probably be best excluded by adrenal scintigraphy with NP-59, a radioiodinated derivative of cholesterol.[194] Benign lesions almost always take up the isotope, while malignant ones almost always do not. Most tumors larger than 4 cm are resected since a significant number of them are malignant. Primary Aldosteronism (See also Chap. 64 )

This disease is relatively rare in unselected populations (see Table 28-5 ), although it has been recognized in considerably more patients screened by a plasma aldosterone/renin activity ratio.[195] PATHOPHYSIOLOGY.

Primary aldosterone excess usually arises from solitary benign adenomas. As diagnostic tests have improved and become more readily available, larger numbers of patients with minimal features have been recognized.[196] Many of these patients have been found to have bilateral adrenal hyperplasia, the number averaging about one-third of all cases of aldosteronism. MINERALOCORTICAL HYPERTENSION.

In addition to the usual forms of primary aldosteronism, two unusual but interesting variants have been identified. One, familial glucocorticoid-suppressible aldosteronism, is caused by a mutation in the genes involved in coding for the aldosterone synthase enzyme normally found only in the outer zone glomerulosa and the 11-beta-hydroxylase enzyme in the zone fasciculata.[197] The chimeric gene induces an enzyme that catalyzes the synthesis of 18-hydroxylated cortisol in the zona fasciculata. Since this zone is under the control of adrenocorticotropic hormone (ACTH), the glucocorticoid suppressibility of the syndrome is explained. Since a few patients with classic primary aldosteronism show glucocorticoid suppression, the diagnosis should be made by genetic testing for the chimeric gene.[198] The other unusual form of mineralocorticoid hypertension is caused by deficiency of the enzyme 11-beta-hydroxysteroid dehydrogenase (11beta-OHSD) in the renal tubule, where it normally converts cortisol (which has the ability to act on the mineralocorticoid receptor) to cortisone (which does not). Persistence of high levels of cortisol induces all the features of mineralocorticoid excess. The 11beta-OHSD enzyme may be congenitally absent (the syndrome of apparent mineralocorticoid excess) or inhibited by the glycyrrhetenic acid contained in licorice.[199] Another unusual syndrome with hypertension and hypokalemia but suppressed mineralocorticoid secretion is Liddle syndrome, wherein the kidney reabsorbs excess sodium and wastes potassium because of a mutation in the beta or gamma subunits of the epithelial sodium channel.[200]

Whatever the source, excess mineralocorticoid usually causes hypertension and hypokalemia, defined as a plasma potassium level below 3.2 mEq/liter. Very rarely, mineralocorticoid excess has been recognized in normotensive persons.[201] Not so rarely, hypokalemia may be absent or only intermittent, but in most patients with adenomas, persistent hypokalemia is observed.[196] The hypertension begins as a volume overload but soon converts, as apparently do all forms of hypertension, to increased peripheral resistance. Hypertension may be severe, and cardiovascular complications, particularly stroke, common.[202] In association with the increased pressure and expanded blood volume, renin secretion is suppressed. Although this finding has been almost invariable with hyperaldosteronism, the overwhelming majority of hypertensive patients with suppressed renin do not have mineralocorticoid excess. DIAGNOSIS.

Serious consideration should be given to the diagnosis of primary aldosteronism when hypertension and hypokalemia coexist. If normokalemic patients with the disease are missed, little will be lost as long as the patients are protected by appropriate treatment of the hypertension. Since such treatment is likely to include a diuretic, significant hypokalemia will probably soon become manifested and make the diagnosis obvious. If hypokalemia is present, excessive urinary potassium excretion (above 30 mmol/day) is strongly suggestive of mineralocorticoid excess. A high plasma aldosterone/renin ratio in plasma is a useful screening test that can be performed immediately upon recognition of hypokalemia in a hypertensive patient, but with the knowledge that a high ratio may reflect only a suppressed renin level. Therefore, not only should plasma renin levels be low, but plasma aldosterone levels should be elevated, with a ratio of well above 30.[203] Although this ratio is being increasingly used to screen for primary aldosteronism,

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it has not always been found to be abnormal in patients with the syndrome. [204] Therefore, the finding of increased urinary aldosterone levels or failure to suppress plasma aldosterone levels by volume expansion or by a single dose of an ACE inhibitor also may be useful.[203] ESTABLISHING THE PATHOLOGY.

Once the diagnosis of primary aldosteronism is made, the type of adrenal pathology should be determined, and only patients with a tumor should be subjected to surgery and those with bilateral hyperplasia treated by medical therapy. The best initial study is adrenal CT or MRI (Fig. 28-17) . However, the ability of these scans to identify hitherto

hidden degrees of adrenal pathology may engender confusion; the usual nodularity seen in the remainder of a gland that harbors a solitary adrenal adenoma may give the appearance of bilateral hyperplasia, and some larger hyperplastic nodules may look like adenomas.[205] Therefore, unless the scan is unequivocal, additional tests to discriminate between adenoma and hyperplasia should be done (Fig. 28-17) . Various maneuvers are available.[196] Basal levels of serum 18-hydroxycorticosterone (18-OHB) and changes in plasma aldosterone levels after 2 hours of upright posture from 8 A.M.to 10 A.M.usually distinguish patients with adenomas (who generally have basal 18-OHB levels above 65 ng/dl and falls in plasma aldosterone in the upright posture) from those with bilateral hyperplasia (who usually have basal 18-OHB levels below 50 ng/dl and postural rises in plasma aldosterone presumably invoked by their supersensitivity to posture-mediated rises in renin-angiotensin). In addition, most adenomas but few hyperplastic glands secrete increased amounts of 18-hydroxylated cortisol, which suggests that they harbor similar mutant genes as found in the glucocorticoid-suppressible syndrome. If the type of adrenal disorder is still uncertain, bilateral adrenal vein catheterization with analysis of venous aldosterone and cortisol levels should be performed by radiologists who are experienced with the technique. THERAPY.

Once the diagnosis of primary aldosteronism is made and the type of adrenal disorder has been established, the choice of therapy is fairly easy: Patients with a solitary adenoma should have the tumor resected, now more and more frequently done by laparoscopic surgery. Those with bilateral hyperplasia should be treated with spironolactone (see Chap. 64 ) and, if necessary, a thiazide diuretic or other antihypertensive drugs. Fortunately, the doses of spironolactone required for chronic therapy are usually low enough to avoid bothersome side effects. When an adenoma is resected, about half of patients will become normotensive, while the others, although improved, remain hypertensive, either from preexisting primary hypertension or from renal damage caused by prolonged secondary hypertension.[206] CUSHING SYNDROME (see also Chap. 64 )

Hypertension occurs in about 80 percent of patients with Cushing syndrome.[207] If left untreated, it can cause marked LVH and congestive heart failure. As with hypertension of other endocrine causes, the longer it is present, the less likely it is to disappear when the underlying cause is relieved. MECHANISM OF HYPERTENSION.

Blood pressure may increase for a number of reasons. Secretion of mineralocorticoids may also be increased along with cortisol. The excess cortisol may overwhelm the ability of renal 11beta-OHSD to convert it to the inactive cortisone, and renal mineralocorticoid receptors are activated by the excess cortisol to retain sodium and expand fluid volume.[199] Cortisol stimulates the synthesis of renin substrate and the expression of angiotensin II receptors, which may be responsible for enhanced pressor

effects.[208] DIAGNOSIS.

The syndrome should be suspected in patients with truncal obesity, thin skin, muscle weakness, and osteoporosis. If clinical features are suggestive, the diagnosis can be either ruled out or virtually ensured by the measurement of free cortisol in a 24-hour urine sample or the simple overnight dexamethasone suppression test. [209] In normal subjects, the level of plasma cortisol in a sample drawn at 8 A.M.after a bedtime dose of 1 mg of dexamethasone should be below 2 mug/100 mg. If the level is higher, additional work-up is in order to establish both the diagnosis of cortisol excess and the pathological type. The 1-mg overnight suppression test has a specificity of 87%; the traditional 2-mg/day (0.5 mg every 6 hours) or 48-hour low-dose dexamethasone screening test has been recommended since it provides almost 100% specificity.[207] When an abnormal screening test is present, some would immediately perform pituitary and adrenal CT or MRI scans to elucidate the type of pathology. However, most authorities continue to recommend as additional high-dose dexamethasone suppression test at 2.0 mg every 6 hours for 2 days, with measurement of urinary free cortisol excretion and plasma cortisol levels. If Cushing syndrome is caused by excess pituitary ACTH drive with bilateral adrenal hyperplasia, urinary free cortisol will be suppressed to below 40 percent of the control value with the 2.0-mg dose. Plasma ACTH assays provide an additional means of differentiating pituitary and ectopic ACTH excess from adrenal tumors with ACTH suppression.[207] The response to corticotropin-releasing hormone and inferior petrosal sinus sampling may help identify a pituitary cause of the syndrome. THERAPY.

In about two-thirds of patients with Cushing syndrome, the process begins with overproduction of ACTH by the pituitary, which leads to bilateral adrenal hyperplasia. Although pituitary hyperfunction may reflect a hypothalamic disorder, the majority of patients have discrete pituitary adenomas that can usually be resected by selective transsphenoidal microsurgery. If an adrenal tumor is present, it should be removed surgically. With earlier diagnosis and more selective surgical therapy, it is hoped that more patents with Cushing syndrome will be cured without a need for lifelong glucocorticoid replacement therapy and with permanent relief of their hypertension. Temporarily and rarely permanently, therapy may require one of a number of medical approaches.[210] CONGENITAL ADRENAL HYPERPLASIA.

Two other enzymatic defects may induce hypertension by interfering with cortisol biosynthesis. Low levels of cortisol lead to increased ACTH, which increases the accumulation of precursors

Figure 28-17 Flow diagram for the progressive work-up of confirmed primary aldosteronism, with additional steps to take when initial studies are aberrant. Rare, angiotensin II-responsive adenomas may demonstrate features of hyperplasia but lateralize by venous sampling or scintigraphy. On the other hand, primary adrenal hyperplasia may demonstrate features of an adenoma except for equally high steroid levels by venous sampling. GRA = glucocorticoid-remediable aldosteronism; 18-OH-B = 18-hydroxycorticosterone; 18-oxo-F = 8-hydrocortisol. (From Kaplan NM: Primary aldosteronism. In Kaplan NM [ed]: Clinical Hypertension. 7th ed. Baltimore, Williams & Wilkins, 1998, p 378.)

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proximal to the enzymatic block, specifically, DOC, which induces mineralocorticoid hypertension. The more common of these is 11-hydroxylase deficiency which has been attributed to various mutations in the gene [211] and leads to virilization (from excessive androgens) and hypertension with hypokalemia (from excessive DOC). The other is 17-hydroxylase deficiency, which also causes hypertension from excess DOC but, in addition, causes failure of secondary sexual development because sex hormones are also deficient.[212] Affected children are hypertensive, but the defect in sex hormone synthesis may not become obvious until after puberty. Thereafter, affected males display ambiguity of sexual development and fail to mature. PHEOCHROMOCYTOMA (see also Chap. 64 )

The wild fluctuations in blood pressure and dramatic symptoms of pheochromocytoma usually alert both the patient and the physician to the possibility of this diagnosis. However, such fluctuations may be missed, or as occurs in half the patients, the hypertension may be persistent.[212A] The symptoms may be incorrectly ascribed to psychoneurosis by practitioners not sensitized to "spells," which usually represent menopausal hot flushes or anxiety-induced hyperventilation.[33] Panic attacks may simulate a "pheo spell." [213] Unfortunately, if the diagnosis of pheochromocytoma is missed, severe complications may arise from exceedingly high blood pressure and damage to the heart by catecholamines (see Chap. 64 ). Stroke and hypertensive crises with encephalopathy and retinal hemorrhage may occur, probably because blood pressure levels soar in vessels unprepared by a chronic hypertensive condition. Fortunately, a simple and inexpensive test will detect the disease with virtual certainty, so diagnostic indecision should be minimized. PATHOPHYSIOLOGY.

The cells of the sympathetic nervous system arise from the primitive neural crest as primitive stem cells called sympathogonia. These cells differentiate into ganglion cells, neuroblasts, and chromaffin cells. Tumors develop from each of these cell types; ganglioneuromas and neuroblastomas usually occur in children, whereas tumors arising from chromaffin cells, i.e., pheochromocytomas, occur at all ages anywhere along the sympathetic chain and rarely in aberrant sites.[214] About 15 percent of

pheochromocytomas are extraadrenal; nonsecreting ones are called paragangliomas or chemodectomas. Of the 85 percent of pheochromocytomas that arise in the adrenal medulla, 10 percent are bilateral and another 10 percent are malignant. Multiple adrenal tumors are particularly common in patients with simple familial pheochromocytoma and multiple endocrine neoplasia (MEN) type 2A in association with medullary carcinoma of the thyroid (Sipple syndrome) or with mucosal ganglioneuromas in addition (type 2B). The MEN-2 syndromes are inherited as autosomal dominants with mutations on chromosome 10.[215] Diffuse medullary hyperplasia may precede the development of tumors, and the tumors may in fact reflect extreme degrees of nodular hyperplasia. About 20% of cases of Von Hippel-Lindau disease with retinal angiomas and multiple other tumors are associated with a pheochromocytoma[216] as are 1% of cases of type 1 neurofibromatosis.[217] Secretion from nonfamilial pheochromocytomas varies considerably, with small tumors tending to secrete larger proportions of active catecholamines. If the predominant secretion is epinephrine, which is formed primarily in the adrenal medulla, the symptoms reflect its effects--mainly systolic hypertension caused by increased cardiac output, tachycardia, sweating, flushing, and apprehension. If norepinephrine is predominantly secreted, as from some of the adrenal tumors and from almost all extraadrenal tumors, the symptoms include both systolic and diastolic hypertension from peripheral vasoconstriction but less tachycardia, palpitations, and anxiety. The hemodynamic features of 24 untreated patients with surgically proven pheochromocytomas were quite similar to those found in 24 untreated patients of similar sex, age, weight, and blood pressure with primary hypertension, with increased total peripheral resistance as the primary mechanism in both groups.[218] DIAGNOSIS.

Many more hypertensive patients have variable blood pressure and "spells" than the 0.1 percent or so who harbor a pheochromocytoma. Spells with paroxysmal hypertension may occur with a number of stresses, and a large number of conditions may involve transient catecholamine release. A pheochromocytoma should be suspected in patients with hypertension that is either paroxysmal or persistent and accompanied by the symptoms and signs listed in Table 28-14 . In addition, children and patients with rapidly accelerating hypertension should be screened. Those whose tumors secrete predominantly epinephrine are prone to postural hypotension from a contracted blood volume and blunted sympathetic reflex tone. Suspicion should be heightened if activities such as bending over, exercise, palpation of the abdomen, smoking, or dipping snuff cause repetitive spells that begin abruptly, advance rapidly, and subside within minutes. High levels of catecholamines may induce myocarditis (Chap. 48) , which may progress to cardiomyopathy and left ventricular failure. TABLE 28-14 -- FEATURES SUGGGESTIVE OF PHEOCHROMOCYTOMA

Hypertension: Persistent or Paroxysmal Markedly variable blood pressures (± orthostatic hypotension) Sudden paroxysms (± subsequent hypertension) in relation to Stress: anesthesia, angiography, parturition Pharmacological provocation: histamine, nicotine, caffeine, beta blockers, glucocorticoids, tricyclic antidepressants Manipulation of tumors: abdominal palpation, urination Rare patients persistently normotensive Unusual settings Childhood, pregnancy, familial Multiple endocrine adenomas: medullary carcinoma of the thyroid (MEN-2), mucosal neuromas (MEN-2B) Neurocutaneous lesions: neurofibromatosis Associated Symptoms Sudden spells with headache, sweating, palpitations, nervousness, nausea, and vomiting Pain in chest or abdomen Associated Signs Sweating, tachycardia, arrhythmia, pallor, weight loss MEN=multiple endocrine neoplasia. Electrocardiographic changes of ischemia may also be seen. Beta blockers given to such patients may raise the pressure and induce coronary spasm through blockade of beta-mediated vasodilation. LABORATORY CONFIRMATION.

The easiest and best procedure is either a 24-hour or spot urine assay for total metanephrine.[219] This catecholamine metabolite is least affected by various interfering substances, including antihypertensive drugs, with the exception of labetalol, which may cause markedly elevated levels of all catecholamines.[220] In addition to the effects of labetalol, urinary metanephrine excretion is increased if patients are taking sympathomimetic or dopaminergic drugs or are under acute, severe stress such as an acute myocardial infarction or severe congestive heart failure. Interference with the measurement of metanephrine may occur for the next few days after the use of radiographic contrast media containing methylglucamine and lead to a falsely low value. Therefore, the urine should be collected before coronary angiography or other such procedures are done. If urine assays are equivocal, measurement of a plasma norepinephrine level 3 hours after a single 0.3-mg oral dose of the adrenergic inhibitor clonidine has been shown to separate nonpheochromocytoma patients, whose levels are suppressed, from those with disease whose levels are not suppressed.[218] LOCALIZATION OF THE TUMOR.

Once the diagnosis has been made, medical therapy should be started and the tumor localized by CT or MRI, which usually demonstrates these typically large tumors with ease. Radioisotopes that localize in chromaffin tissue are available and of additional help in the few patients in whom localization is not possible by CT or MRI. THERAPY.

Once diagnosed and localized, pheochromocytomas should be resected. Although preoperative alpha-adrenergic blockade has been recommended, fewer operative and postoperative problems were encountered in patients who had been treated with a calcium channel blocker.[221] If the tumor is unresectable, chronic medical therapy with the alpha blocker phenoxybenzamine (Dibenzyline) or the inhibitor of catechol synthesis alphamethyltyrosine (Demser) can be used. Other Causes of Hypertension

A host of other causes of hypertension are known (see Table 28-4 ). One that is probably becoming more common is ingestion of various drugs--prescribed (e.g., cyclosporine or tacrolimus[222] and erythropoietin[223] ), over the counter (e.g., phenylpropanolamine), and illicit (e.g., cocaine). Obstructive sleep apnea has been well characterized as a cause of significant, but reversible, hypertension. [224] COARCTATION OF THE AORTA (see Chaps. 43 and 44 ).

Congenital narrowing of the aorta may occur at any level of the thoracic or abdominal aorta. It is usually found just beyond the origin of the left subclavian artery or distal to the insertion of the ligamentum arteriosum. The coarctation may be localized or more diffuse. Other cardiac anomalies usually accompany the latter and give rise to considerable mortality during the first year of life, although operative

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treatment of both the coarctation and associated anomalies may reduce the mortality rate. With less severe postductal lesions, damage is more insidious, and symptoms may not appear until the teenage years or later. Hypertension in the arms and weak or absent femoral pulses are the classic features of coarctation. The pathogenesis of the hypertension may be more complicated than simple mechanical obstruction; a generalized vasoconstrictor mechanism is likely to be involved and may be either renin-angiotensin or sympathetic nervous activity.[225] The lesion may be detected by two-dimensional echocardiography, and aortography proves the diagnosis. The obstruction should be corrected in early childhood either by surgery[226] or by angioplasty.[227] Immediately after either, blood pressure may transiently rise even further, and mesenteric arteritis may develop. These changes may reflect very

high levels of renin-angiotensin and catecholamines and can be prevented by the prophylactic use of beta blockers. HORMONAL DISTURBANCES.

Hypertension is seen in as many as half of patients with a variety of hormonal disturbances, including acromegaly,[228] hypothyroidism,[229] and hyperparathyroidism. Diagnosis of the latter two conditions has been made easier by readily available blood tests, and affected hypertensives may be relieved of their high blood pressure by correction of the hormonal disturbance. Such relief happens more frequently with hypothyroidism than with hyperparathyroidism.[230] Hypertension after Cardiac Surgery

Transient hypertension may develop postoperatively for various reasons: pain, physical and emotional excitement, hypoxia, hypercapnia, and excessive volume loads. More severe hypertension has been noted to follow a number of cardiovascular surgical procedures: 1. Coronary bypass surgery. The incidence, exceeding 33 percent, is far higher than after other major cardiac or noncardiac surgery, except after heart transplantation. The hemodynamic pattern of increased peripheral resistance can be explained by the markedly elevated plasma catecholamine levels measured in such patients in the presence of normal renin-angiotensin levels.[231] In patients who had previously received beta blocker therapy, postoperative hypertension may also reflect a rebound phenomenon. Therefore, continuation of beta blocker therapy through the perioperative period is likely to reduce the frequency of the problem. If it occurs, parenteral therapy is often required, and intravenous nicardipine has been found to be very effective.[232] 2. Aortic valve replacement. Transient hypertension may give way to more permanent hypertension. In one series, 53 percent of 116 patients were hypertensive 5 years after surgery, and hypertension was a major determinant of late failure of the homograft valve.[233] 3. Closure of an atrial septal defect.[234] 4. Cardiac transplantation. After cardiac denervation and with current immunosuppression consisting of cyclosporine or tacrolimus and high doses of adrenal steroids, hypertension is almost invariable and can be resistant to intensive therapy.[235] Ambulatory monitoring should be performed since a considerable "white coat" effect has been noted and, therefore, more intensive therapy may not be required.[236] HYPERTENSION DURING PREGNANCY (see also Chap. 65 ) In as many as 10 percent of first pregnancies in previously normotensive women, hypertension appears after 20 weeks, i.e., gestational hypertension, and may progress to preeclampsia when the hypertension is complicated by proteinuria, edema, or hematological or hepatic abnormalities or progress to eclampsia, with cerebral

symptoms leading to convulsions.[237] Women with hypertension predating pregnancy have an even higher incidence of preeclampsia and a greater likelihood of early delivery of small-for-gestational-age babies,[238] who are in turn more prone to the development of hypertension as adults.[76] Gestational hypertension is of unknown cause but occurs more frequently in primigravid women or in subsequent pregnancies with a different father, thus suggesting an immunological mechanism. Additional predisposing factors include increased age, black race, multiple gestations, concomitant heart or renal disease, and chronic hypertension.[239] Endothelial cell dysfunction may be an underlying defect.[240] The diagnosis is usually based on a rise in pressure of 30/15 mm Hg or more to a level above 140/90. Although some measure the Korotkoff fourth sound (muffling), the fifth sound (disappearance) is closer to the true diastolic and should be used. CLINICAL FEATURES.

The features shown in Table 28-15 should help distinguish gestational hypertension and preeclampsia from chronic, primary hypertension. The distinction should be made because management and prognosis are different: Gestational hypertension is self-limited and rarely recurs in subsequent pregnancies, whereas chronic hypertension progresses and usually complicates subsequent pregnancies. Separation may be difficult because of a lack of knowledge of prepregnancy blood pressure and because of the usual tendency for high pressure to fall considerably during the middle trimester so that hypertension present before pregnancy may not be recognized. In gestational hypertension, the blood pressure usually rises only late in pregnancy. Among 84 patients with an onset of hypertension before 37 weeks' gestation, 55 had renal disease documented by kidney biopsy 6 months postpartum, when morphological changes caused solely by gestational hypertension should have subsided.[241] Gestational hypertension was the diagnosis in only 10 percent of primiparous women with onset of hypertension before 37 weeks, whereas it was the diagnosis in three-fourths of primigravid women with onset of hypertension after 37 weeks. The hemodynamic features of gestational hypertension are a further rise in cardiac output than usually seen in normal pregnancy, accompanied by profound vasoconstriction that reduces intravascular capacity even more than blood volume.[242] The mother may be particularly vulnerable to encephalopathy because of her previously normal TABLE 28-15 -- DIFFERENCES BETWEEN PREECLAMPSIA AND CHRONIC HYPERTENSION FEATURE PREECLAMPSIA CHRONIC HYPERTENSION Age (yr)

Young (30)

Parity

Primigravida

Multigravida

Onset

After 20 wk of pregnancy

Before 20 wk of pregnancy

Weight gain and edema

Sudden

Gradual

Systolic blood pressure

160

Funduscopic findings

Spasm, edema

Arteriovenous nicking, exudates

Proteinuria

Present

Absent

Plasma uric acid

Increased

Normal

Blood pressure after delivery

Normal

Elevated

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blood pressure. As is described in more detail below, cerebral blood flow is normally maintained constant over a fairly narrow range of mean arterial pressure, roughly between 60 and 100 mm Hg in normotensive individuals. In a previously normotensive young woman, an acute rise in blood pressure to 150/100 mm Hg may exceed the upper limit of autoregulation and result in a "breakthrough" of cerebral blood flow (acute dilation) that leads to cerebral edema, convulsions, and all the clinical manifestations of eclampsia. PREVENTION.

Beyond delay of pregnancy until after the teens and better prenatal care, no other manuever has been shown to prevent preeclampsia, including low doses of aspirin[243] or supplemental calcium.[244] Treatment

GESTATIONAL HYPERTENSION.

Women with gestational hypertension and their fetuses can be protected from excessive morbidity and mortality by maneuvers that lower blood pressure without impairing uteroplacental perfusion. These maneuvers include modified bed rest, a nutritious diet with normal amounts of sodium, and antihypertensive agents when diastolic blood pressure above 100 mm Hg indicates impairment in renal function and predisposition to overt eclampsia. However, as noted by Redman and Roberts, the cure is achieved by delivery, which removes the diseased tissue--the placenta. In short, the need is to deliver before it is too late. To achieve this apparently simple end, the clinician must detect the symptomless prodromal condition by screening all

pregnant women, admit to hospital those with advanced preeclampsia so as to keep track of an unpredictable situation, and time preemptive delivery to maximize the safety of mother and baby. [245] Caution is advised in the use of drugs for mild gestational hypertension, traditionally limited to methyldopa. Drug treatment of maternal blood pressure does not improve perinatal outcome and may be associated with fetal growth retardation. Most authorities recommend antihypertensive drugs only if diastolic pressures remain above 100 mm Hg.[246] The only drugs that are contraindicated are ACE inhibitors and angiotensin II receptor blockers because of their propensity to induce neonatal renal failure.[246] If the syndrome advances and eclampsia threatens before the 32nd week of gestation, expectant management (bed rest, oral antihypertensives, and intensive fetal monitoring) provides better eventual outcomes than does more aggressive therapy (glucocorticoids for 48 hours followed by delivery either by induction or cesarean section).[246] If parenteral antihypertensives are needed, hydralazine works well. CHRONIC HYPERTENSION.

If pregnancy begins while a woman is receiving antihypertensive drug therapy, the medications, including diuretics, are usually continued in the belief that the mother should be protected and that the fetus will not suffer from any sudden hemodynamic shifts such as occur when therapy is first begun. However, despite modern treatment, the incidence of perinatal mortality and fetal growth retardation remains higher in patients with chronic hypertension.[238] MANAGEMENT OF ECLAMPSIA.

With appropriate care of gestational hypertension, eclampsia hardly ever supervenes; when it does, however, maternal and fetal mortality remain very high. Excellent results have been reported with the use of magnesium sulfate to prevent convulsions.[247] Patients with severe eclampsia who have persistent oliguria after a fluid challenge should undergo hemodynamic monitoring since management may require additional volume or a reduction in preload or afterload. CONSEQUENCES OF PREGNANCY-RELATED HYPERTENSION.

The long-term prognosis of women with gestational hypertension is excellent. When 200 women with the most severe form, eclampsia, were monitored for up to 44 years, the distribution of blood pressure was identical to that in the general population.[248] Chesley concluded that "eclampsia neither is a sign of latent essential hypertension nor causes hypertension." Nonetheless, when compared with women who were normotensive, the overall prognosis for women who had hypertension during pregnancy is not as good, probably because of causes other than preeclampsia, including unrecognized chronic primary hypertension.[249] After delivery, transient or persistent hypertension may develop in the mother. In many,

early primary hypertension may have been masked by the hemodynamic changes of pregnancy. Postpartum heart failure may develop in some women; the heart failure may be an idiopathic cardiomyopathy but is usually related to hypertension, preexisting heart disease, or complications of pregnancy.[250] HYPERTENSIVE CRISIS DEFINITIONS.

A number of clinical circumstances may require rapid reduction of blood pressure (Table 28-16) . These circumstances may be separated into emergencies, which require immediate reduction of blood pressure (within 1 hour), and urgencies, which can be treated more slowly. A persistent diastolic pressure exceeding 130 mm Hg is often associated with acute vascular damage; some patients may suffer vascular damage from lower levels of pressure, while others manage to withstand even higher levels without apparent harm. As discussed below, the rapidity of the rise may be more important than the absolute level in producing acute vascular damage. Therefore, in practice, all patients with diastolic blood pressure above 130 mm Hg should be treated, some more rapidly with parenteral drugs and others more slowly with oral agents, as described on p. 991 . When the rise in pressure causes retinal hemorrhage, exudates, or papilledema, the term accelerated-malignant hypertension is used. Hypertensive encephalopathy is characterized TABLE 28-16 -- CIRCUMSTANCES REQUIRING RAPID TREATMENT OF HYPERTENSION

Accelerated-malignant hypertension with papilledema Cerebrovascular Hypertensive encephalopathy Atherothrombotic brain infarction with severe hypertension Intracerebral hemorrhage Subarachnoid hemorrhage Cardiac Acute aortic dissection Acute left ventricular failure Acute or impending myocardial infarction After coronary bypass surgery Renal Acute glomerulonephritis Renal crises from collagen-vascular diseases Severe hypertension after kidney transplantation Excessive circulating cathecholamines Pheochromocytoma crisis Food or drug interactions with monoamine oxidase inhibitors Sympathomimetic drug use (cocaine) Rebound hypertension after sudden cessation of antihypertensive drugs Eclampsia Surgical Severe hypertension in patients requiring immediate surgery Postoperative hypertension Postoperative bleeding from vascular suture lines Severe body burns Severe epistaxis From Kaplan NM: Management of hypertensive emergencies. Lancet 344:1335, 1994. © by the Lancet Ltd., 1994.

967

by headache, irritability, alterations in consciousness, and other manifestations of central nervous dysfunction with sudden and marked elevations in blood pressure. Symptoms can be reversed by a reduction in pressure. INCIDENCE.

In less than 1 percent of patients with primary hypertension, the disease progresses to an accelerated-malignant phase. Although the incidence is probably falling as a consequence of more widespread treatment of hypertension, no difference was found in the numbers of patients seen in Birmingham, England, from 1970 to 1993,[251] reflecting the very low rates of control of hypertension in England. Any hypertensive disease can initiate a crisis. Some, including pheochromocytoma and

renovascular hypertension, do so at a higher rate than seen with primary hypertension. However, since hypertension is of unknown cause in over 90 percent of all patients, most hypertensive crises appear in the setting of preexisting primary hypertension. PATHOPHYSIOLOGY.

Whenever blood pressure rises and remains above a critical level, various processes set off a series of local and systemic effects that cause further rises in pressure and vascular damage eventuating in accelerated-malignant hypertension Studies in animals and humans by Strandgaard and Paulson have elucidated the mechanism of hypertensive encephalopathy.[252] First, they directly measured the caliber of pial arterioles over the cerebral cortex in cats whose blood pressure was varied over a wide range of infusion by vasodilators or angiotensin II. As the pressure fell, the arterioles became dilated; as the pressure rose, they become constricted. Thus, constant cerebral blood flow was maintained by means of autoregulation, which is dependent on the cerebral sympathetic nerves. However, when mean arterial pressure rose above 180 mm Hg, the tightly constricted vessels could no longer withstand the pressure and suddenly dilated. This dilation began in an irregular manner, first in areas with less muscle tone and then diffusely with production of generalized vasodilation. This "breakthrough" of cerebral blood flow hyperperfuses the brain under high pressure and thereby causes leakage of fluid into the perivascular tissue and results in cerebral edema and the syndrome of hypertensive encephalopathy. In human subjects, cerebral blood flow was measured repetitively by an isotopic technique while blood pressure was lowered or raised with vasodilators or vasoconstrictors in a manner similar to that used in the animal studies. [252] Curves depicting cerebral blood flow as a function of arterial pressure demonstrated autoregulation with a constancy of flow over mean pressures in normotensive persons from about 60 to 120 mm Hg and in hypertensive patients from about 110 to 180 mm Hg (Fig. 28-18) . This "shift to the right" in hypertensive patients is the result of structural thickening of the arterioles as an adaptation to the chronically elevated pressure. When pressure was raised beyond the upper limit of autoregulation, the same "breakthrough"

Figure 28-18 Idealized curves of cerebral blood flow at varying levels of systemic blood pressure in normotensive and hypertensive subjects. Rightward shift is shown in autoregulation with chronic hypertension. (Adapted from Strandgaard S, Olesen J, Skinhtoi E, Lassen NA: Autoregulation of brain circulation in severe arterial hypertension. BMJ 1:507, 1973.)

TABLE 28-17 -- CLINICAL CHARACTERISTICS OF HYPERTENSIVE CRISIS

Blood pressure: Usually >140 mm Hg diastolic Funduscopic findings: Hemorrhage, exudate, papilledema Neurological status: Headache, confusion, somnolence, stupor, visual loss, focal deficits, seizures, coma Cardiac findings: Prominent apical impulse, cardiac enlargement, congestive failure Renal: Oliguria, azotemia Gastrointestinal: Nausea, vomiting From Kaplan NM: Clinical Hypertension. 6th ed. Baltimore, Williams & Wilkins, 1994, p 283. with hyperperfusion occurred as was seen in the animal studies. In previously normotensive persons whose vessels have not been altered by prior exposure to high pressure, breakthrough occurred at a mean arterial pressure of about 120 mm Hg; in hypertensive patients, the breakthrough occurred at about 180 mm Hg. These studies confirm clinical observations. In previously normotensive persons, severe encephalopathy occurs with relatively little hypertension. In children with acute glomerulonephritis and in women with eclampsia, convulsions may occur as a result of hypertensive encephalopathy with blood pressure readings as low as 150/100 mm Hg. Obviously, chronically hypertensive patients withstand such pressures without difficulty; however, when pressure increases significantly, encephalopathy may also develop even in these patients. MANIFESTATIONS AND COURSE.

The symptoms and signs of hypertensive crises are usually dramatic (Table 28-17) . However, some patients may be relatively asymptomatic despite markedly elevated pressure and extensive organ damage. Young black men are particularly prone to hypertensive crisis with severe renal insufficiency but little obvious prior distress. When the blood pressure is sufficiently high to induce encephalopathy or accelerated-malignant hypertension, the following clinical features are frequently present: 1. Renal insufficiency with protein and red cells in the urine and azotemia; acute oliguric renal failure may also develop. 2. Elevated levels of plasma renin from the diffuse intrarenal ischemia resulting in secondary aldosteronism, often manifested by hypokalemia. Although not causal, the secondarily elevated renin and aldosterone levels most likely exacerbate the hypertensive process. 3. Microangiopathic hemolytic anemia with red cell fragmentation and intravascular coagulation. 4. Cardiac size and function may not be abnormal in those in whom malignant hypertension suddenly develops. If left untreated, patients die quickly of brain damage or more gradually of renal damage. Before effective therapy was available, less than 25 percent of patients with malignant hypertension survived 1 year and only 1 percent survived 5 years. [253] With therapy

including renal dialysis, over 90 percent survive 1 year and about 80 percent survive 5 years. Death in patients with severe hypertension is usually TABLE 28-18 -- CONDITIONS TO BE DIFFERENTIATED FROM A HYPERTENSIVE CRISIS Acute left ventricular failure Uremia from any cause, particularly with volume overload Cerebrovascular accident Subarachnoid hemorrhage Brain tumor Head injury Epilepsy (postictal) Collagen diseases, particularly lupus, with cerebral vasculitis Encephalitis Overdose and withdrawal from narcotics, amphetamines, etc. Hypercalcemia Acute anxiety with hyperventilation syndrome

968

from stroke or renal failure if it occurs in the first few years after onset. If therapy keeps patients alive for longer than 5 years, death will usually be due to coronary artery disease, in which case factors other than the high pressure per se are probably also involved. DIFFERENTIAL DIAGNOSIS.

The presence of hypertensive encephalopathy or accelerated-malignant hypertension demands immediate, aggressive therapy to lower blood pressure effectively, often before the specific cause is known. However, certain serious diseases, as well as psychogenic problems, i.e., acute anxiety with hyperventilation or panic attacks, can mimic a hypertensive crisis (Table 28-18) and management of these conditions obviously requires different diagnostic and therapeutic approaches. In particular, blood pressure should not be lowered too abruptly in a patient with a stroke. [254] Specific therapy for hypertensive crises is described in the next chapter ( p. 991 ).

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REFERENCES DEFINITIONS, PREVALENCE, AND CONSEQUENCES OF HYPERTENSION The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure: Arch Intern Med 157:2413, 1997. 1.

Barker WH, Mullooly JP, Linton KLP: Trends in hypertension prevalence, treatment and control in a well-defined older population. Hypertension 31:552, 1998. 2.

Berlowitz DR, Ash AS, Hickey EC, et al: Inadequate management of blood pressure in a hypertensive population. N Engl J Med 339:1957, 1998. 3.

Andersson OK, Almgre T, Persson B, et al: Survival in treated hypertension: Follow up study after two decades. BJM 317:167-171, 1998. 4.

Woodwell DA: National Ambulatory Medical Care Survey: 1997 Summary. Advance Data from Vital and Health Statistics, No. 305. Hyattsville, MD, National Center for Health Statistics, 1999. 5.

Kaplan NM: Primary hypertension: Pathogensis. In Clinical Hypertension. Baltimore, Williams & Wilkins, 1998, pp 41-101. 6.

Martinez MA, Garcia-Puig, J, Martin JC: Frequency and determinants of white coat hypertension in mild to moderate hypertension. Am J Hypertens 12:251, 1999. 7.

Rasmussen SL, Torp-Pedersen C, Borch-Johnson K, Ibsen H: Normal values for ambulatory blood pressure and differences between casual blood pressure and ambulatory blood pressure: Results from a Danish population survey. J Hypertens 16:1415, 1998. 8.

Khattar RS, Senior R, Swales JD, Lahiri A: Value of ambulatory intra-arterial blood pressure monitoring in the long term prediction of left ventricular hypertrophy and carotid atherosclerosis in essential hypertension. J Hum Hypertens 13:111, 1999. 9.

10.

Pickering TG: Blood pressure measurement and detection of hypertension. Lancet 344:31, 1994.

Mejia AD, Egan BM, Schork NJ, Zweifler AJ: Artifacts in measurement of blood pressure and lack of target organ involvement in the assessment of patients with treatment-resistant hypertension. Ann Intern Med 112:270, 1990. 11.

Landray MJ, Lip GYD: White coat hypertension: A recognised syndrome with uncertain implications. J Hum Hypertens 13:5, 1999. 12.

Khatter RS, Senior R, Lahiri A: Cardiovascular outcome in white-coat versus sustained mild hypertension. Circulation 98:1892, 1998. 13.

14.

Muller JE: Circadian variation in cardiovascular events. Am J Hypertens 12:35S, 1999.

15.

Elliott WJ: Circadian variation in blood pressure. Am J Hypertens 12(Suppl): 43, 1999.

Verdecchia P, Porcellati C, Schillaci G, et al: Ambulatory blood pressure: An independent predictor of prognosis in essential hypertension. Hypertension 34:793, 1994. 16.

Matthews CE, Pate RP, Jackson KL, et al: Exaggerated blood pressure response to dynamic exercise and risk of future hypertension. J Clin Epidemiol 51:29, 1998. 17.

Allison TG, Cordeiro MAS, Miller TD, et al: Prognostic significance of exercise-induced systemic hypertension in healthy subjects. Am J Cardiol 83:371, 1999. 18.

O'Donnell CJ, Kannel WB: Cardiovascular risks of hypertension: Lessons from observational studies. J Hypertens 16(Suppl):3, 1998. 19.

Froom P, Bar-David M, Ribak J, et al: Predictive value of systolic blood pressure in young men for elevated systolic blood pressure 12 to 15 years later. Circulation 68:467, 1983. 20.

Verdecchia P, Schillaci G, Borgioni C, et al: Ambulatory pulse pressure: A potent predictor of total cardiovascular risk in hypertension. Hypertension 32:983, 1998. 21.

Mathias CJ, Kimber JR: Postural hypotension: Causes, clinical features, investigation, and management. Annu Rev Med 50:317, 1999. 22.

MacMahon S, Peto R, Cutler J, et al: Blood pressure, stroke, and coronary heart disease: I. Prolonged differences in blood pressure: Prospective observational studies corrected for the regression dilution bias. Lancet 335:765, 1990. 23.

Guidelines Subcommittee: 1999 World Health Organization-International Society of Hypertension guidelines for the management of hypertension. J Hypertens 17:151, 1999. 24.

Hypertension Detection and Follow-up Program Cooperative Group: Blood pressure studies in 14 communities: A two-stage screen for hypertension. JAMA 237:2385, 1977. 25.

26.

Lieberman E: Hypertension in childhood and adolescence. In Kaplan NM (ed): Clinical Hypertension.

Baltimore, Williams & Wilkins, 1998, p 407. Burt VL, Whelton P, Roccella EJ, et al: Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension 25:3050, 1995. 27.

Dyer AR, Liu K, Walsh M, et al: Ten-year incidence of elevated blood pressure and its predictors: The Cardia Study. J Hum Hypertens 13:13, 1999. 28.

Rudnick JV, Sackett DL, Hirst S, Holmes C: Hypertension in family practice. Can Med Assoc J 3:492, 1977. 29.

Sinclair AM, Isles CG, Brown I, et al: Secondary hypertension in a blood pressure clinic. Arch Intern Med 147:1289, 1987. 30.

Anderson GH Jr, Blakemann N, Streeten DHP: The effect of age on prevalence of secondary forms of hypertension in 4429 consecutively referred patients. J Hypertens 12:609, 1994. 31.

Coughlin SS, Trock B, Criqui MH, et al: The logistic modeling of sensitivity, specificity, and predictive value of a diagnostic test. J Clin Epidemiol 45:1, 1992. 32.

Kaplan NM: Anxiety-induced hyperventilation: A common cause of symptoms in patients with hypertension. Arch Intern Med 157:945, 1997. 33.

Cooper WD, Glover DR, Hombrey JM, Kimber GR: Headache and blood pressure: Evidence of a close relationship. J Hum Hypertens 3:41, 1989. 34.

The Pooling Project Research Group: Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events. Final report of the pooling project. J Chronic Dis 31:201, 1978. 35.

36.

Rose G: Strategy of prevention: Lessons from cardiovascular disease. BMJ 282: 1847, 1981.

Liese AD, Mayer-Davis EJ, Haffner SM: Development of the multiple metabolic syndrome: An epidemiologic perspective. Epidemiol Rev 20:157, 1998. 37.

Rosmond R, Bjorntorp P: Blood pressure in relation to obesity, insulin, and the hypothalamic-pituitary-adrenal axis in Swedish men. J Hypertens 16:1721, 1998. 38.

Keith NM, Wagener HP, Barker NW: Some different types of essential hypertension: Their course and prognosis. Am J Med Sci 197:332, 1939. 39.

Dahlof B, Stenkula S, Hansson L: Hypertensive retinal vascular changes: Relationship to LV hypertrophy and arteriolar changes before and after treatment. Blood Press 1:35, 1992. 40.

Schussheim AE, Devereux RB, de Simone G: Usefulness of subnormal midwall fractional shortening in predicting left ventricular exercise dysfunction in asymptomatic patients with systemic hypertension. Am J Cardiol 79:1070, 1997. 41.

Di Bello V, Pedrinelli R, Giorgi D: Ultrasonic myocardial texture versus Doppler analysis in hypertensive heart. Hypertension 33:66, 1999. 42.

Vasan RS, Levy D: The role of hypertension in the pathogenesis of heart failure. Arch Intern Med 156:1789, 1996. 43.

Gimelli A, Schneider-Eicke J, Neglia D, et al: Homogeneously reduced versus regionally impaired myocardial blood flow in hypertensive patients: Two different patterns of myocardial perfusion associated with degree of hypertrophy. J Am Coll Cardiol 31:366, 1998. 44.

Karam R, Lever HM, Healy BP: Hypertensive hypertrophic cardiomyopathy or hypertrophic cardiomyopathy with hypertension? A study of 78 patients. J Am Coll Cardiol 13:580, 1989. 45.

Dries DL, Exner DV, Gersh BJ, et al: Racial differences in the outcome of left ventricular dysfunction. N Engl J Med 340:609, 1999. 46.

Kahan T: The importance of left ventricular hypertrophy in human hypertension. J Hypertens 16(Suppl):23, 1998. 47.

Devereux RB, Koren MH, DeSimone, G, et al: LV mass as a measure of preclinical hypertensive disease. Am J Hypertens 5(Suppl); 175, 1992. 48.

Gottdiener JS, Reda DJ, Williams DW, Materson BJ: Left atrial size in hypertensive men: Influence of obesity, race and age. J Am Coll Cardiol 29:651, 1997. 49.

Gottdiener JS, Reda DJ, Materson BJ, et al: Importance of obesity, race and age to the cardiac structural and functional effects of hypertension. J Am Coll Cardiol 24:1492, 1994. 50.

Verdecchia P, Porcellati C, Zampi I, et al: Asymmetric left ventricular remodeling due to isolated septal thickening in patients with systemic hypertension and normal left ventricular masses. Am J Cardiol 73:247, 1994. 51.

Koren MJ, Devereux RB, Casale PN, et al: Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 144:345, 1991. 52.

Ichkhan K, Molnar J, Somberg J: Relation of left ventricular mass and QT dispersion in patients with systematic hypertension. Am J Cardiol 79:508, 1997. 53.

Ofili EO, Cohen JD, St Vrain JA, et al: Effect of treatment of isolated systolic hypertension on left ventricular mass. JAMA 279:778, 1998. 54.

969

Verdecchia P, Schillaci G, Borgioni C, et al: Prognostic significance of serial changes in left ventricular mass in essential hypertension. Circulation 97:48, 1998. 55.

Kannel WB: Contribution of the Framingham Study to preventive cardiology. J Am Coll Cardiol 15:206, 1990. 56.

Haider AW, Chen L, Larson MG, et al: Antecedent hypertension confers increased risk for adverse outcomes after initial myocardial infarction. Hypertension 30:1020, 1997. 57.

Hansson L, Zanchetti A, Carruthers SG, et al: Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 351:1755, 1998. 58.

Nishijo M, Nakagawa H, Morikawa Y, et al: Microalbuminuria and hypertension in nondiabetic Japanese men. Am J Hypertens 12:16, 1999. 59.

Pedrinelli R, Giampietro O, Carmassi F, et al: Microalbuminuria and endothelial dysfunction in essential hypertension. Lancet 344:14, 1994. 60.

Klag MJ, Whelton PK, Randall BL, et al: End-stage renal disease in African-American and white men. JAMA 277:1293, 1997. 61.

Glynn RJ, Beckett LA, Hebert L, et al: Current and remote blood pressure and cognitive decline. JAMA 281:438, 1999. 62.

Davis BR, Vogt T, Frost PH, et al: Risk factors for stroke and type of stroke in persons with isolated systolic hypertension. Stroke 29:1333, 1998. 63.

Kohara K, Zhao B, Jiang Y, et al: Relation of left ventricular hypertrophy and geometry to asymptomatic cerebrovascular damage in essential hypertension. Am J Cardiol 83:367, 1999. 64.

Management Committee: Untreated mild hypertension. A report by the Management Committee of the Australian Therapeutic Trial in Mild Hypertension. Lancet 1:185, 1982. 65.

Jackson R, Barham P, Bills J, et al: Management of raised blood pressure in New Zealand: A discussion document. BMJ 307:107, 1993. 66.

MECHANISMS OF PRIMARY (ESSENTIAL) HYPERTENSION Lund-Johnson P: Central haemodynamics in essential hypertension at rest and during exercise: A 20-year follow-up study. J Hypertens 7(Suppl):52, 1989. 67.

Post WS, Larson MG, Levy D: Hemodynamic predictors of incident hypertension. Hypertension 24:585, 1994. 68.

Kim J-R, Kiefe, CI, Liu K, et al: Heart rate and subsequent blood pressure in young adults. The CARDIA study. Hypertension 33:640, 1999. 69.

70.

Harrap SB: Hypertension: Genes versus environment. Lancet 344:169, 1994.

71.

Luft FC: Molecular genetics of human hypertension. J Hypertens 16:1871, 1998.

Staessen JA, Kuznetsova T, Wang JG, et al: M235T angiotensin gene polymorphism and cardiovascular renal risk. J Hypertens 17:9, 1999. 72.

Davies E, Holloway CD, Ingram MC, et al: Aldosterone excretion rate and blood pressure in essential hypertension are related to polymorphic differences in the aldosterone synthase gene CYP11B2. Hypertension 33:703, 1999. 73.

74.

Tonolo G, Melis MG, Secchi G, et al: Association of Trp64Arg beta3 -adrenergic-receptor gene

polymorphism with essential hypertension in the Sardinian population. J Hypertens 17:33, 1999. Pratt RE, Dzau, VJ: Genomics and hypertension: Concepts, potentials and opportunities. Hypertension 33:238, 1999. 75.

Law CM, Shiell AW: Is blood pressure inversely related to birth weight? The strength of evidence from a systematic reivew of the literature. J Hypertens 14:935, 1996. 76.

Brenner BM, Chertow GM: Congenital oligonephropathy: An inborn cause of adult hypertension and progressive renal injury? Curr Opin Nephrol Hypertens 2:691, 1993. 77.

Brenner MB, Anderson S: The interrelationships among filtration surface area, blood pressure, and chronic renal disease. J Cardiovasc Pharmacol 19(Suppl):1, 1992. 78.

Guyton AC: Kidneys and fluids in pressure regulation: Small volume but large pressure changes. Hypertension 19(Suppl):2, 1992. 79.

Sealey JE, Blumenfeld JD, Bell GM, et al: On the renal basis for essential hypertension: Nephron heterogeneity with discordant renin secretion and sodium excretion causing a hypertensive vasoconstriction-volume relationship. J Hypertens 6:763, 1988. 80.

Woolfson RG, Poston L, de Wardener HE: Digoxin-like inhibitors of active sodium transport and blood pressure. The current status. Kidney Int 46:297, 1994. 81.

Strazzullo P, Siani A, Cappuccio FP, et al: Red blood cell sodium-lithium countertransport and risk of future hypertension. Hypertension 31:1284, 1998. 82.

83.

Richards AM: The natriuretic peptides and hypertension. J Intern Med 235:534, 1994.

84.

Weinberger MH: Salt sensitivity of blood pressure in humans. Hypertension 27:481, 1996.

Ferri C, Bellini C, Desideri G, et al: Clustering of endothelial markers of vascular damage in human salt-sensitive hypertension. Hypertension 32:862, 1998. 85.

Uzu T, Fuji T, Nishimura M, et al: Determinants of circadian blood pressure rhythm in essential hypertension. Am J Hypertens 12:35, 1999. 86.

Morimoto A, Uzu T, Fuji T, et al: Sodium sensitivity and cardiovascular events in patients with essential hypertension. Lancet 350:1734, 1997. 87.

Schmidlin O, Forman A, Tanaka M, et al: NaCl-induced renal vasoconstriction in salt-sensitive African Americans. Hypertension 33:633, 1999. 88.

Ganguli MC, Grimm RH Jr, Svendsen KH, et al: Urinary sodium and potassium profile of blacks and whites in relation to education in two different geographic urban areas. Am J Hypertens 12:69, 1999. 89.

Lever AF, Harrap SB: Essential hypertension: A disorder of growth with origins in childhood? J Hypertens 10:101, 1992. 90.

91.

Folkow B: "Structural factor" in primary and secondary hypertension. Hypertension 16:89, 1990.

92.

Lever AF: Slow pressor mechanisms in hypertension. A role for hypertrophy of resistance vessels? J

Hypertens 4:515, 1986. Noon JP, Walker BR, Webb DJ, et al: Impaired microvascular dilatation and capillary rarefaction in young adults with a predisposition to high blood pressure. J Clin Invest 99:1873, 1997. 93.

Pries AR, Secomb TW, Gaehtgens P: Structural autoregulation of terminal vascular beds: Vascular adaptation and development of hypertension. Hypertension 33:153, 1999. 94.

White M, Fourney A, Mikes E, Leenen FHH: Effects of age and hypertension on cardiac responses to the alpha1 -agonist phenylephrine in humans. Am J Hypertens 12:151, 1999. 95.

Reeves RA, Shapiro AP, Thompson ME, Johnsen A-M: Loss of nocturnal decline in blood pressure after cardiac transplantation. Circulation 73:401, 1986. 96.

Goldstein DS, Golczynska A, Stuhlmuller J, et al: A test of the "epinephrine" hypothesis in humans. Hypertension 33:3643, 1999. 97.

Markovitz JH, Matthews KA, Kannel WB, et al: Psychological predictors of hypertension in the Framingham Study: Is there tension in hypertension? JAMA 270:2439, 1993. 98.

Smith S, Julius S, Jamerson K, et al: Hematocrit levels and physiologic factors in relationship to cardiovascular risk in Tecumseh, Michigan. J Hypertens 12:455, 1994. 99.

Perini C, Smith DHG, Neutel JM, et al: A repressive coping style protecting from emotional distress in low-renin essential hypertensives. J Hypertens 12:601, 1994. 100.

Colon GP, Quint DJ, Dickinson LD, et al: Magnetic resonance evaluation of ventrolateral medullary compression in essential hypertension. J Neurosurg 88:226, 1998. 101.

Panza JA, Epstein SE, Quyyumi AA: Circadian variation in vascular tone and its relation to sympathetic vasoconstrictor activity. N Engl J Med 325:986, 1991. 102.

103.

Yee KM, Struthers AD: Aldosterone blunts the baroreflex response in man. Clin Sci 95:687, 1998.

Brunner HR, Sealey JE, Laragh JH: Renin subgroups in essential hypertension. Further analysis of their pathophysiological and epidemiological characteristics. Circ Res 32(Suppl 1):99, 1973. 104.

105.

Goldblatt H: Reflections. Urol Clin North Am 2:219, 1975.

Martens JR, Reaves PY, Lu D, et al: Prevention of renovascular and cardiac pathophysiological changes in hypertension by angiotensin II type 1 receptor antisense gene therapy. Proc Natl Acad Sci U S A 95:2664, 1998. 106.

Horiuchi M, Akishita M, Dzau VJ: Recent progress in angiotensin II type 2 receptor research in the cardiovascular system. Hypertension 33:613, 1999. 107.

Morishita R, Gibbons GH, Ellison KE, et al: Evidence for direct local effect of angiotensin in vascular hypertrophy. J Clin Invest 94:978, 1994. 108.

Reaven GM, Laws A: Insulin resistance, compensatory hyperinsulinaemia and coronary heart disease. Diabetologia 37:948, 1994. 109.

Cardillo C, Killcoyne CM, Nambi S, et al: Vasodilator response to systemic but not to local hyperinsulinemia in the human forearm. Hypertension 32:740, 1998. 110.

DiBello V, Giampietro O, Pedrinelli R, et al: Can insulin action induce myocardial texture alterations in essential hypertension? Am J Hypertens 12:283, 1999. 111.

Steinberg HO, Brechtel G, Johnson A, et al: Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. J Clin Invest 94:1172, 1994. 112.

Ruschitzka F, Corti R, Noll G, Luscher TF: A rationale for treatment of endothelial dysfunction in hypertension. J Hypertens 17(Suppl 1):25, 1999. 113.

Rizzoni D, Porteri E, Castellano M, et al: Endothelial dysfunction in hypertension is independent from the etiology and from vascular structure. Hypertension 31:335, 1998. 114.

Rudic RD, Shesely EG, Maeda N, et al: Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J Clin Invest 101:731, 1998. 115.

Cardillo C, Kilcoyne CM, Cannon RO III, et al: Attenuation of cyclic nucleotide-mediated smooth muscle relaxation in blacks as a cause of racial differences in vasodilator function. Circulation 99:90, 1999. 116.

Muiesan ML, Salvetti M, Monteduro C, et al: Effect of treatment on flow-dependent vasodilation of the brachial artery in essential hypertension. Hypertension 33:575, 1999. 117.

Cardillo C, Kilcoyne CM, Waclawiw M, et al: Role of endothelin in the increased vascular tone of patients with essential hypertension. Hypertension 33:753, 1999. 118.

119.

Margolius HS: Kallikreins and kinins. Hypertension 26:221, 1995.

Muirhead EE, Brooks B, Byers LW: Biologic differences between vasodilator prostaglandins and medullipin I. Am J Med Sci 303:86, 1992. 120.

970

Tsuda K, Kinoshita Y, Nishio I, Masuyama Y: Adrenomedullin and membrane fluidity of erythrocytes in mild-essential hypertension. J Hypertens 17:201, 1999. 121.

Bost L, Primatesta P, Dong W, Poulter N: Blood lead and blood pressure: Evidence from the Health Survey for England 1995. J Hum Hypertens 13:123, 1999. 122.

Ascherio A, Hennekens, C, Willett WC, et al: Prospective study of nutritional factors, blood pressure and hypertension among US women. Hypertension 27:1065, 1996. 123.

Cox BD, Whichelow MJ, Prevost AT: The development of cardiovascular disease in relation to anthropometric indices and hypertension in British adults. Int J Obes 22:966, 1998. 124.

Kannel WB, Garrison RJ, Dannenberg AL: Secular blood pressure trends in normotensive persons: The Framingham study. Am Heart J 125:1154, 1993. 125.

Huang Z, Willett WC, Manson J-A: Body weight, weight change and risk for hypertension. Ann Intern Med 128:81, 1998. 126.

Rosengren A, Wedel H, Wilhelmsen L: Body weight and weight gain during adult life in men in relation to coronary heart disease and mortality. Eur Heart J 20:269, 1999. 127.

128.

Bray GA: Overweight is risking fate. J Clin Endocrinol Metab 84:10, 1999.

Phillip BG, Narkiewicz K, Pesek CA, et al: Effects of obstructive sleep apnea on endothelin-1 and blood pressure. J Hypertens 17:61, 1998. 129.

Endre T, Mattiasson I, Hulthen UL, et al: Insulin resistance is coupled to low physical fitness in normotensive men with a family history of hypertension. J Hypertens 12:81, 1994. 130.

Paffenbarger RS Jr: Contributions of epidemiology to exercise science and cardiovascular health. Med Sci Sports Exerc 20:426, 1988. 131.

Truelsen T, Gronbaek M, Schnohr P, Boysen G: Intake of beer, wine and spirits and risk of stroke: The Copenhagen city heart study. Stroke 29:2467, 1998. 132.

133.

Seppa K, Sillanaukee P: Binge drinking and ambulatory blood pressure. Hypertension 33:79, 1999.

Kiechl S, Willeit J, Poewe W, et al: Insulin sensitivity and regular alcohol consumption: Large, prospective, cross sectional population study (Bruneck study). BMJ 313:1040, 1996. 134.

Randin D, Vollenweider P, Tappy L, et al: Suppression of alcohol-induced hypertension by dexamethasone. N Engl J Med 332:1733, 1995. 135.

Hsieh ST, Saito K, Miyajima T, et al: Effects of alcohol moderation on blood pressure and intracellular cations in mild essential hypertension. Am J Hypertens 8:696, 1995. 136.

Giannattasio C, Mangoni AA, Stella ML, et al: Acute effects of smoking on radial artery compliance in humans. J Hypertens 12:691, 1994. 137.

Kannel WB, Anderson K, Wilson PWF: White blood cell count and cardiovascular disease. JAMA 267:1253, 1992. 138.

Wilson DK, Sica DA, Miller SB: Ambulatory blood pressure nondipping status in salt-sensitive and salt-resistant black adolescents. Am J Hypertens 12:159, 1999. 139.

Parmer RJ, Stone RA, Cervenka JH: Renal hemodynamics in essential hypertension: Racial differences in response to changes in dietary sodium. Hypertension 24:752, 1994. 140.

Schillaci G, Verdecchia P, Borgioni C, et al: Early cardiac changes after menopause. Hypertension 32:764, 1998. 141.

Gillman MW, Cook N, Rosner B, et al: Identifying children at high risk for the development of essential hypertension. J Pediatr 122:837, 1993. 142.

143.

Loggie JMH: Hypertension in children. Heart Dis Stroke 3:147, 1994.

Murphy JK, Alpert BS, Walker SS: Ethnicity, pressor reactivity, and children's blood pressure. Hypertension 20:327, 1992. 144.

Tarnow L, Rossing P, Gall M-A, et al: Prevalence of arterial hypertension in diabetic patients before and after the JNC-V. Diabetes Care 17:1247, 1994. 145.

The Hypertension in Diabetes Study Group: Hypertension in diabetes study (HDS): I. Prevalence of hypertension in newly presenting type 2 diabetic patients and the association with risk factors for cardiovascular and diabetic complications. J Hypertens 11:309, 1993. 146.

White WB, et al: Management of patients with hypertension and diabetes mellitus. Am J Med 108:238, 2000. 146A.

Tuomilehto J, Rastenyte D, Birkenhager WH, et al: Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med 340:677, 1999. 147.

IDENTIFIABLE (SECONDARY) FORMS OF HYPERTENSION Beral V, Hermon C, Kay C, et al: Mortality associated with oral contraceptive use: 25 year follow up of cohort of 46,000 women from Royal College of General Practitioners' oral contraception study. BMJ 31:96, 1999. 148.

Fuchs N, Dusterberg B, Weber-Diehl F, Muhe B: The effect on blood pressure of a monophasic oral contraceptive containing ethinylestradiol and Gestogen. Contraception 51:335, 1995. 149.

Royal College of General Practitioners: Hypertension. In Oral Contraceptives and Health. New York, Pitman, 1974, p 37. 150.

Weir RJ: Effect on blood pressure of changing from high to low dose steroid preparation in women with oral contraceptive induced hypertension. Scott Med J 27:212, 1982. 151.

Ribstein J, Halimi J-M, du Cailar G, Mimran A: Renal characteristics and effect of angiotensin suppression in oral contraceptive users. Hypertension 33:90, 1999. 152.

Gosland IF, Walton C, Felton C, et al: Insulin resistance, secretion and metabolism in users of oral contraceptives. Clin Endocrinol 74:64, 1992. 153.

Writing Group for the PEPI Trial: Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 273:199, 1995. 154.

Sourander L, Rajala T, Raiha I, et al: Cardiovascular and cancer morbidity and mortality and sudden cardiac death in postmenopausal women on oestrogen replacement therapy (ERT). Lancet 352:1965, 1998. 155.

Pinto S, Virdis A, Ghiadoni L, et al: Endogenous estrogen and acetylcholine-induced vasodilation in normotensive women. Hypertension 29:268, 1997. 156.

Valderrabano F, Gomez-Campdera F, Jones EHP: Hypertension as cause of end-stage renal disease: Lessons from international registries. Kidney Int 54(Suppl):60, 1998. 157.

Ghose RR, Harinda V: Unrecognized high pressure chronic retention of urine presenting with systemic arterial hypertension. BMJ 298:1626, 1989. 158.

159.

Thadhani R, Pascual M, Bonventre JV: Acute renal failure. N Engl J Med 334:1148, 1996.

Palmer BF, Henrich WL: Clinical acute renal failure with nonsteroidal anti-inflammatory drugs. Semin Nephrol 15:214, 1995. 160.

161.

Coruzzi P, Novarini A: Which antihypertensive treatment in renal vasculitis? Nephron 62:372, 1992.

Smith LH, Drach G, Hall P, et al: National High Blood Pressure Education Program (NHBPEP) review paper on complications of shock wave lithotripsy for urinary calculi. Am J Med 91:635, 1991. 162.

Lazarus JM, Bourgoignie JJ, Buckalew VM, et al: Achievement and safety of a low blood pressure goal in chronic renal disease. The modification of diet in renal disease study group. Hypertension 29;641, 1997. 163.

Goonasekera CD, Shah V, Wade AM, et al: 15-year follow-up of renin and blood pressure in reflux nephropathy. Lancet 347:640, 1996. 164.

Moore MA, Epstein M, Agodoa L, Dworkin LD: Current strategies for management of hypertensive renal disease. Arch Intern Med 159:23, 1999. 165.

Baboolal K, Evans C, Moore RH: Incidence of end-stage renal disease in medically treated patients with severe bilateral atherosclerotic renovascular disease. Am J Kidney Dis 31:971, 1998. 166.

Gaede P, Vedel P, Parving H-HP, Pedersen O: Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: The Steno type 2 randomised study. Lancet 353:617, 1999. 167.

Ismail N, Becker B, Strzelczyk P, Ritz E: Renal disease and hypertension in noninsulin-dependent diabetes mellitus. Kidney Int 55:1, 1999. 168.

Klag MJ, Whelton PK, Perneger TV: Analgesics and chronic renal disease. Curr Opin Nephrol Hypertens 5:236, 1996. 169.

Kang ES, Tevlin MT, Wang YB, et al: Hemodialysis hypotension: Interaction of inhibitors, iNOS, and the interdialytic period. Am J Med Sci 317:9, 1999. 170.

Rahman M, Dixit A, Donley V, et al: Factors associated with inadequate blood pressure control in hypertensive hemodialysis patients. Am J Kidney Dis 33:498, 1999. 171.

Martinez-Castelao A, Hueso M, Sanz V, et al: Treatment of hypertension after renal transplantation: Long-term efficacy of verapamil, enalapril, and doxazosin. Kidney Int 54(Suppl):130, 1998. 172.

Strandgaard S, Hansen U: Hypertension in renal allograft recipients may be conveyed by cadaveric kidneys from donors with subarachnoid hemorrhage. BMJ 292:1041, 1986. 173.

Mann SJ, Pickering TG: Detection of renovascular hypertension: State of the art: 1992. Ann Intern Med 227:845, 1992. 174.

Hansen KJ, Deitch JS, Dean RH: Renovascular disease in blacks: Prevalence and result of operative management. Am J Med Sci 315:337, 1998. 175.

Bookstein JJ: Segmental renal artery stenosis in renovascular hypertension. Radiology 90:1073, 1968. 176.

Oskin TC, Hansen KJ, Deitch JS, et al: Chronic renal artery occlusion: Nephrectomy versus revascularization. J Vasc Surg 29:140, 1999. 177.

van de Ven PJG, Beutler JJ, Kaatee R, et al: Antiogensin converting enzyme inhibitor-induced renal dysfunction in atherosclerotic renovascular disease. Kidney Int 53:986, 1998. 178.

Block MJ, Trost DW, Pickering TG, et al: Prevention of recurrent pulmonary edema in patients with bilateral renovascular disease through renal artery stent placement. Am J Hypertens 12:1, 1999. 179.

Textor SC, Canzanello VJ: Radiographic evaluation of the renal vasculature. Curr Opin Nephrol Hypertens 5:541, 1996. 180.

Leertouwer TC, Gussenhoven EJ, van Jaarsveld BC, et al: In-vitro validation, with histology, of intravacular ultrasound in renal arteries. J Hypertens 17:271, 1999. 181.

Leung DA, Hoffmann U, Pfammatter T, et al: Magnetic resonance angiography versus duplex sonography for diagnosing renovascular disease. Hypertension 33:726, 1999. 182.

Gerber LM, Mann SJ, Muller FB, et al: Response to the captopril test is dependent on baseline renin profile. J Hypertens 12:173, 1994. 183.

184.

Derkx FHM, Schalekamp MADH: Renal artery stenosis and hypertension. Lancet 344:237, 1994.

van Jaarsveld BC, Krijnen P, Derkx FHM, et al: The place of renal scintigraphy in the diagnosis of renal artery stenosis. Arch Intern Med 157:1226, 1997. 185.

Mimran A: Renal effects of antihypertensive agents in parenchymal renal disease and renovascular hypertension. J Cardiovasc Pharmacol 19(Suppl 6):45, 1992. 186.

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van de Ven PJG, Kaatee R, Beutler JJ, et al: Arterial stenting and balloon angioplasty in ostial atherosclerotic renovascular disease: A randomized trial. Lancet 353:282, 1999. 187.

188.

Aurell M, Jensen G: Treatment of renovascular hypertension. Nephron 75:373, 1997.

189.

Textor SC: Renovascularization in atherosclerotic renal artery disease. Kidney Int 53:799, 1998.

Haab F, Duclos JM, Guyenne T, et al: Renin secreting tumors: Diagnosis, conservative surgical approach and long term results. J Urol 153:1781, 1995. 190.

Leckie BJ, Birnie G, Carachi R: Renin in Wilms' tumor: Prorenin as an indicator. J Clin Endocrinol Metab 79:1742, 1994. 191.

Mantero F, Masini AM, Opocher G, et al: Adrenal incidentaloma: An overview of hormonal data from the National Italian Study Group. Horm Res 47:284, 1997. 192.

Tsushima Y: Different lipid contents between aldosterone-producing and nonhyperfunctioning adrenocortical adenomas: In vivo measurement using chemical-shift magnetic resonance imaging. J Clin Endocrinol Metab 79:1759, 1994. 193.

Kloos RT, Gross MD, Francis IR, et al: Incidentally discovered adrenal masses. Endocr Rev 16:460, 1995. 194.

Lim PO, Rodgers P, Cardale K, et al: Potentially high prevalence of primary aldosteronism in a primary-care population. Lancet 353:40, 1999. 195.

196.

Ganguly A: Primary aldosteronism. N Engl J Med 339:1828, 1998.

Lifton RP, Dluhy RG, Powers M, et al: A chimaeric 11beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 355:262, 1992. 197.

Mulatero P, Veglio F, Pilon C, et al: Diagnosis of glucocorticoid-remediable aldosteronism in primary aldosteronism: Aldosterone response to dexamethasone and long polymerase chain reaction for chimeric gene. J Clin Endocrinol Metab 83:2573, 1998. 198.

199.

Cooper M, Stewart PM: The syndrome of apparent mineralocorticoid excess. Q J Med 91:453, 1998.

Abriel H, Loffing J, Rebhun JF, et al: Defective regulation of the epithelial Na + channel by Nedd4 in Liddle's syndrome. J Clin Invest 103:667, 1999. 200.

Suzuki Y, Nakada T, Izumi T, et al: Primary aldosteronism due to aldosterone producing adenoma without hypertension. J Urol 16:1272, 1999. 201.

Nishimura M, Uzu T, Fujii T, et al: Cardiovascular complications in patients with primary aldosteronism. Am J Kidney Dis 33:261, 1999. 202.

Rossi GP, Rossi E, Pavan E, et al: Screening for primary aldosteronism with a logistic multivariate discriminant analysis. Clin Endocrinol 49:713, 1998. 203.

Weinberger MH, Fineberg NS: The diagnosis of primary aldosteronism and separation of two major subtypes. Arch Intern Med 153:2125, 1993. 204.

205.

Doppman JL, Gill JR Jr: Hyperaldosteronism: Sampling of adrenal veins. Radiology 198:309, 1996.

Proye CA, Mulliez EAR, Bruno M, et al: Essential hypertension: First reason for persistent hypertension after unilateral adrenalectomy for primary aldosteronism? Surgery 124:1128, 1998. 206.

Newell-Price J, Trainer P, Besser M, Grossman A: The diagnosis and differential diagnosis of Cushing's syndrome and pseudo-Cushing's state. Endocr Rev 19:647, 1998. 207.

Sato A, Suzuki H, Murakami M, et al: Glucocorticoid increases angiotensin II type 1 receptor and its gene expression. Hypertension 23:25, 1994. 208.

Montwill J, Igoe D, McKenna T: The overnight dexamethasone test is the procedure of choice in screening for Cushing's syndrome. Steroids 59:296, 1994. 209.

210.

Trainer PJ, Besser M: Cushing's syndrome: Therapy directed at the adrenal glands. Endocrinol

Metab Clin North Am 23:571, 1994. Geley S, Kapelari K, Johrer K, et al: CYP11B1 mutations causing congenital adrenal hyperplasia due to 11beta-hydroxylase deficiency. J Clin Endocrinol Metab 81:2896, 1996. 211.

Hermans C, de Plaen J-F, de Nayer P, Maiter D: Case report: 17 alpha-Hydroxylase/17,20-lase deficiency: A rare cause of endocrine hypertension. Am J Med 312:126, 1996. 212.

Noshiro T, et al: Changes in clinical features and long-term prognosis in patients with pheochromocytoma. Am J Hypertens 13:35, 2000. 212A.

Hoshide S, Kario K, Fuzikawa H, et al: Persistant hypertensive non-dipper triggered by panic disorder. J Hum Hypertens 13:215, 1999. 213.

214.

Whalen RK, Althausen AF, Daniels GH: Extra-adrenal pheochromocytoma. J Urol 147:1, 1992.

Eng C: The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung's disease. N Engl J Med 335:943, 1996. 215.

Karsdorp N, Elderson A, Wittebol-Post D, et al: Von Hippel-Lindau disease: New strategies in early detection and treatment. Am J Med 97:158, 1994. 216.

Cappuccio FP, Allan R, Barron J, et al: Secondary hypertension and clinical genetics: Usual presentation with unusual diagnosis. J Hum Hypertens 13:79, 1999. 217.

Bravo EL: Evolving concepts in the pathophysiology, diagnosis and treatment of pheochromocytoma. Endoc Rev 15:356, 1994. 218.

Ito U, Obara T, Okamoto T, et al: Efficacy of single-voided urine metanephrine and normetanephrine assay for diagnosing pheochromocytoma. World J Surg 22:684, 1998. 219.

Feldman JM: Falsely elevated urinary excretion of catecholamines and metanephrines in patients receiving labetalol therapy. J Clin Pharmacol 27:288, 1987. 220.

Ulchaker JC, Goldfarb DA, Bravo EL, Novick AC: Successful outcomes in pheochromocytoma surgery in the modern era. J Urol 161:764, 1999. 221.

Takeda Y, Miyamori I, Furukawa K, et al: Mechanisms of FK 506-induced hypertension in the rat. Hypertension 33:130, 1999. 222.

Ni Z, Wang XQ, Vaziri ND: Nitric oxide metabolism in erythropoietin-induced hypertension. Hypertension 32:724, 1998. 223.

van Houwelingen KG, van Uffelen R, van Vliet ACM: The sleep apnoea syndromes. Eur Heart J 20:858, 1999. 224.

Ross RD, Clapp SK, Gunther S, et al: Augmented norepinephrine and renin output in response to maximal exercise in hypertensive coarctation patients. Am Heart J 123:1293, 1992. 225.

Stewart AB, Ahmen R, Travill CM, Newman CGH: Coarctation of the aorta--life and health 20-44 years after surgical repair. Br Heart J 69:65, 1993. 226.

de Giovanni JV, Lip GYH, Osman K, et al: Percutaneous balloon dilatation of aortic coarctation in adults. Am J Cardiol 77:435, 1996. 227.

Colao A, Cuocolo A, Marzullo P, et al: Effects of 1-year treatment with octreotide on cardiac performance in patients with acromegaly. J Clin Endocrinol Metab 84:17, 1999. 228.

229.

Saito I, Saruta T: Hypertension in thyroid disorders. Endocrinol Metab Clin North Am 23:379, 1994.

Stefenelli T, Abela C, Frank H, et al: Cardiac abnormalities in patients with primary hyperparathyroidism: Implications for follow-up. J Clin Endocrinol Metab 82: 106, 1997. 230.

Leslie JB: Incidence and aetiology of perioperative hypertension. Acta Anaesthesiol Scand 37(Suppl 99):5, 1993. 231.

Halpern NA, Goldberg M, Neely C, et al: Postoperative hypertension: A multicenter prospective randomized comparison between intravenous nicardipine and sodium nitroprusside. Crit Care Med 20:1637, 1992. 232.

Estafanous FG, Tarazi RC, Buckley S, Taylor PC: Arterial hypertension in immediate postoperative period after valve replacement. Br Heart J 40:718, 1978. 233.

Cockburn JS, Benjamin IS, Thomson RM, Bain WH: Early systemic hypertension after surgical closure of atrial septal defect. J Cardiovasc Surg 16:1, 1975. 234.

Elliott WJ: Traditional drug therapy of hypertension in transplant recipients. J Hum Hypertens 12:845, 1998. 235.

Vanhaecke J, Cleemput JV, Droogne W, et al: Out-patient versus in-hospital ambulatory 24 h blood pressure monitoring in heart transplant recipients. J Hum Hypertens 13:199, 1999. 236.

Saudan P, Brown MA, Buddle ML, Jones M: Does gestational hypertension become pre-eclampsia? Br J Obstet Gynaecol 105:1177, 1998. 237.

Sibai BM, Lindheimer M, Hauth J, et al: Risk factors for preeclampsia, abruptio placentae, and adverse neonatal outcomes among women with chronic hypertension. N Engl J Med 339:667, 1998. 238.

Ness RB, Roberts JM: Heterogeneous causes constituting the single syndrome of preeclampsia. Am J Obstet Gynecol 175:1365, 1996. 239.

Roggensack AM, Zhang Y, Davidge ST: Evidence for peroxynitrite formation in the vasculature of women with preeclampsia. Hypertension 33:83, 1999. 240.

Ihle BU, Long P, Oats J: Early onset pre-eclampsia: Recognition of underlying renal disease. BMJ 294:79, 1987. 241.

Roberts JM, Redman CWG: Pre-eclampsia: More than pregnancy-induced hypertension. Lancet 341:1447, 1993. 242.

243.

Duley L: Aspirin for preventing and treating pre-eclampsia. BMJ 318:751, 1999.

Levine RJ, Hauth JC, Curet LB, et al: Trial of calcium to prevent preeclampsia. N Engl J Med 337:69, 1997. 244.

245.

Redman CWG, Roberts JM: Management of pre-eclampsia. Lancet 34: 1451, 1993.

246.

Sibai BM: Treatment of hypertension in pregnant women. N Engl J Med 335:257, 1996.

Coetzee EJ, Dommisse J, Anthony J: A randomised controlled trial of intravenous magnesium sulphate versus placebo in the management of women with severe pre-eclampsia. Br J Obstet Gynaecol 105:300, 1998. 247.

Chesley LC: Hypertension in pregnancy: Definitions, familial factor, and remote prognosis. Kidney Int 18:234, 1980. 248.

Nisell H, Lintu H, Lunell NO, et al: Blood pressure and renal function seven years after pregnancy complicated by hypertension. Br J Obstet Gynaecol 102:870, 1995. 249.

250.

Lampert MB, Lang RM: Peripartum cardiomyopathy. Am Heart J 130:860, 1995.

HYPERTENSIVE CRISES Lip GYH, Beevers M, Beevers G: The failure of malignant hypertension to decline. A survey of 24 years' experience in a multiracial population in England. J Hypertens 12:1297, 1994. 251.

Strandgaard S, Paulson OB: Cerebral blood flow and its pathophysiology in hypertension. Am J Hypertens 2:486, 1989. 252.

253.

Kaplan NM: Management of hypertensive emergencies. Lancet 344:1335, 1994.

254.

Alberts MJ: Diagnosis and treatment of ischemic stroke. Am J Med 106:211, 1999.




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Chapter 29 - Systemic Hypertension: Therapy NORMAN M. KAPLAN

As noted at the beginning of Chapter 28 , the number of patients being treated for hypertension has expanded markedly during the past 25 years so that it is now the leading reason for office visits to physicians. Nonetheless, in various developed countries--from the United Kingdom and Canada, which have national health schemes that cover everyone, to the United States, with its sporadic coverage--only 15 to 30 percent of hypertensive patients have their disease under good control. [1] This apparent paradox of expanded coverage but continued poor control is not the consequence of either the ineffectiveness of available therapy or an unwillingness of physicians to provide it. In controlled trials, most patients with the most prevalent form of hypertension, previously called "mild" but now referred to as grade 1, i.e., diastolic blood pressure (DBP) between 90 and 100 mm Hg, achieve excellent control with one of many drugs.[2] Relatively few patients are truly resistant to therapy.[3] The problem derives from the inherent nature of hypertension: induced by common but unhealthy life styles, asymptomatic and persistent, with overt consequences delayed by 10 to 30 years so that the costs of therapy, both in money and in adverse effects, seem on the surface to outweigh benefits to be derived from adherence to the regimen. Furthermore, behind the inherent nature of the disease that often interferes with

patients' adherence to their physician's requests, there lurks yet another disquieting feature of the therapy of most hypertension: It may not benefit the majority of patients who adhere faithfully to their treatment. [4] Even among such elderly patients as enrolled in the Systolic Hypertension in the Elderly Program (SHEP) trial, 111 would need to be treated for 5 years to prevent one cardiovascular death and 19 treated to prevent one cardiovascular event.[5] Because of the costs and side effects of therapy, caution is needed in the use of medication as a preventive measure.[6] Yet another element, the issue of cost-effectiveness, has been introduced into the debate about the value of treating all patients with any degree of hypertension.[7] As the escalating costs of health care consume a greater share of society's resources, two opposing forces have risen: one, the need for less expensive illness care, and the other, the relatively large cost of prevention when indiscriminately applied to low-risk subjects. Therefore, it is likely that the calls for more selective and targeted antihypertensive therapy will be more widely listened to in the future. We examine the evidence for benefits of therapy and then apply this evidence to the criteria for the initiation of therapy for individual patients. BENEFITS OF THERAPY The treatment of hypertension is aimed not at simple reduction of blood pressure but at prevention of the cardiovascular complications that are known to accompany the high pressure. During the past 30 years, many randomized, controlled trials (RCTs) have tested the ability of antihypertensive drugs--primarily diuretics and adrenergic inhibitors--to prevent strokes and heart attacks. Although such RCTs have limited ability to aid in clinical decisions about individual patients,[8] few other aspects of clinical practice have as strong an evidence base as does the treatment of hypertension. A series of meta-analyses have portrayed the effects of therapy in a progressively enlarging number of completed trials.[9] [10] [11] They have shown a uniform and persistent reduction in morbidity and mortality from stroke averaging 40 percent, a reduction that exactly fits what was predicted from epidemiological evidence if the attributable risk had been completely reversed.[12] On the other hand, the impact on coronary artery disease reported in 1990 was only 14 percent,[9] below the 20 to 25 percent predicted if the risk attributed to blood pressure had been completely reversed. [12] By 1997, however, data from three reported trials enrolling elderly patients[5] [13] [14] brought the overall impact on coronary events to a 16 percent reduction, with confidence limits of 8 to 23 percent, which overlap the excess 20 to 25 percent risk predicted from epidemiological evidence (Fig. 29-1) . The protection against stroke has been shown to apply even to patients older than 80 years.[11] In the six trials that included 1670 patients older than 80 years, the half who were treated with either diuretics or dihydropyridine calcium antagonists had a 36 percent reduction in stroke, a 39 percent reduction in heart failure, and a statistically significant 22 percent reduction in major coronary events. [11] The explanation for the progressively better results in the RCTs likely reflects the inclusion of higher-risk subjects. As shown in Figure 29-2 , absolute benefit in stroke prevention is progressively greater, the higher the stroke rate event in the placebo

group.[15] In a like manner, benefits of treatment were first documented for patients with severe hypertension,[16] then for those with moderate disease, and only later for those with lesser degrees of hypertension.[17] The difficulty in showing clear benefits of treatment in the larger part of the hypertensive population, those with stage 1 or blood pressures from 140/90 to 160/100 mm Hg (see Table 28-2) must be reconciled with the fact that even though their individual risk is relatively low, their sheer

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Figure 29-1 Meta-analysis of randomized, placebo-controlled clinical trials in hypertension according to first-line treatment strategy. Trials indicate number of trials with at least one endpoint of interest. For these comparisons, the numbers of participants randomized to active treatment and placebo, respectively, were 7768 and 12,075 for high-dose diuretic therapy, 4305 and 5116 for low-dose diuretic therapy, and 6736 and 12,147 for beta-blocker therapy. Because the Medical Research Council trials included two active arms, the placebo group is included twice in these totals (for diuretic comparison and for beta-blocker comparison). The total numbers of participants randomized to active and control therapy were 24,294 and 23,926, respectively. RR = relative risk; CI = confidence interval; HDFP = Hypertension Detection and Follow-up Program. (Data from Psaty BM, Smith NL, Siscovick DS, et al: Health outcomes associated with antihypertensive therapies used as first-line agents. JAMA 277:739, 1997.)

number causes them to make a major contribution to the overall population risk from hypertension, as shown in Figure 28-2 . This fact has given rise to two important guidelines for clinical practice: first, the critical need for prevention of hypertension by population-wide life style modifications[18] ; second, the rationale for considering blood pressure in the larger context of overall cardiovascular risk. THRESHOLD FOR THERAPY The value of life style modifications is documented in the next section of this chapter. The rationale for a broader look at risk beyond blood pressure was first formalized by a group of investigators from New Zealand[19] and has now been incorporated into both the 1997 report of the U.S. Joint National Committee (JNC-6)[20] and the 1999 World Health Organization-International Society of Hypertension (WHO-ISH) guidelines.[1] The basis for risk assessment and stratification provided in JNC-6 are shown in Tables 28-8 and 28-9 ( pp. 950 , 951 ). The somewhat more detailed list of factors influencing risk in the 1999 WHO-ISH report is shown in Table 29-1 . The stratification in both reports is similar, with a fourth "very high" risk group having associated clinical conditions added in the WHO-ISH report, as are the recommendations for management: Low-risk patients with blood pressures as high as 159/99 mm Hg should be given life style modification; high-risk patients with blood pressures as low as 130/85 mm Hg should be immediately started on drug therapy (see Table 28-9) . The WHO-ISH report provides additional data on the absolute effects of treatment on cardiovascular risk (Table 29-2) . As shown, relatively small benefits have been seen in RCTs of about 5 years' duration in low-risk patients, although with more intensive therapy to lower blood pressure by 20/10 mm Hg,

they too can achieve more impressive protection. All in all, these recommendations have placed the decision to treat individual patients with different levels of blood pressure and degrees of overall cardiovascular risk into a much more rational framework. Lest practitioners be concerned about the recommendation to withhold drug therapy from low-risk patients with blood pressure as high as 159/99 mm Hg, recall the experience of the placebo-treated half of the patients in the Australian trial[21] : Over 4 years, the average DBP fell below 95 mm Hg in 47.5 percent of patients with baseline DBP of 95 to 109 mm Hg, and increased morbidity and mortality were seen only in those whose average DBP remained above 100 mm Hg. If drug therapy is not given, close surveillance of all patients must be provided, because from 10 to 17 percent of the placebo-treated patients in various trials had progression of their blood pressure to a level above that considered an indication for active treatment. Moreover, all patients should be strongly advised to use the appropriate life style modifications described beginning on page 975 . Systolic Pressure in the Elderly

The New Zealand recommendations are that therapy be given to the elderly at lower levels of pressure because they "generally have a higher absolute risk of cardiovascular disease and therefore derive greater benefit from treatment."[19] The elderly achieved even greater protection from coronary disease in three trials. Furthermore, protection from congestive heart failure was even more impressive, therapy reducing the incidence by over 50 percent.[5] [13] Moreover,

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TABLE 29-1 -- FACTORS INFLUENCING PROGNOSIS Risk Factors for Target-Organ Damage Associated Clinical Cardiovascular Conditions Diseases

Used for Risk Stratification Levels of systolic and diastolic blood pressure (grades 1-3) Men >55 yr Women >65 yr Smoking Total cholesterol level >6.5 mol/liter (250 mg/dl) Diabetes Family history of premature cardiovascular diseaes

Left ventricular hypertrophy (electrocardiogram, echocardiogram, or radiograph) Proteinuria and/or slight elevation of plasma creatinine concentration (1.2-2.0 mg/dl) Ultrasound or radiological evidence of atherosclerotic plaque (carotid, ilac, and femoral arteries, aorta) Generalized or focal narrowing of the retinal arteries

Cerebrovascular disease Ischemic stroke Cerebral hemorrhage Transient ischemic attack Heart disease Myocardial infarction Angina Coronary revascularization Congestive heart failure Renal disease Diabetic nephropathy Renal failure (plasma creatinine concentration >2.0 mg/dl) Vascular disease Dissecting aneurysm Symptomatic arterial disease Advanced hypertensive retinopathy Hemorrhages or exudates Papilledema

Other Factors Adversely Influencing Prognosis Reduced high-density lipoprotein cholesterol Raised low-density lipoprotein cholesterol Microalbuminuria in diabetes Impaired glucose intolerance Obesity Sedentary life style Raised fibrinogen level High-risk socioeconomic group High-risk ethnic group High-risk geographical region From Guidelines Subcommittee: 1999 World Health Organization-International Society of Hypertension guidelines for the management of hypertension. J Hypertens 17:151-183, 1999.

Figure 29-2 Comparison of proportionate or relative (top) and absolute (bottom) benefit from reduction in the incidence of stroke in the six trials in the elderly, as well as in one other with similar design but in which the absolute risk of stroke was much lower. Event rates are for fatal and nonfatal stroke combined. Aust = Australian study; EWPHE = European Working Party on High Blood Pressure in the Elderly trial;

Coope = Cooper and Warrender; MRC = Medical Research Council trials; SHEP = Systolic Hypertension in the Elderly Program trial; STOP = Swedish Trial in Old Patients with Hypertension. (From Lever AF, Ramsay LE: Treatment of hypertension in the elderly. J Hypertens 13:571-579, 1995.)

TABLE 29-2 -- ABSOLUTE EFFECTS OF TREATMENT ON CARDIOVASCULAR RISK From the results of randomized, controlled trials, it appears that each reduction of 10 to 14 mm Hg in systolic blood pressure and 5 to 6 mm Hg in diastolic blood pressure confers about two-fifths less stroke, one-sixth less coronary heart disease, and, in Western populations, one-third fewer major cardiovascular events overall. In patients with grade I hypertension, monotherapy with most agents produces reductions in blood pressure of about 10/5 mm Hg. In patients with higher grades of hypertension, it is possible to achieve sustained blood pressure reductions of 20/10 mm Hg or more, particularly if combination drug therapy is used. The estimated absolute effects of such blood pressure reductions on cardiovascular disease (CVD) risk (fatal plus nonfatal stroke or myocardial infarction) are as follows: Absolute Treatment Effects (CVD Events Prevented per 1000 Patients-Years) Patient Group

Absolute Risk (CVD Events over 10yr)(%)

10/5 mm Hg

20/10 mm Hg

Low risk

17

Between these strata, the estimated absolute treatment benefits range from less than five events prevented per thousand patient-years of treatment (low risk) to more than 17 events prevented per thousand patient-years of treatment (very high risk). The absolute benefits for stroke and coronary artery disease will be augmented by smaller absolute benefits for congestive heart failure and renal disease. These estimates of benefit are based on relative risk reductions observed in trials of about 5 years' duration. Longer-term treatment over decades could produce larger risk reductions. From Guidelines Subcommittee: 1999 World Health Organization-International Society of Hypertension guidelines for the management of hypertension. J Hyperten 17:151, 1999.

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not included in Figure 29-1 are the results of the Syst-Eur trial, in which a long-acting dihydropyridine calcium antagonist, nitrendipine, was found to provide significant reductions in stroke and coronary events[22] and dementia[23] and particularly impressive protection against all endpoints among the diabetic patients enrolled in the trial.[24] Similar protection against stroke and coronary mortality has been shown in a similar trial of elderly Chinese with systolic hypertension.[25] Based on the four trials in the elderly patients with pure systolic hypertension, the need to consider systolic levels in the decision to treat is obvious. In fact, the difference between the typically elevated systolic levels and the usually lower diastolic levels, i.e., a widened pulse pressure in the elderly is most predictive of future cardiovascular risk.[26] USE OF SURROGATE ENDPOINTS.

All of the preceding discourse on the benefits of therapy and the threshold for treatment has involved "hard" endpoints: morbidity and mortality. Some argue that softer endpoints should also be taken into account, using as surrogates one or another sign of cardiovascular damage that may be easier to assess and quicker to appear. These include regression of left ventricular hypertrophy or carotid artery stenosis and reduction of proteinuria. Most, however, hold to the need for the hard endpoints. GOAL OF THERAPY Once having decided to treat, the clinician must consider the goal of therapy. In the past, most physicians assumed that the effects of reduction of blood pressure on cardiovascular risk would fit a straight line downward (line A in Fig. 29-3) , [27] justifying the opinion "the lower, the better." However, as noted, data from large trials indicated a more gradual decline in risk when pressures were reduced to moderate levels (line B in Fig. 29-3) , DBP approximately 95 mm Hg in the IPPPSH trial.[28] Subsequently, Cruickshank[29] called attention to a J curve (line C in Fig. 29-3) , reflecting a progressive fall in risk as pressure is lowered, but only to a certain level; below that level, the risk for coronary ischemic events rises again. Additional evidence for the J curve has been added to the six retrospective studies analyzed by Cruickshank, including two prospective studies of sizable numbers of patients.[30] [31] The apparent propensity to induce myocardial ischemia when pressures are lowered below a certain critical threshold may not apply to other vital organs. Therefore, maximal protection against stroke or renal damage may require greater reductions in pressure than the coronary circulation can safely handle. Because the presence of a J curve could reflect lower blood pressures as a consequence of coronary disease rather than a cause, the Hypertension Optimal Treatment (HOT) trial was performed.[32] Almost 19,000 patients with initial mean blood pressure of 170/105 mm Hg were randomly allocated to one of three target diastolic pressures: 90, 85, or 80 mm Hg. Treatment was based on a long-acting dihydropyridine

calcium antagonist, felodipine, with additional drugs added to achieve the desired goal. Diastolic pressures were significantly reduced by more than 20 mm Hg in all three groups, but at the end, only 4 mm Hg separated them, so it was not possible to prove or disprove a J curve. The least cardiovascular mortality was seen at a blood pressure of 139/86 mm Hg; the least morbidity, at 138/83 mm Hg (Fig. 29-4) . In the absence of a placebo group, the absolute degree of protection could not be ascertained, but most of the benefit was noted in the 1500 diabetic patients who had a 51 percent reduction in major cardiovascular events in those in the below 80 mm Hg target group compared with the below 90 mm Hg target group. Even though a J curve is suggested in the left portion of the lowest panel, the major positive result of this massive trial is that the safest blood pressure for most patients is less than 140/85 mm Hg, a level that only a small minority of patients are now achieving. As noted in JNC-6 and WHO-ISH guidelines, the goal must be less than 140/90 mm Hg for most patients, including the elderly, and less than 130/85 mm Hg for those at high risk, including all diabetic persons.

Figure 29-3 Three models representing hypothetical relationships between levels of blood pressure and risk of cardiovascular disease. (From Epstein FH: Proceedings of the XVth International Congress of Therapeutics, September 5-9, 1979. Brussels, Excerpta Medica, 1980.)

Even though the current guidelines have clarified the questions of whom to treat with drugs for mild hypertension and how much the pressure should be reduced, each patient must be considered separately, taking various factors into account. The foregoing discussion should indicate the wisdom of withholding drug therapy from many of these patients, at least until the effects of time and life style modifications have been given a chance, thereby avoiding too fast and too great reductions in pressure. Once good control of blood pressure in a patient has been achieved, it may be possible to reduce or withdraw drug therapy. Perhaps one fourth of patients who have initially mild hypertension and who achieve good control with therapy will remain normotensive for at least 1 year after their therapy is stopped. [33] However, such patients need to remain under observation. LIFE STYLE MODIFICATIONS Interest in the use of various nondrug therapies, better called life style modifications, for the treatment of hypertension has risen markedly in the past few years, yet many practitioners either do not use them or use them in a casual, perfunctory manner. This hesitant attitude can be attributed both to the sparseness of firm evidence indicating that these therapies succeed and to the difficulty many have faced in convincing patients to adhere to them. This situation is likely to change: Evidence for the effectiveness of these approaches in lowering blood pressure is growing,[34] [35] techniques for improving adherence are being popularized, and patients seem increasingly willing to adopt changes in life style. These changes come at a propitious time, when many more individuals are being identified as hypertensive and are considered in need of lowering

of

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Figure 29-4 Estimated incidence with 95 percent confidence intervals of cardiovascular events (top three panels) and mortality (bottom panel) blood pressure in the 18,790 hypertensive patients treated in the Hypertension Optimal Treatment (HOT) trial. (From Hansson L, Zanchetti A, Carruthers SG, et al: Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment [HOT] randomised trial. Lancet 351:1755, 1998.)

blood pressure. Although most have turned first to drugs, the evidence presented in the previous section suggests that these can be safely withheld from many hypertensive individuals to allow life style modifications a chance to be effective. The need for strong and immediately effective therapy was clear when the majority of patients had fairly severe hypertension; however, as a larger number of patients with mild hypertension have entered the picture, a more gradual approach to their treatment seems more appropriate. In addition, increasing awareness of the need to address other risk factors, such as dyslipidemia and glucose intolerance, along with hypertension has given additional emphasis to the value of life style modifications that can favorably affect them as well. Just as the increased awareness of the problem of patients' frequent poor adherence to drug therapy has led to attempts to improve the situation, similar attention toward adherence to life style modifications is likely to improve their effectiveness. These measures should be introduced gradually and gently. Too many and too drastic changes in life style may discourage patients from accepting them. Eventually, however, all hypertensive patients should benefit from moderate restriction of dietary salt, reduction of excess body weight, regular exercise, and moderation of alcohol intake.[20] The ability of these life style modifications to prevent hypertension has not been documented, although fewer subjects with high-normal pressures proceed into hypertension over 3 to 7 years while they practice these modalities.[36] [37] Because hypertension slowly develops over 20 to 40 years and normotensive persons have little if any decline in blood pressure even with potent antihypertensive drugs, the failure to lower blood pressure or prevent hypertension in a few years should not be taken as proof that these life style changes will not work over longer intervals. AVOIDANCE OF TOBACCO.

The major pressor effect of tobacco is easily missed because patients are not allowed to smoke in places where blood pressures are recorded. With automatic monitoring, the effect is easy to demonstrate [38] (Fig. 29-5) , and blood pressure immediately falls when smokers quit.[39] Patients who smoke or dip snuff should be strongly and repeatedly told to stop. Failing that, they should be advised to monitor their blood pressure while they smoke because such pressures are at least partially responsible for increased risks for

cardiovascular disease and should be the target of antihypertensive therapy. WEIGHT REDUCTION.

Relatively small increases in body weight increase the incidence of hypertension,[40] and even small decreases in excess weight lower blood pressure.[34] In a review of adequately controlled intervention studies, a

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Figure 29-5 Changes in systolic blood pressure (SBP) over 15 minutes after smoking the first cigarette of the day within the first 5 minutes (solid circles), during no activity (open-circles), and during sham smoking (triangles) in normotensive smokers. (From Groppelli A, Giorgi DMA, Omboni S, et al: Blood pressure and heart rate response to repeated smoking before and after beta blockade and selective alpha 1 -inhibition. J Hypertens 10:495, 1992.)

1.0-kg decrease in body weight was accompanied by an average reduction of 1.6/1.3 mm Hg in blood pressure.[41] The fall in blood pressure may reflect many effects including improvements in insulin sensitivity, amelioration of sleep apnea, and decreased sensitivity to sodium. Although the rate of recidivism among obese persons is high, an attempt at weight reduction in all obese hypertensive patients should be made, using whatever level of caloric restriction a patient is able to maintain. DIETARY SODIUM RESTRICTION.

On page 952 , evidence incriminating the typically high sodium content of the diet of persons living in developed, industrialized societies was presented as a cause of hypertension. Once hypertension is present, modest salt restriction may help lower the blood pressure. In a review by Cutler and colleagues of 32 well-controlled intervention studies in which daily intake (based on urinary sodium excretion) was reduced by a median of 77 mmol/24 hr, blood pressures fell an average of 4.8/2.5 mm Hg in the hypertensive individual.[42] There is probably a dose-response relation--the more sodium reduction, the greater the blood pressure decline. In a small but well-controlled study, the reduction in blood pressure was shown to be 8/5 mm Hg on a daily sodium intake of 100 mmol and 16/9 mm Hg on a 50 mmol/day intake.[43] However, rigid degrees of sodium restriction are not only difficult for patients to achieve but may also be counterproductive.[44] The marked stimulation of renin-aldosterone and sympathetic nervous activity that accompanies rigid sodium restriction may prevent the blood pressure from falling and increase the amount of potassium wastage if diuretics are concomitantly used. Not all hypertensive persons respond to a moderate degree of sodium restriction to the recommended level of 100 mmol sodium, or 2.4 gm/day. Blacks and elderly patients may be more responsive to sodium restriction, perhaps

because of their lower renin responsiveness. Even if the blood pressure does not fall with moderate degrees of sodium restriction, patients may still benefit: improved beta-adrenergic responsiveness.[45] Increased antihypertensive effectiveness of other drugs[46] less diuretic-induced potassium wastage, and reduction in left ventricular hypertrophy[47] all have been reported among patients on moderate sodium restriction. Although there is no certainty that moderate sodium restriction will help, the little evidence suggesting that it will hurt[48] has been shown to be invalid.[49] In overweight persons, a lower sodium intake was associated with a reduced risk of cardiovascular disease.[49] Therefore, I consider sodium restriction to be useful for all persons, as a preventive measure in those who are normotensive and, more certainly, as partial therapy in those who are hypertensive. The easiest way to accomplish moderate sodium restriction is to substitute natural foods for processed foods, because natural foods are low in sodium and high in potassium whereas most processed foods have had sodium added and potassium removed. It is hoped that food processors will gradually reduce the large amounts of salt they often add to processed foods, but in the meantime, patients should be asked to avoid those foods whose label indicates more than 300 mg of sodium per portion. Additional guidelines include the following: 1. Add no sodium chloride to food during cooking or at the table. 2. If a salty taste is desired, use a half sodium and half potassium chloride preparation (such as Lite Salt) or a pure potassium chloride substitute. 3. Avoid or minimize the use of "fast foods," many of which have high sodium content. 4. Recognize the sodium content of some antacids and proprietary medications. (For example, Alka-Seltzer contains more than 500 mg of sodium; Rolaids is virtually sodium free.) POTASSIUM SUPPLEMENTATION.

Some of the advantages of a lower sodium intake may relate to its tendency to increase body potassium content, both by a coincidental increase in dietary potassium intake and by a decrease in potassium wastage if diuretics are being used. Potassium deficiency exerts many effects that may increase blood pressure, and potassium infusions increase the vasodilating effect of acetylcholine, apparently through the nitric oxide pathway.[50] Potassium supplements have been shown to reduce the blood pressure an average of 3.1/2.0 mm Hg in 33 RCTs published before July 1995.[51] Nonetheless, potassium supplements are too costly and potentially hazardous for routine use in normolcalemic hypertensive persons. Patients should be protected from potassium depletion and encouraged to increase dietary potassium intake, which may be enough to lower blood pressure. MAGNESIUM SUPPLEMENTATION.

Only a few controlled trials find an effect on blood pressure with magnesium

supplements.[52] However, those who are magnesium depleted may not be able to replete concomitant potassium deficiency.[53] CALCIUM SUPPLEMENTATION.

An increase in free calcium concentration in vascular smooth muscle cells may be a final step in the pathogenesis of primary hypertension. Nonetheless, some hypertensive patients have a lower calcium intake and higher urinary calcium excretion than do normotensive persons.[54] In 42 mostly short-term studies of either calcium supplements (in 33) or dietary intervention (in 9) in 4560 nonpregnant adults, the blood pressure fell 1.44/0.84 mm Hg.[55] Because calcium supplements sometimes raise blood pressure and increase the risk of kidney stones, the best course is to ensure that calcium intake is not inadvertently reduced by reduction of milk and cheese consumption in an attempt to reduce saturated fat and sodium intake when supplemental calcium is not taken. OTHER DIETARY CHANGES.

Significant reductions in blood pressure were observed in hypertensive persons who ate a diet rich in fruits and vegetables, an effect that was further accentuated when low-fat dairy foods were substituted for high-fat foods.[35] The effect was greater in hypertensive than in normotensive persons and in blacks than in whites. This fall in blood pressure, accomplished without change in sodium or caloric intake, could reflect increases in fiber, potassium, or other ingredients. Some lowering of the blood pressure has been noted in studies of a lacto-ovo-vegetarian diet,[56] high fiber intake,[57] and high doses of omega-3 fatty acids from fish oil.[58] Consumption of dried garlic powder lowered diastolic pressure in four of seven trials compared with placebo.[59] In 11 carefully controlled trials involving 522 subjects who consumed an average of 5 cups of caffeine-containing coffee, the mean blood pressure rose 2.4/1.2 mm Hg.[60] An even greater effect was noted in elderly hypertensive individuals.[61] Even though consumption of tea has been found to be associated with a lower risk of myocardial infarction,[62] it too may raise blood pressure.[63] MODERATION OF ALCOHOL.

Moderate alcohol consumption, less than 1 oz of ethanol per day, does not increase the prevalence of hypertension. Heavier drinking clearly exerts a pressor effect that makes alcohol abuse the most common cause of reversible hypertension.[64] One to two portions of alcohol-containing beverages a day, containing 0.5 to 1.0 oz of ethanol, need not be prohibited, particularly because fewer coronary events[65] and strokes[66] have been noted in those who consume that amount. PHYSICAL EXERCISE.

Although the systolic pressure rises considerably during dynamic (aerobic) exercise, vascular compliance increases[67] and resting blood pressure usually falls[68] in hypertensive persons after regular exercise programs. Even in obese individuals,

cardiorespiratory fitness is associated with lower cardiovascular disease mortality.[69] Although pure static exercise acutely raises both systolic and diastolic pressures, repetitive circuit weight training also lowers blood pressure.[70] RELAXATION TECHNIQUES.

A review of 26 reports of various forms of relaxation--transcendental meditation, yoga, biofeedback, psychotherapy--reports that they were no more effective in lowering blood pressure than were sham controls.[71]

978

COMBINED THERAPIES

When several life style modifications are combined, additional antihypertensive effects may accrue. The best study is the placebo arm of the Treatment of Mild Hypertension Study (TOMHS),[2] in which 234 mildly hypertensive persons followed a 48-month regimen of moderate sodium restriction, weight loss, regular exercise, and moderation of alcohol use. Despite relatively small changes in weight (average loss of 6.6 lbs), sodium intake (reduction of 10 percent), exercise level, and alcohol consumption, these patients had an 8.6/8.6 mm Hg decline in blood pressure at the end of the 4-year program. Moreover, they experienced improvements in lipid profile and reduction in left ventricular mass. THE POTENTIAL OF LIFE STYLE MODIFICATIONS

Part of the antihypertensive effect reported in this and other trials of life style modification may be attributable to the nonspecific reduction in blood pressure so often noted when repeated readings are taken. Such decreases may reflect a statistical regression toward the mean, a placebo effect, or relief of anxiety and stress with time. The same phenomenon is probably also responsible for much of the initial response to drug therapy, so that success may be attributed to both drugs and nondrugs when it is deserved by neither. Nonetheless, increasingly long and strong evidence from controlled studies attests to the efficacy of multifaceted nondrug programs to reduce the blood pressure. Whether such success can be achieved by individual practitioners is uncertain. However, because help is available, including various educational materials for patients, professional assistants such as dietitians and psychologists, and groups organized for weight reduction, exercise, and relaxation therapies, the effort seems both increasingly easy and likely to be successful in lowering blood pressure. ANTIHYPERTENSIVE DRUG THERAPY If the life style modifications just described are not followed or prove to be ineffective, or

if the level of hypertension at the onset is so high that immediate drug therapy is deemed necessary, the general guidelines listed in Table 29-3 should be helpful in improving patients' adherence to lifelong treatment. General Guidelines

The guidelines listed in Table 29-3 are all aimed at providing effective 24-hour control of hypertension in a manner that encourages adherence to the regimen. The approach is based on known pharmacological principles and proven ways to improve adherence. It is designed for the 90 percent of patients with fairly mild hypertension, in whom a gradual approach is feasible. Once the selection of the most appropriate agent for initial therapy has been made (by a process that is discussed further in the next section), a relatively low dose of a single drug should be started, aiming for a reduction of 5 to 10 mm Hg in blood pressure at each step. Many physicians, by nature and training, desire to control a patient's hypertension rapidly and completely. Regardless of which drugs are used, this approach often leads to undue fatigue, TABLE 29-3 -- GENERAL GUIDELINES TO IMPROVE PATIENTS' ADHERENCE TO ANTIHYPERTENSIVE THERAPY 1. Be aware of the problem of nonadherence and be alert to signs of patients' nonadherence. 2. Establish the goal of therapy: to reduce blood pressure to normotensive levels with minimal or no side effects. 3. Educate the patient about the disease and its treatment. a. Involve the patient in decision-making. b. Encourage family support. 4. Maintain contact with the patient. a. Encourage visits and calls to allied health personnel. b. Allow the pharmacist to monitor therapy. c. Give feedback to the patient via home blood pressure readings. d. Make contact with patients who do not return. 5. Keep care inexpensive and simple. a. Do the least work-up needed to rule out secondary causes. b. Obtain follow-up laboratory data only yearly unless indicated more often. c. Use home blood pressure readings. d. Use nondrug, no-cost therapies. e. Use the fewest daily doses of drugs needed. f. If appropriate, use combination tablets. g. Tailor medication to daily routines. 6. Prescribe according to pharmacological principles.

a. Add one drug at a time. b. Start with small doses, aiming for 5 to 10 mm Hg reductions at each step. c. Prevent volume overload with adequate diuretic and sodium restriction. d. Take medication immediately on awakening or after 4A.M. if patient awakens to void. e. Ensure 24-hour effectiveness by home or ambulatory monitoring. f. Continue to add effective and tolerated drugs, stepwise, in sufficient doses to achieve the goal of therapy. g. Be willing to stop unsuccessful therapy and try a different approach. h. Adjust therapy to ameliorate side effects that do not spontaneously disappear. From Kaplan NM: Clinical Hypertension. 7th ed. Baltimore, Williams & Wilkins, 1998, p 188. weakness, and postural dizziness, which many patients find intolerable, particularly when they felt well before therapy was begun. Although hypokalemia and other electrolyte abnormalities may be responsible for some of these symptoms, a more likely explanation has been provided by the studies of Strandgaard and Haunso.[72] As shown in Figure 29-6 , they demonstrated the constancy of cerebral blood flow by autoregulation over a range of mean arterial pressures from about 60 to 120 mm Hg in normal subjects and from 110 to 180 mm Hg in patients with hypertension. This shift to the right protects hypertensive patients from a surge of blood flow, which could cause cerebral edema. However, the shift also predisposes hypertensive patients to cerebral ischemia when blood pressure is lowered.

Figure 29-6 Mean cerebral blood flow autoregulation curves from normotensive, severely hypertensive, and effectively treated hypertensive patients are shown. (Modified from Strandgaard [Circulation 53:720, 1976.] From Strandgaard S, HaunsO S: Why does antihypertensive treatment prevent stroke but not myocardial infarction? Lancet 2:658, 1987. © by the Lancet Ltd.)

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Figure 29-7 Theoretical therapeutic and toxic logarithmic-linear dose-response curves. The horizontal axis is a logarithmic scale with arbitrary dose units. The vertical axis is a linear scale showing percentage of maximum possible response. See text for discussion. (From Fagan TC: Remembering the lessons of basic pharmacology. Arch Intern Med 154:1430, 1994. Copyright 1994 American Medical Association.)

The lower limit of autoregulation necessary to preserve a constant cerebral blood flow in hypertensive patients is a mean of about 110 mm Hg. Thus, acutely lowering the pressure from 160/110 mm Hg (mean=127) to 140/85 mm Hg (mean=102) may induce cerebral hypoperfusion, although hypotension in the accepted sense has not been produced. This provides an explanation for what many patients experience at the start of antihypertensive therapy, i.e., manifestations of cerebral hypoperfusion, even though

blood pressure levels do not seem inordinately low. Thus, the approach to antihypertensive therapy should be gradual in order to avoid symptoms related to overly aggressive blood pressure reduction. Fortunately, as shown in the middle of Figure 29-6 , if therapy is continued for a period, the curve of cerebral autoregulation shifts back toward normal, allowing patients to tolerate greater reductions in blood pressure without experiencing symptoms. STARTING DOSAGES.

The need to start with a fairly small dose also reflects a greater responsiveness of some patients to doses of medication that may be appropriate for the majority. All drugs exert increasing effect with increasing doses, portrayed by a log-linear dose-response curve[73] (Fig. 29-7) . However, different patients require different absolute amounts of drug for their own dose response. As a hypothetical example, for the majority of patients, 50 mg of the beta blocker atenolol would provide a moderate response, shown as point A on the therapeutic effect curve, whereas a dose of 25 mg would provide only a minimal response. At dose A, providing the significant albeit partial response, the side effects would be minimal, as shown by point A on the curve of toxic effect. If a starting dose of 100 mg were used, the therapeutic effect would be near maximal (point B) but the side effects would be much greater as well (point B ). Therefore, a lower starting dose is preferable for most patients. However, the response to a given dose is not the same for all patients but rather assumes a bell-shaped curve; some patients are very sensitive to that dose and some very resistant, the majority having a moderate response. Therefore, a significant minority of patients--the very sensitive ones--would obtain a near-maximal response to the 25-mg dose and would better be started on 12.5 mg in order to achieve a moderate therapeutic effect (point A) with minimal side effects (point A ). Without knowing how individual patients will respond, the safest and easiest approach is to start at a dose that probably is not enough for most patients. The situation was well described by Herxheimer.[74] "For a new drug to penetrate the market quickly, it should be rapidly effective in a high proportion of patients and simple to use. To achieve this, the dosage of the first prescription is therefore commonly set at about the ED90 level, i.e., the dose which the early clinical (phase 2) studies have been shown to be effective in 90 percent of the target population, provided that the unwanted effects at this dose are considered acceptable. In 25 percent of patients, a smaller--perhaps much smaller--dose (the ED25 ) will be effective. The patients in this quartile are the most sensitive to the drug and are liable to receive far more than they need if they are given the ED90 . They are also likely to be more sensitive to the dose-related side effects of the drug." As I have written,[75] Herxheimer goes on to recommend a logical solution: Starting

doses should be less than the usual maximal effective dose. For this to be effective, however, physicians must be willing to start most patients with a dose of medication that will not be fully effective. As he states, "The disadvantage from the marketing standpoint is that for the majority of patients the dose must be titrated. That is time-consuming for doctors and patients and more difficult to explain to them. A drug requiring dose titration cannot be presented as the 'quick fix', the instant good news that marketing departments love." [74] The quick fix is inappropriate for most hypertensive patients. To allow for autoregulation of blood flow to maintain perfusion to vital organs when perfusion pressure is lowered, the decline in pressure should be relatively small and gradual.[75] More precipitous reductions in pressure, as frequently occur with larger starting doses, may induce considerable hypoperfusion that results in symptoms that are at least bothersome (fatigue, impotence) and that may be potentially hazardous (postural hypotension, coronary ischemia). It is far better to start low and go slow. [75] DRUG COMBINATIONS.

Combinations of smaller doses of two drugs from different classes have been marketed to take advantage of the differences in the dose-response curves for therapeutic and toxic (side) effects shown in Figure 29-7 .[20] By combining two drugs, each at a dose near point A, a greater antihypertensive effect is provided (up to point B), but because the side effects are not additive for different classes of drugs, they remain at point A . A combination of low doses of a beta blocker (bisoprolol) and a diuretic (hydrochlorothiazide) has been approved for initial therapy for hypertension, after it was shown to provide antihypertensive efficacy far beyond that of each component but with no more side effects than with each separately.[76] More low-dose combinations are likely to become available. For the 50 percent or so of patients who do not respond to their initial therapy, combinations of two, three, or four drugs are needed.[32] Many of these can be provided in single tablets, thereby reducing cost and possibly improving adherence.[77] COMPLETE COVERAGE WITH ONCE DAILY DOSING.

A number of choices within each of the six major classes of antihypertensive drugs now available provide full 24-hour efficacy. Therefore, single daily dosing should be feasible for virtually all patients, thereby improving adherence to therapy. Moreover, the use of longer-acting agents avoids the potential of inducing too great a peak effect in order to provide an adequate effect at the end of the dosing interval (the trough). As seen in Figure 29-8 , moderate doses of various formulations of calcium antagonists provide similar peak effects but different trough effects at the end of 24 hours.[78] Moreover, because many patients occasionally skip a dose of their drugs, there is an additional value in using agents with inherently long duration of action that covers the skipped dose as well (Fig. 29-9) . Long-acting choices are available within each class.[20] However, because patients differ not only in terms of degree of response but also in terms of the duration of effect, the prudent course is to document the patient's response at the end of the dosing interval by home or ambulatory monitoring. With this approach, the abrupt surge in blood pressure that occurs on awakening will be blunted, and, it is hoped, patients can be

better protected from the increased incidence of cardiovascular catastrophes at this critical time.[79] If short-acting medications are taken at bedtime to ensure coverage in the early morning, ischemia to vital organs might be induced by the combination of the maximal effect of the drug within the first 3 to 6 hours after intake and the usual nocturnal decline in pressure.[80] Therefore, the safest course is to take medications with 24-hour duration of action as early in the morning as possible, as early as 4 or 5 A.M. if the patient awakens to urinate. THE INITIAL CHOICE.

The initial choice of antihypertensive therapy is perhaps the most important decision made

980

Figure 29-8 Trough blood pressure changes (red bars), peak blood pressure changes (pink bars), and trough-to-peak ratios (numbers) observed after treatment with various calcium antagonists. All drugs were given on a once-daily basis. V = verapamil; NT = nitrendipine; D = diltiazem extended release; N GITS = nifedipine gastrointestinal therapeutic system; A = amlodipine; SBP = systolic blood pressure; DBP = diastolic blood pressure. *P < 0.05; **P < 0.01 versus baseline (From Mancia G, Cattaneo BM, Omboni S, Grassi G: Clinical benefits of a consistent reduction in blood pressure. J Hypertens 16 [Suppl 6]:S35, 1998.)

in the treatment process. That drug is likely to be effective in about half the patients and, if no significant overt side effects occur, may be taken for many years. If the choice is ineffective or bothersome, the patient's confidence may be shaken, postponing or preventing adequate control. Two guidelines by expert committees have been published.[1] [20] The JNC-6 recommends diuretics or beta blockers as initial therapy for the relatively small portion of patients with uncomplicated hypertension, and drugs from all of the six major classes for patients with either a compelling indication or a comorbid condition that has been shown to respond well to a particular therapy.[20] The 1999 WHO-ISH

Figure 29-9 Forty-eight-hour systolic and diastolic blood pressure profile in 24 elderly subjects with isolated systolic hypertension. The 48-hour monitoring was done at the end of a 6-month administration of amlodipine at a dose of 5 to 10 mg daily and in the pretreatment placebo period. Amlodipine was administered at the beginning of the 48-hour monitoring period while the subsequent dose to be given 24 hours later was purposely missed. (From Mancia G, Cattaneo BM, Omboni S, Grassi G: Clinical benefits of a consistent reduction in blood pressure. J Hypertens 16 [Suppl 6]:S35, 1998.)

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CLASS OF DRUG

TABLE 29-4 -- GUIDELINES FOR SELECTING DRUG TREATMENT COMPELLING POSSIBLE COMPELLING POSSIBLE INDICATIONS INDICATIONS CONTRAINDICATIONS CONTRAINDICATIONS

Diuretics

Heart failure Elderly patients Systolic hypertension

Beta blockers

ACE inhibitors

Diabetes

Gout

Dyslipidemia Sexually active men

Angina Heart failure After myocardial Pregnancy infarction Diabetes Tachyarrhythmias

Asthma and COPD Heart block**

Dyslipidemia Athletes and physically active patients Peripheral vascular disease

Heart failure Left ventricular dysfunction After myocardial infarction Diabetic nephropathy

Pregnancy Hyperkalemia Bilateral renal artery stenosis

Calcium Angina antagonists Elderly patients Systolic hypertension

Peripheral vascular disease

Alpha blockers

Glucose intolerance Dyslipidemia

Prostatic hypertrophy

Angiotensin ACE inhibitor II cough antagonists

Heart failure

Heart block


Orthostatic hypotension

Pregnancy Bilateral renal artery stenosis Hyperkalemia

COPD=chronic obstructive pulmonary disease. *Grade 2 or 3 atrioventricular block; grade 2 or 3 atrioventricular block with verapamil or diltiazem; verapamil or diltiazem. ACE=angiotensin-converting enzyme;

guidelines broaden the number of compelling indications (Table 29-4) but give equal weight to all classes of drugs if there are no specific reasons to use one, stating that

"There is as yet no evidence that the main benefits of treating hypertension are due to any particular drug property rather than to lowering of blood pressure per se."[1] In practice, little difference remains between these two major guidelines. Until the many additional trials comparing different types of drugs now in progress are completed, [81] these guidelines should be followed. Appropriately individualized therapy will thereby be provided, maximizing the potential for a good fit between patient need and drug potential. SUBSTITUTION.

Even after a careful attempt to select the most appropriate drug for an individual patient, the choice may be either ineffectual in perhaps a third or unacceptable because of side effects in another 10 to 20 percent of all patients. Although the overall effectiveness of all approved drugs is about equal in the general population, individual patients show considerable variability in their response to different drugs.[82] Therefore, the physician must be willing to discontinue the initial choice and try a drug from another category. In a more structured trial-and-error approach that has been described, each patient is put through several double-blind, randomized crossover trials against placebos to determine the best drug.[83] However, this approach probably is too much trouble for most physicians and patients. Although other approaches have been recommended, including one based on the renin profile,[84] the general principles shown in Tables 29-3 and 29-4 should serve well to ensure that each patient receives a drug likely to provide good control and few side effects. For patients with more severe hypertension, in whom the first choice can be expected to be only partially effective, the stepped-care approach is logical. A diuretic enhances the effectiveness of most other drugs used, preventing the "pseudotolerance" that develops because of the fluid retention that frequently follows the use of some adrenergic blocking drugs and vasodilators. Increasingly, an angiotensin-converting enzyme (ACE) inhibitor or calcium antagonist is being chosen as the second or third drug when triple therapy is needed. THE GOAL OF THERAPY.

As discussed earlier, caution is advised in lowering diastolic pressure below 80 mm Hg, the apparent nadir of the J curve, particularly in patients prone to coronary disease. On the other hand, lower levels are needed in high-risk patients such as those with diabetes and nephropathy.[85] The overriding problem is not that a few patients may be endangered by too aggressive therapy but rather that even with presumably adequate current therapy, maximal protection against cardiovascular complications is not being provided.[86] Recall that twice as many hypertensive patients in the United States are being treated as are being controlled to a blood pressure of 140/90 mm Hg, providing reasonable protection to only 27 percent of patients.[20] DIURETICS (See also Chap. 18)

Diuretics useful in the treatment of hypertension may be divided into four major groups by their primary site of action within the tubule, starting in the proximal portion and moving to the collecting duct[86A] [86B] : (1) agents acting on the proximal tubule, such as carbonic anhydrase inhibitors, which have limited antihypertensive efficacy; (2) loop diuretics; (3) thiazides and related sulfonamide compounds; and (4) potassium-sparing agents. A thiazide is the usual choice, often in combination with a potassium-sparing agent. Loop diuretics should be reserved for those patients with renal insufficiency or resistant hypertension. MECHANISM OF ACTION.

All diuretics initally lower the blood pressure by increasing urinary sodium excretion and by reducing plasma volume, extracellular fluid volume, and cardiac output. Within 6 to 8 weeks, the lowered plasma, extracellular fluid volume, and cardiac output return toward normal. At this point and beyond, the lower blood pressure is related to a decline in peripheral resistance, thereby improving the underlying hemodynamic defect of hypertension. The mechanism responsible for the lowered peripheral resistance may involve potassium channel activation,[87] but initial diuresis is needed because diuretics fail to lower the blood pressure when the excreted sodium is returned or when given to patients who have nonfunctioning kidneys and are undergoing long-term dialysis. With the shrinkage in blood volume and lower blood pressure, increased secretion of renin and aldosterone retards the

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continued sodium diuresis. Both renin-induced vasoconstriction and aldosterone-induced sodium retention prevent continued diminution of body fluids and progressive reduction in blood pressure while diuretic therapy is continued. CLINICAL EFFECTS.

With continuous diuretic therapy, blood pressure usually falls about 10 mm Hg, although the degree depends on various factors, including the initial height of the pressure, the quantity of sodium ingested, the adequacy of renal function, and the intensity of the counterregulatory renin-aldosterone response.[87A] The antihypertensive effect of the diuretic persists indefinitely, although it may be overwhelmed by dietary sodium intake exceeding 8 gm/day. If other antihypertensive drugs are used, a diuretic may also be needed. Without a concomitant diuretic, antihypertensive drugs that do not block the renin-aldosterone mechanism may cause sodium retention. This mechanism probably reflects the success of the drugs in lowering the blood pressure and may involve the abnormal renal pressure-natriuresis relationship that is presumably present in primary hypertension. Just as more pressure is needed to excrete a given load of sodium in a hypertensive

individual, so does a lowering of pressure toward normal incite sodium retention. The critical need for adequate diuretic therapy to keep intravascular volume diminished has been repeatedly documented.[88] Therefore, diuretics are likely to continue to be widely used in antihypertensive therapy. Drugs that inhibit the renin-aldosterone mechanism, such as ACE inhibitors, or drugs that induce some natriuresis themselves, such as calcium antagonists, may continue to work without the need for concomitant diuretics. However, a diuretic enhances the effectiveness of all other types of drugs, including calcium antagonists.[89] DOSAGE AND CHOICE OF AGENT.

Most patients with mild to moderate hypertension and serum creatinine concentrations less than 2.0 mg/dl respond to the lower doses of the various diuretics listed in Table 29-5 . An amount equivalent to 12.5 mg of hydrochlorothiazide is usually adequate; larger doses have some additional antihypertensive effect but at the price of additional potassium wastage and insulin resistance. For uncomplicated hypertension, a moderately long-acting thiazide is a logical choice, and a single morning dose of hydrochlorothiazide provides a 24-hour antihypertensive effect. The nonthiazide agent indapamide has special properties that make it an attractive choice; it seldom disturbs lipid or glucose levels.[90] With renal failure, manifested by a serum creatinine level exceeding 2.0 mg/dl or creatinine clearance less than 25 ml/min, thiazides are usually not effective, and repeated doses of furosemide, one or two doses of torsemide, or a single dose of metolazone is needed. SIDE EFFECTS.

A number of biochemical changes often accompany successful diuresis, including a decrease in plasma potassium level and increases in glucose, insulin, and cholesterol levels (Fig. 29-10) . Most of these are minimized or absent with low doses of diuretic. Hypokalemia.

The degree of potassium wastage and hypokalemia is directly related to the dose of diuretic; serum potassium level falls an average of 0.7 mmol/liter with 50 mg of hydrochlorothiazide 0.4 with 25, and little if any with 12.5.[91] Hypokalemia due to high doses of diuretic may precipitate potentially hazardous ventricular ectopic activity and increase the risk of primary cardiac arrest, [92] even in patients not known to be susceptible because of concomitant digitalis therapy or myocardial irritability. Most patients are unaware of mild diuretic-induced hypokalemia, although it may contribute to leg cramps, polyuria, and muscle weakness, but subtle interference with antihypertensive therapy may accompany even mild hypokalemia, and correction of hypokalemia may result in a reduction in blood pressure.[93]

TABLE 29-5 -- DIURETICS AND POTASSIUM-SPARING AGENTS

AGENT

DAILY DOSE (mg)

DURATION OF ACTION (hr)

Bendroflumethiazide (Naturetin)

01.25-5.0

>18

Benzthiazide (Aquatag, Exna)

12.5-50

12-18

Chlorothiazide (Diruil)

125-500

6-12

Cyclothiazide (Anhydron)

0.125-1

18-24

Hydrochlorothiazide (Esidrix, HydroDIURIL, Oretic)

6.25-50

12-18

Hydroflumethiazide (Saluron)

12.5-50

18-24

Methyclothiazide (Enduron)

2.5-5.0

>24

Polythiazide (Renese)

1-4

24-48

Trichlormethiazide (Metahydrin, Naqua)

1-4

>24

Chlorthalidone (Hygroton)

12.5-50

24-72

Indapamide (Lozol)

1.25-2.5

24

Metolazone (Mykrox, Zaroxolyn)

0.5-10

24

Quinethazone (Hydromox)

25-100

18-24

Bumetanide (Bumex)

0.5-5

4-6

Ethacrynic acid (Edecrin)

25-100

12

Furosemide (Lasix)

40-480

4-6

Torsemide (Demadex)

5-40

12

Amiloride (Midamor)

5-10

24

Spironolactone (Aldactone)

25-100

8-12

Triamterene (Dyrenium)

50-100

12

Thiazides

Related Sulfonamide Compounds

Loop Diuretics

Potassium-Sparing Agents

From Kaplan NM: Clinical Hypertension. 7th ed. Baltimore, Williams & Wilkins, 1998, p 190.

Prevention of hypokalemia is preferable to correction of potassium deficiency. The following maneuvers should help prevent diuretic-induced hypokalemia:

Use the smallest dose of diuretic needed.

Use a moderately long-acting (12- to 18-hour) diuretic, such as hydrocholorothiazide, because longer-acting drugs (e.g., chlorthalidone) may increase potassium loss. Restrict sodium intake to less than 100 mmol/day (i.e., 2.4 gm sodium). Increase dietary potassium intake. Restrict concomitant use of laxatives. Use a combination of a thiazide with a potassium-sparing agent except in patients with renal insufficiency or in association with an ACE inhibitor or angiotensin II-receptor blocker. Concomitant use of a beta blocker or an ACE inhibitor diminishes potassium loss by blunting the diuretic-induced rise in renin-aldosterone. If hypokalemia is to be treated, these principles should be followed, along with some form of supplemental potassium. Potassium chloride is preferred for correction of the associated alkalosis. If tolerated, granular potassium chloride can be given as a salt substitute; extra potassium will thereby be provided while sodium intake is reduced. Caution is necessary when supplemental potassium chloride is given to older patients with borderline renal function, in whom hyperkalemia may be induced. HYPOMAGNESEMIA.

In some patients, concomitant diuretic-induced magnesium deficiency prevents restoration of intracellular deficits of potassium[94] so that hypomagnesemia should be corrected. Magnesium

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Figure 29-10 The mechanisms by which chronic diuretic therapy may lead to various complications. The mechanism for hypercholesterolemia remains in question, although it is shown as arising via hypokalemia. Cl = Clearance; PRA = plasma renin activity; GFR = glomerular filtration rate. (From Kaplan NM: Clinical Hypertension. 7th ed. Baltimore, Williams & Wilkins, 1998, p 193.)

deficiency may also be responsible for some of the arrhythmias ascribed to hypokalemia. HYPERURICEMIA.

The serum uric acid level is elevated in as many as one-third of untreated hypertensive patients. With long-term high-dose diuretic therapy, hyperuricemia appears in another

third of patients, probably as a consequence of increased proximal tubular reabsorption accompanying volume contraction. Diuretic-induced hyperuricemia may precipitate acute gout, most frequently in those who are obese and consume large amounts of alcohol.[95] Because asymptomatic hyperuricemia does not cause urate deposition, most investigators agree that it need not be treated. If therapy is used, a uricosuric drug such as probenecid should be given. HYPERLIPIDEMIA.

Serum cholesterol levels often rise after diuretic therapy, but after 1 year, no adverse effects were noted in those who responded to smaller doses.[96] HYPERGLYCEMIA AND INSULIN RESISTANCE.

High doses of diuretics may impair glucose tolerance and precipitate diabetes mellitus, probably because they increase insulin resistance and hyperinsulinemia.[97] The manner by which diuretics increase insulin resistance is uncertain, but in view of the many potential pressor actions of hyperinsulinemia (see Chap. 28) , this could be a significant problem. HYPERCALCEMIA.

A slight rise in serum calcium levels, less than 0.5 mg/dl, is frequent with thiazide diuretic therapy, at least in part because increased calcium reabsorption accompanies the increased sodium reabsorption in the proximal tubule induced by contraction of extracellular fluid volume.[98] The rise is of little concern except in patients with previously unrecognized hyperparathyroidism, who may experience a much more marked rise. On the other hand, the diuretic-induced positive calcium balance is associated with a reduction in the incidence of osteoporosis in the elderly.[99] IMPOTENCE.

An increase in the incidence of impotence was noted among men who took 15 mg of chlorthalidone, the diuretic being the only one of five classes of agents attended by this effect.[100] RENAL CELL CARCINOMA.

A significant increase in renal cell carcinoma among diuretic users was found in a search of nine case control and three cohort studies.[101] Methodological problems are inherent in this type of analysis,[102] and the overall positive effects of diuretic use far outweigh their hazard, a situation similar to oral contraceptive use. LOOP DIURETICS.

Loop diuretics are usually needed in the treatment of hypertensive patients with renal

failure, defined here as a serum creatinine level exceeding approximately 2.0 mg/dl. Furosemide has been most widely used, although either torsemide or metolazone may be as effective, and each requires only a single daily dose. Many physicians use furosemide in the management of uncomplicated hypertension, but this drug provides less antihypertensive action when given once or twice a day than do longer-acting diuretics, which maintain a slight volume contraction. POTASSIUM-SPARING AGENTS.

These drugs are normally used in combination with a thiazide diuretic. Of the three currently available, one (spironolactone) is an aldosterone antagonist; the other two (triamterene and amiloride) are direct inhibitors of potassium secretion. In combination with a thiazide diuretic, they diminish the amount of potassium wasting. Although they are more expensive than thiazides alone, they may decrease the total cost of therapy by reducing the need to monitor and treat potassium depletion. Moreover, low doses of spironolactone may prevent myocardial fibrosis and reduce mortality in patients with heart failure.[103] An Overview of Diuretics in Hypertension

Diuretics have been effective for the treatment of millions of hypertensive patients during the past 40 years. They reduce DBP and maintain it below 90 mm Hg in about half of all hypertensive patients, providing the same degree of effectiveness as most other antihypertensive drugs. In two groups that constitute a rather large portion of the hypertensive population, the elderly and blacks, diuretics may be particularly effective.[104] One-half of a diuretic tablet per day is usually all that is needed, minimizing cost and maximizing adherence to therapy. Even lower doses, i.e., 6.25 mg of hydrochlorothiazide, may be adequate when combined with other drugs.[76] The side effects of high-dose diuretic therapy are usually not overly bothersome, but the hypokalemia, hypercholesterolemia, hyperinsulinemia, and worsening of glucose tolerance that often accompany prolonged high-dose diuretic therapy gave rise to concerns about their long-term benignity. However, lower doses are usually just as potent as higher doses in lowering the blood pressure and less likely to induce metabolic mischief.[91] Therefore, the advocacy of low-dose diuretic therapy in the 1997 JNC-6 report[20] and the 1999 WHO-ISH report[1] is appropriate. ADRENERGIC INHIBITORS A number of drugs that inhibit the adrenergic nervous system are available, including some that act centrally on vasomotor center activity, peripherally on neuronal catecholamine

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TABLE 29-6 -- ADRENERGIC INHIBITORS USED IN TREATMENT OF HYPERTENSION Peripheral Neuronal Inhibitors Reserpine Guanethidine (Ismelin) Guanadrel (Hylorel) Bethanidine (Tenathan) Central Adrenergic Inhibitors Methyldopa (Aldomet) Clonidine (Catapres) Guanabenz (Wytensin) Guanfacine (Tenex) Alpha-Receptor Blockers Alpha1 and alpha2 receptor Phenoxybenzamine (Dibenzyline) Phentolamine (Regitine) Alpha1 receptor Doxazosin (Cardura) Prazosin (Minipress) Terazosin (Hytrin) Beta-Receptor Blocker Acebutolol (Sectral) Atenolol (Tenormin) Betaxolol (Kerlone) Bisoprolol (Zebeta) Carteolol (Cartrol) Metoprolol (Lopressor, Toprol) Nadolol (Corgard) Penbutolol (Levatol) Pindolol (Visken) Propranolol (Inderal) Timolol (Blocadren) Alpha- and Beta-Receptor Blocker Labetalol (Normodyne, Trandate) Carvedilol (Coreg) discharge, or by blocking alpha- and/or beta-adrenergic receptors (Table 29-6) ; some act at numerous sites. Figure 29-11 , a schematic view of the ending of an adrenergic nerve and the effector cell with its receptors, depicts how some of these drugs act. When the nerve is stimulated, norepinephrine, which is synthesized intraneuronally and stored in granules, is released into the synaptic

Figure 29-11 Simplified schematic view of the adrenergic nerve ending showing that norepinephrine (NE) is released from its storage granules when the nerve is stimulated and enters the synaptic cleft to bind to alpha1 and beta receptors on the effector cell (postsynaptic). In addition, a short feedback loop exists, in which NE binds to alpha2 and beta receptors on the neuron (presynaptic), to inhibit or to stimulate further release, respectively.

cleft. It binds to postsynaptic alpha- and beta-adrenergic receptors and thereby initiates various intracellular processes. In vascular smooth muscle, alpha stimulation causes constriction and beta stimulation causes relaxation. In the central vasomotor centers, sympathetic outflow is inhibited by alpha stimulation; the effect of central beta stimulation is unknown. An important aspect of sympathetic activity involves the feedback of norepinephrine to alpha- and beta-adrenergic receptors located on the neuronal surface, i.e., presynaptic receptors. Presynaptic alpha-adrenergic receptor activation inhibits release, whereas presynaptic beta activation stimulates further norepinephrine release. The presynaptic receptors probably has a role in the action of some of the drugs to be discussed. Elucidation and quantification of the various actions of these drugs remain incomplete. The listing in Table 29-6 is based on the predominant site of action according to currently available data. The action of beta-adrenergic receptor blockers involves a peripheral effect, but they almost certainly also act on central vasomotor mechanisms. Drugs That Act Within the Neuron

Reserpine, guanethidine, and related compounds act differently to inhibit the release of norepinephrine from peripheral adrenergic neurons. RESERPINE.

Reserpine, the most active and widely used of the derivatives of the rauwolfia alkaloids, depletes the postganglionic adrenergic neurons of norepinephrine by inhibiting its uptake into storage vesicles, exposing it to degradation by cytoplasmic monoamine oxidase. The peripheral effect is predominant, although the drug enters the brain and depletes central catecholamine stores as well. This probably accounts for the sedation and depression accompanying reserpine use. The drug has certain advantages. Only one dose a day is needed; in combination with a diuretic, the antihypertensive effect is significant, greater than that noted with nitrendipine in one comparative study[105] ; little postural hypotension is noted; and many patients experience no side effects. The drug has a relatively flat dose-response curve, so that a dose of only 0.05 mg/day gives almost as much antihypertensive effect as 0.125 or 0.25 mg/day but fewer side effects. Although it remains popular in some places and is recommended as an inexpensive choice where resources are limited,[1] reserpine has progressively declined in use

because it has no commercial sponsor. GUANETHIDINE.

This agent and a series of related guanidine compounds, including guanadrel, bethanidine, and debrisoquine, act by inhibiting the release of norepinephrine from the adrenergic neurons, perhaps by a local anesthetic-like effect on the neuronal membrane. In order to act, the drug must be transported actively into the nerve through an amine pump. Their low lipid solubility prevents guanidine compounds from entering the brain, so that sedation, depression, and other side effects involving the central nervous system do not occur. The initial predominant hemodynamic effect is decreased cardiac output: after continued use, peripheral resistance declines. Blood pressure is reduced further when the patient is upright, owing to gravitational pooling of blood in the legs, because compensatory sympathetic nervous system-mediated vasoconstriction is blocked. This results in the most common side effect, postural hypotension. Unlike reserpine, guanethidine has a steep dose-response curve, so that it can be successfully used in treating hypertension of any degree in daily doses of 10 to 300 mg. Like reserpine, it has a long biological half-life and may be given once daily. As other drugs have become available, guanethidine and related compounds have been relegated mainly to the treatment of severe hypertension unresponsive to all other agents. Drugs That Act on Receptors Predominantly Central Alpha Agonists

Until the mid-1980's, methyldopa was the most widely used of the adrenergic receptor blockers, but its use has declined as beta blockers and other drugs have become more popular. In addition, three other drugs--clonidine, guanabenz, and guanfacine, which act similarly to methyldopa but have fewer serious side effects--have become available.

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METHYLDOPA.

The primary site of action of methyldopa is within the central nervous system, where alpha-methylnorepinephrine, derived from methyldopa, is released from adrenergic neurons and stimulates central alpha-adrenergic receptors, reducing the sympathetic outflow from the central nervous system. [106] The blood pressure mainly falls as a result of a decrease in peripheral resistance with little effect on cardiac output. Renal blood flow is well maintained, and significant postural hypotension is unusual. Therefore, the drug has been used in hypertensive patients with renal failure or cerebrovascular disease and remains the most commonly used agent for pregnancy-induced

hypertension (see Chaps. 28 and 65) . Methyldopa need be given no more than twice daily, in doses ranging from 250 to 3000 mg/day. Side effects include some that are common to centrally acting drugs that reduce sympathetic outflow: sedation, dry mouth, impotence, and galactorrhea. However, methyldopa causes some unique side effects that are probably of an autoimmune nature, because a positive antinuclear antibody test result occurs in about 10 percent of patients who take the drug, and red cell autoantibodies occur in about 20 percent. Clinically apparent hemolytic anemia is rare, probably because methyldopa also impairs reticuloendothelial function so that antibody-sensitized cells are not removed from the circulation and hemolyzed. Inflammatory disorders in various organs have been reported, most commonly involving the liver (with diffuse parenchymal injury similar to viral hepatitis).[107] CLONIDINE.

Although of different structure, clonidine shares many features with methyldopa. It probably acts at the same central sites, has similar antihypertensive efficacy, and causes many of the same bothersome but less serious side effects (e.g., sedation, dry mouth). It does not, however, induce the autoimmune and inflammatory side effects. As an alpha-adrenergic receptor agonist, the drug also acts on presynaptic alpha receptors and inhibits norepinephrine release, and plasma catecholamine levels fall.[108] The drug has a fairly short biological half-life, so that when it is discontinued, the inhibition of norepinephrine release disappears within about 12 to 18 hours, and plasma catecholamine levels rise. This is probably responsible for the rapid rebound of the blood pressure to pretreatment levels and the occasional appearance of withdrawal symptoms, including tachycardia, restlessness, and sweating. If the rebound requires treatment, clonidine may be reintroduced or alpha-adrenergic receptor antagonists given. Clonidine is available in a transdermal preparation, which may provide smoother blood pressure control for as long as 7 days with fewer side effects. However, bothersome skin rashes preclude its use in perhaps one-fourth of patients. GUANABENZ.

This drug differs in structure but shares many characteristics with both methyldopa and clonidine, acting primarily as a central alpha agonist. It may differ, however, in not causing fluid retention. GUANFACINE.

This drug is also similar to clonidine but is longer acting, which enables once-a-day

dosing and minimizes rebound hypertension.[109] Alpha-Adrenergic Receptor Antagonists

Before 1977, the only alpha blockers used to treat hypertension were phenoxybenzamine (Dibenzyline) and phentolamine (Regitine). These drugs are effective in acutely lowering blood pressure, but their effects are offset by an accompanying increase in cardiac output, and side effects are frequent and bothersome. Their limited efficacy may reflect their blockade of presynaptic alpha-adrenergic receptors, which interferes with the feedback inhibition of norepinephrine release (see Fig. 29-11) . Increased catecholamine release would then blunt the action of postsynaptic alpha-adrenergic receptor blockade. Their use has largely been limited to the treatment of patients with pheochromocytomas. PRAZOSIN.

This was the first of a group of selective antagonists of the postsynaptic alpha 1 receptors. By blocking alpha-mediated vasoconstriction, prazosin induces a decline in peripheral resistance with both venous and arteriolar dilation. Because the presynaptic alpha-adrenergic receptor is left unblocked, the feedback loop for the inhibition of norepinephrine release is intact, an action that is also certainly responsible for the greater antihypertensive effect of the drug and the absence of concomitant tachycardia, tolerance, and renin release. Inhibition of norepinephrine release may also account for the propensity toward greater first-dose reductions in blood pressure. OTHER ALPHA BLOCKERS.

Two other alpha blockers, terazosin and doxazosin, have slower onset and longer duration of action, so they may be given once daily with less propensity for first-dose hypotension. Selective alpha blockers are as effective as other first-line antihypertensives.[2] When given to patients whose condition is poorly controlled on standard triple therapy (diuretic, beta blocker, and vasodilator), they may reduce blood pressure even more than anticipated. They can be safely and effectively used by patients with renal failure. The favorable hemodynamic changes--a fall in peripheral resistance with maintenance of cardiac output--make them an attractive choice for patients who wish to remain physically active. In addition, blood lipids are not adversely altered and may actually improve with alpha blockers, unlike the adverse effects observed with diuretics and beta blockers.[110] Moreover, improved insulin sensitivity with lesser rises in plasma glucose and insulin levels after a glucose load has been observed with alpha blockers.[111] Alpha blockers decrease the smooth muscle tone of the bladder neck and prostate, relieving the obstructive symptoms of prostatism. [112] They are then an excellent choice for older men with hypertension and benign prostatic hypertrophy. In a large, double-blind, randomized trial of older patients (>55 years) with hypertension (ALLHAT), the alpha adrenergic blocker doxazosin, when compared with the diuretic

chlorthalidone, was associated with significantly higher risks for stroke and congestive heart failure.[112A] Side effects, beyond first-dose postural hypotension, include the nonspecific effects of lower blood pressure, such as dizziness, weakness, fatigue, and headaches. Most patients, however, find the drugs easy to take, with little sedation, dry mouth, or impotence. Beta-Adrenergic Receptor Antagonists (See also Chaps. 23 and 37)

In the 1980's, beta-adrenergic receptor blockers became the most popular form of antihypertensive therapy after diuretics, reflecting their relative effectiveness and freedom from many bothersome side effects. For the majority of patients, beta blockers are usually easy to take, because somnolence, dry mouth, and impotence are seldom encountered. Because beta blockers have been found to reduce mortality if taken either before or after acute myocardial infarction [113] (i.e., secondary prevention), it was assumed that they might offer special protection against initial coronary events, i.e., primary prevention. However, in four large clinical trials, a beta blocker provided less protection than did a low-dose diuretic (see Fig. 29-1) .[10] Nevertheless, their efficacy in treatment of congestive heart failure will likely stimulate their use.[114] THE VARIOUS BETA BLOCKERS.

Beta blockers now available in the United States are listed in Table 29-6 , and others are available in other countries. A number of agents with additional vasodilatory effects are available elsewhere; these may be free of many of the unfavorable hemodynamic and adverse effects of currently available agents. Pharmacologically, those now available differ considerably from one another with respect to degree of absorption, protein binding, and bioavailability. However, the three most important differences affecting their clinical use are cardioselectivity, intrinsic sympathomimetic activity, and lipid solubility. Despite these differences, they all seem to be about equally as effective as antihypertensives. Cardioselectivity.

As seen in Figure 29-12 , beta blockers can be classified by their degree of cardioselectivity relative to their blocking effect on the beta1 -adrenergic receptors in the heart compared with that on the beta 2 receptors in the bronchi, peripheral blood vessels, and elsewhere.

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Figure 29-12 Classification of beta-adrenergic receptor blockers based on cardioselectivity and intrinsic

sympathomimetic activity (ISA). Those not approved for use in the United States are in italics. (From Kaplan NM: Clinical Hypertension. 7th ed. Baltimore, Williams & Wilkins, 1998, p 206.)

Such cardioselectivity can be easily shown using small doses in acute studies; with the rather high doses used to treat hypertension, much of this selectivity is lost. Intrinsic Sympathomimetic Activity (ISA).

Some of these drugs have ISA, interacting with beta receptors to cause a measurable agonist response but at the same time blocking the greater agonist effects of endogenous catecholamines. As a result, although in usual doses they lower the blood pressure about the same degree as do other beta blockers, they cause a smaller decline in heart rate, cardiac output, and renin levels. Lipid Solubility.

Atenolol and nadolol are among the least lipid soluble of the beta blockers. Because they do not enter the brain as readily, they may cause fewer central nervous system side effects.[115] Mechanism of Action.

Despite these and other differences, the various beta blockers now available are approximately equipotent as antihypertensive agents. A number of possible mechanisms are likely to be involved in their antihypertensive action. In those without ISA, cardiac output falls 15 to 20 percent and renin release is reduced about 60 percent. Central nervous system beta-adrenergic receptor blockade may reduce sympathetic discharge, but similar antihypertensive effects are seen with those drugs that are more lipid soluble, and therefore in high concentration within the central nervous system, and those that are less lipid soluble. At the same time that beta blockers lower blood pressure through various means, their blockade of peripheral beta-adrenergic receptors inhibits vasodilation, leaving alpha receptors open to catecholamine-mediated vasoconstriction. Over time, however, vascular resistance tends to return to normal, which presumably preserves the antihypertensive effect of a reduced cardiac output.[116] Clinical Effects.

Even in small doses, beta blockers begin to lower the blood pressure within a few hours. Although progressively higher doses have usually been given, careful study has shown a near-maximal effect from smaller doses. For example, in a double-blind crossover study involving 24 patients, 40 mg of propranolol twice a day provided the same antihypertensive effects as 80, 160, or 240 mg twice a day.[116A] The degree of blood pressure reduction is at least comparable to that noted with other antihypertensive drugs.[2] Beta blockers may be particularly well suited for younger and middle-aged hypertensive patients, especially nonblacks, and for patients with myocardial ischemia

and high levels of stress.[113] Because the hemodynamic responses to stress are reduced, however, they may interfere with athletic performance.[117] SPECIAL USES FOR BETA BLOCKERS

COEXISTING ISCHEMIC HEART DISEASE.

Even without evidence that beta blockers protect patients from initial coronary events, the antiarrhythmic and antianginal effects of these drugs make them especially valuable in hypertensive patients with coexisting coronary disease. COEXISTING HEART FAILURE.

As described elsewhere (see Chap. 18) , beta blockers have been found to reduce mortality in patients with congestive heart failure.[114] PATIENTS WITH HYPERKINETIC HYPERTENSION.

Some hypertensive patients have increased cardiac output that may persist for many years. Beta blockers are particularly effective in such patients, but a reduction in exercise capacity may necessitate restriction of their use in young athletes. PATIENTS WITH MARKED ANXIETY.

The somatic manifestations of anxiety--tremor, sweating, and tachycardia--can be helped, without the undesirable effects of methods commonly used to control anxiety, such as alcohol and tranquilizers. PERIOPERATIVE STRESS.

The ultra-short-acting cardioselective agent esmolol has been successfully used to prevent postintubation tachycardia and hypertension,[118] and atenolol protects patients with coronary disease during surgery.[119] SIDE EFFECTS.

Most of the side effects of beta blockers relate to their major pharmacological action, the blockade of beta-adrenergic receptors. Certain concomitant problems may worsen when beta-adrenergic receptors are blocked, including peripheral vascular disease and bronchospasm. The most common side effect is fatigue, which is probably a consequence of decreased cardiac output and the decreased cerebral blood flow that may accompany successful lowering of the blood pressure by any drug (see Fig. 29-6) . More direct effects on the central nervous system--insomnia, nightmares, and hallucinations--occur in some

patients. An association with depression appears to be accounted for by various confounding variables.[120] Diabetic patients may have additional problems with beta blockers, more so with nonselective ones. The responses to hypoglycemia, both the symptoms and the counterregulatory hormonal changes that raise blood glucose levels, are partially dependent on sympathetic nervous activity. Diabetic patients who are susceptible to hypoglycemia may not be aware of the usual warning signals and may not rebound as quickly. The majority of noninsulin-dependent diabetic patients can take these drugs without difficulty, although their diabetes may be exacerbated, probably from beta blocker interference with insulin sensitivity.[111] When a beta blocker is discontinued, angina pectoris and myocardial infarction may occur.[121] Because patients with hypertension are more susceptible to coronary disease, they should be weaned gradually and given appropriate coronary vasodilator therapy. Perturbations of lipoprotein metabolism accompany the use of beta blockers.[122] Nonselective agents cause greater rises in triglycerides and reductions in cardioprotective high-density lipoprotein-cholesterol levels, whereas ISA agents cause less or no effect and some agents such as celiprolol may raise high-density lipoprotein cholesterol levels. Patients with renal failure may take beta blockers without additional hazard, although modest reductions in renal blood flow and glomerular filtration rate have been measured, presumably from renal vasoconstriction. Caution is advised in the use of beta blockers in patients suspected of harboring a pheochromocytoma (Chaps. 28 and 64) , because unopposed alpha-adrenergic agonist action may precipitate a serious hypertensive crisis if this disease is present. The use of beta blockers during pregnancy has been clouded by scattered case reports of various fetal problems. Moreover, prospective studies have found that the use of beta blockers during pregnancy may lead to fetal growth retardation. [123] AN OVERVIEW OF BETA BLOCKERS IN HYPERTENSION.

Beta blockers are specifically recommended for hypertensive patients with concomitant coronary disease, particularly after a myocardial infarction, congestive heart failure, or tachyarrhythmias[1] (see Table 29-4) . If a beta blocker is chosen, those agents that are more cardioselective and lipid insoluble offer the likelihood of fewer perturbations of lipid and carbohydrate metabolism and greater patient adherence to therapy; only one dose a day is needed, and side effects probably are minimized. In patients with heart failure, the initial dose should be very small (e.g., metoprolol 12.5 mg twice daily) and gradually increased to the maintenance dose (100 to 200 mg twice daily) (see Chap. 18) .

987

Alpha- and Beta-Adrenergic Receptor Antagonists

The combination of an alpha and a beta blocker in a single molecule is available in the

forms of labetalol and carvedilol, the latter agent approved for treatment of heart failure as well. The fall in pressure mainly results from a decrease in peripheral resistance, with little or no decline in cardiac output.[124] The most bothersome side effects are related to postural hypotension; the most serious side effect is hepatotoxicity. Intravenous labetalol is used to treat hypertensive emergencies. VASODILATORS In the past, direct-acting arteriolar vasodilators were used mainly as third drugs, when combinations of a diuretic and adrenergic blocker failed to control blood pressure. However, with the availability of vasodilators of different types that can be easily tolerated when used as first or second drugs, wider and earlier application of vasodilators in therapy of hypertension has begun (Table 29-7) . Direct Vasodilators

Hydralazine is the most widely used agent of this type. Minoxidil is more potent but is usually reserved for patients with severe, refractory hypertension associated with renal failure.[20] Nitroprusside and nitroglycerin are given intravenously for hypertensive crises and are discussed on page 991 . HYDRALAZINE.

From the early 1970's, hydralazine, in combination with a diuretic and a beta blocker, was used frequently to treat severe hypertension. The drug acts directly to relax the smooth muscle in precapillary resistance vessels, with little or no effect on postcapillary venous capacitance vessels. As a result, blood pressure falls by a reduction in peripheral resistance, but in the process a number of compensatory processes, which are activated by the arterial baroreceptor arc, blunt the decrease in pressure and cause side effects. With concomitant use of a diuretic to overcome the tendency for fluid retention and an adrenergic inhibitor to prevent the reflex increase in sympathetic activity and rise in renin, the vasodilator is more effective and causes few, if any, side effects. Without the protection conferred by concomitant use of an adrenergic blocker, numerous side effects (tachycardia, flushing, headache, and precipitation of angina) may occur. The drug need be given only twice a day. Its daily dose should be kept below 400 mg to prevent the lupus-like syndrome that appears in 10 to 20 percent of patients who receive more. This reaction, although uncomfortable to the patient, is almost always reversible. The reaction is uncommon with daily doses of 200 mg or less and is more common in slow acetylators of the drug. MINOXIDIL.

This drug vasodilates by opening potassium channels in vascular smooth muscle. Its hemodynamic effects are similar to those of hydralazine, but minoxidil is even more effective and may be used once a day. It is particularly useful in patients with severe

hypertension and renal failure. Even more than with hydralazine, diuretics and adrenergic receptor blockers must be used with minoxidil to prevent the reflex increase in cardiac output and fluid retention. Pericardial effusions have appeared in about 3 percent of those given minoxidil, TABLE 29-7 -- VASODILATOR DRUGS USED TO TREAT HYPERTENSION DRUG RELATIVE ACTION ON ARTERIES (A) OR VEINS (V) Direct Hydralazine

A>>V

Minoxidil

A>>V

Nitroprusside

A=V

Nitroglycerin

V>A

Calcium entry blockers

A>>V

Converting enzyme inhibitors

A>V

Alpha blockers

A=V

TABLE 29-8 -- PHARMACOLOGICAL EFFECTS OF CALCIUM ANTAGONISTS DILTIAZEM VERAPAMIL DIHYDROPYRIDINES Heart rate Myocardial contractility Nodal conduction

-

Periphral vasodilation

Indicates decrease; increase;

in some without renal or cardiac failure. The drug also causes hair to grow profusely, and the facial hirsutism precludes use of the drug in most women. Calcium Antagonists (See also Chap. 37)

These drugs have become the most popular class of agents used in the treatment of hypertension. They differ in both their sites and modes of action (Table 29-8) , with major pharmacological differences between the various dihydropyridines.[125] Dihydropyridines have the greatest peripheral vasodilatory action,[126] with little effect on cardiac automaticity, conduction, or contractility. However, comparative trials have shown that verapamil and diltiazem, which do affect these properties, are also effective antihypertensives, and they may cause fewer side effects related to vasodilation, such as flushing and ankle edema. Calcium antagonists are effective in hypertensive patients of all ages and races[104] and in hypertensive diabetics.[104A] In a large comparative trial, verapamil was more effective than chlorthalidone in promoting regression of carotid intima-media thickness and preventing cardiovascular events.[127] Even more impressively, therapy based on the dihydropyridine nitrendipine provided even greater protection to elderly patients with isolated systolic hypertension in the Syst-Eur trial[22] than did chlorthalidone in the SHEP trial,[5] particularly in those in the two trials with diabetes accompanying the hypertension.[24] Dihydropyridines were also the foundation of therapy in other large trials that found significant reductions in cardiovascular events.[25] [32] Calcium antagonists may cause at least an initial natriuresis, probably by producing renal vasodilation,[128] which may obviate the need for concurrent diuretic therapy. In fact, unlike all other antihypertensive agents, they may have their effectiveness reduced rather than enhanced by concomitant dietary sodium restriction,[129] whereas most careful studies show an enhancement of their effect by concomitant diuretic therapy.[89] Their renal vasodilatory effect allows glomerular filtration rate and renal blood flow to be well maintained as they reduce systemic blood pressure.[130] Because they act primarily to dilate afferent arterioles, these agents could accelerate a decline in renal function by increasing flow within the glomeruli. Although they may not decrease proteinuria as well as ACE inhibitors, they seem to preserve renal function as well.[131] A potentially serious adverse effect of the use of calcium antagonists to treat hypertension was described in a case-control study in which more hypertensive patients who had a myocardial infarction were taking short-acting calcium antagonists than were hypertensive patients who had not had an infarct.[132] The most likely explanation for the finding is exclusion bias, which is an inherent problem with case-control studies in which the cases are at greater risk for the complication than the controls; i.e., higher-risk patients are excluded from the control group but not from the case group. Specifically, short-acting calcium antagonists, which were not approved for the treatment of hypertension

988

and which were more expensive and more difficult to use because they require three doses a day compared with the other approved antihypertensive agents, were probably given to patients considered at higher risk for coronary events. Similar case-control

studies claiming that the use of reserpine was associated with a threefold increase in breast cancer were subsequently shown to be erroneous because of exclusion bias.[133] The decrease in coronary events in large randomized controlled trials with long-acting dihydropyridines[22] [25] [32] is the best proof of the safety of these agents. Similar claims based on case-control studies that calcium anatgonists increase cancer and gastrointestinal bleeding also have not been confirmed.[134] [135] Along with freedom from most of the side effects accompanying other classes, calcium antagonists may be unique in not having their antihypertensive efficacy blunted by nonsteroidal antiinflammatory agents (NSAIDs).[136] Liquid nifedipine has been used effectively to reduce high levels of blood pressure quickly, but the occasional occurrence of cerebral and myocardial ischemia has prompted a call for discontinuation of the practice.[137] Intravenous nicardipine is available for hypertensive emergencies.[138] Renin-Angiotensin Inhibitors (See also Chap. 18)

Activity of the renin-angiotensin system (see Fig. 28-13 ) may be inhibited in four ways ( Fig. 29-13 ), three of which can be applied clinically. The first, use of beta-adrenergic receptor blockers to inhibit the release of renin, was discussed earlier ( p. 986 ). The second, direct inhibition of renin activity by specific renin inhibitors, is being investigated.[139] The third, inhibition of the enzyme that converts the inactive decapeptide angiotensin I to the active octapeptide angiotensin II, is being widely used with orally effective ACE inhibitors. The fourth approach to inhibiting the renin-angiotensin system, blockade of angiotensin's actions by a competitive receptor blocker, is now the basis for the fastest growing class of antihypertensive agents. [140] The AII receptor blockers (ARBs) may offer additional benefits, but their immediate advantage is the absence of cough that often accompanies ACE inhibitors, as well as less angioedema. In the absence of outcome data, both JNC-6[20] and WHO-ISH [1] guidelines recommend their use only if an ACE inhibitor cannot be tolerated. The ARBs are considered after the ACE inhibitors. MECHANISM OF ACTION.

The first of these ACE inhibitors, captopril, was synthesized as a specific inhibitor of the converting enzyme that, in the classical pathway shown in Figure 29-13 , breaks the peptidyldipeptide bond in angiotensin I, preventing the enzyme from attaching to and splitting the angiotensin I structure. Because angiotensin II cannot be formed and angiotensin I is inactive, the ACE inhibitor paralyzes the classical renin-angiotensin system, thereby removing the effects of most endogenous angiotensin II as both a vasoconstrictor and a stimulant to aldosterone synthesis. Interestingly, with long-term use of ACE inhibitors, the plasma angiotensin II levels actually return to previous level while the blood pressure remains lowered[141] ; this suggests that the antihypertensive effect may involve other mechanisms. Because the same enzyme that converts angiotensin I to angiotensin II is also responsible for inactivation of the vasodilating hormone bradykinin, by inhibiting the breakdown of

bradykinin, ACE inhibitors increase the concentration of a vasodilating hormone while they decrease the concentration of a vasoconstrictor hormone. The increased plasma kinin levels may contribute to the vasodilation and improvement in insulin sensitivity observed with ACE inhibitors, but they are also responsible for the most common and bothersome side effect of their use, a dry, hacking cough.[140] ACE inhibitors may also vasodilate by increasing levels of vasodilatory prostaglandins and decreasing levels of vasoconstricting endothelins.[142] Regardless of their mechanism of action, ACE inhibitors lower blood pressure mainly by reducing peripheral resistance with little, if any, effect on heart rate, cardiac output, or body fluid volumes, likely reflecting preservation of baroreceptor reflexes.[143] Their vasodilating effect may also involve restoration of endothelium-dependent relaxation by nitric oxide.[144] As a consequence, resistance arteries become less thickened and more responsive.[145] CLINICAL USE.

In patients with uncomplicated primary hypertension, ACE inhibitors provide antihypertensive effects that are equal to those with other classes,[146] but they are less effective in blacks,[104] perhaps because blacks tend to have lower renin levels. They are equally effective in elderly and younger hypertensive patients. In the large controlled CAPPP trial, in which captopril-based therapy was compared with conventional therapy with diuretic and beta blockers, the two approaches provided essentially identical protection against cardiovascular morbidity and mortality.[146] As a consequence of these results, the WHO-ISH guidelines include ACE inhibitors as a choice for initial therapy.[1] In view of the impressive reduction in morbidity

Figure 29-13 The four sites of action of inhibitors of the renin-angiotensin system. J-G = Juxtaglomerular apparatus; CE = converting enzyme. (From Kaplan NM: Clinical Hypertension. 7th ed. Baltimore, Williams & Wilkins, 1998, p 223.)Risk Factors for Cardiovascular Diseases Left ventricular hypertrophy (electrocardiogram), Associated Clinical Conditions

989

and mortality with ramipril in the HOPE trial of high-risk patients,[146A] the use of ACE inhibitors will almost certainly increase. The initial dose of ACE inhibitor may precipitate a rather dramatic but transient fall in blood pressure[147] that likely reflects a higher level of renin-angiotensin and that could be a harbinger of the presence of renovascular hypertension. Because the therapeutic response will be potentiated by concomitant intravascular volume contraction from a low-sodium diet or diuretics, caution should be taken in starting an ACE inhibitor in those who might be most responsive. The response to an ACE inhibitor is usually well maintained, perhaps because its suppression of aldosterone mitigates the tendency

toward volume expansion that often antagonizes the effects of other antihypertensives. These drugs have been a mixed blessing for patients with renovascular hypertension. On the one hand, the response of plasma renin level to a single dose of captopril may provide a simple diagnostic test for the disease. More importantly, they usually control the blood pressure effectively.[148] On the other hand, the removal of the high levels of angiotensin II that they produce may deprive the stenotic kidney of the hormonal drive to its blood flow, thereby causing a marked decline in renal perfusion so that patients with solitary kidneys or bilateral disease may develop acute and sometimes persistent renal failure.[149] Patients with intraglomerular hypertension, specifically those with diabetic nephropathy or reduced renal functional mass due to other forms of renal parenchymal disease, may benefit especially from the reduction in efferent arteriolar resistance that follows reduction in angiotensin II. The clinical evidence for modulation of the progressive loss of renal function in diabetic and nondiabetic nephropathy is now unequivocal.[150] Whether this effect is quantitatively better with ACE inhibitors than that provided by other drugs is less certain. ACE inhibitors have been widely used in diabetic hypertensive patients, in part on the basis of earlier reports of their ability to improve insulin sensitivity. However, more recent data do not confirm the effect on insulin sensitivity.[151] More impressively, ACE inhibitor-based therapy was somewhat less effective in preventing diabetic complications than was beta-blocker therapy in the large and long United Kingdom Prospective Diabetes Study.[152] Therefore, the need for ACE inhibitors is considered as compelling for diabetic patients with nephropathy, hypertensive patients with heart failure, or systolic dysfunction after a myocardial infarction,[20] but these agents should be considered as equal to other classes in most other circumstances. Nonetheless, they may be the best tolerated antihypertensive agent[153] (along with ARBs), so their use will continue to grow. SIDE EFFECTS.

Most patients who take an ACE inhibitor experience neither the side effects nor the biochemical changes often accompanying other drugs that may be of even more concern even though they are not so obvious; neither rises in lipids, glucose, or uric acid nor reductions in potassium levels are noted. To be sure, ACE inhibitors may cause both specific and nonspecific adverse effects. Among the specific ones are rash, loss of taste, and leukopenia. In addition, they may cause a hypersensitivity reaction with angioneurotic edema or a cough, although often persistent, that is infrequently associated with pulmonary dysfunction.[154] The cough, affecting more than 10 percent of women and about half as many men, may not disappear for 3 weeks after the ACE inhibitor is discontinued.[155] If a cough appears in a patient who needs an ACE inhibitor, an ARB should be substituted. There is at least a potential problem for those patients taking an ACE inhibitor and coincidentally developing volume depletion, as from gastroenteritis, because they may be unable to marshal the compensatory homeostatic responses

TABLE 29-9 -- CLINICAL PHARMACOLOGY OF AVAILABLE ANGIOTENSIN II RECEPTOR BLOCKERS COMPOUND ACTIVE FOOD EFFECT HALF-LIFE METABOLITE (hr) Candesartan (Atacand)

Prodrug

No

9-10

Irbesartan (Avapro)

No

No

11-15

Losartan (Cozaar)

Yes

Modest

2-4

Telmisartan (Micardis)

No

No

18-24

Valsartan (Diovan)

No

Moderate

6-8

that involve increased angiotensin II and aldosterone. Finally, patients with renal insufficiency or on potassium supplements or sparing agents may not be able to excrete potassium loads and therefore may develop hyperkalemia. ANGIOTENSIN II RECEPTOR BLOCKERS

As the number of these agents being marketed quickly increases, they will be more widely used even in the absence of many outcome data. Those now available (Table 29-9) differ little save for a longer duration of action and perhaps a greater dose-response curve with the newer ones than with the first, losartan.[155] As more outcome data become available, ARBs may become an initial choice for many hypertensive patients. However, their price may be a consideration. Moreover, considering their presumed ability to block the response to angiotensin II more completely, they may end up being used in combination with ACE inhibitors.[140] Other Vasodilators

Various other forms of antihypertensive therapy are under investigation. These include endothelin receptor antagonists[156] and agents that inhibit both the ACE and neutral endopeptidase, thereby increasing atrial natriuretic hormone.[157] The distant future may see the application of gene therapy.[158] SPECIAL CONSIDERATIONS IN THERAPY RESISTANT HYPERTENSION.

There are numerous causes of resistance to therapy, usually defined as the failure of DBP to fall below 90 mm Hg despite the use of three or more drugs.[88] Patients often do not respond well because they do not take their medications. On the other hand, what appears to be a poor response based on office readings of blood pressure may be disclosed to be an adequate response when ambulatory or home readings are obtained.[159] However, a number of factors may be responsible for a poor response even if the appropriate medication is taken regularly (Table 29-10) . Most common is volume overload owing either to inadequate diuretic or to excessive dietary sodium

intake. Larger doses or more potent diuretics often bring resistant hypertension under control. Resistance is particularly common in patients with visceral obesity and associated insulin resistance.[160] A frequently overlooked cause is the interference by NSAIDs or aspirin[161] with virtually all antihypertensive drugs, with the exception of calcium antagonists and possibly ARBs.[162] Resistance can usually be overcome by adequate doses of a diuretic, a calcium antagonist, and an ACE inhibitor. ANESTHESIA IN HYPERTENSIVE PATIENTS.

In the absence of significant cardiac dysfunction, hypertension adds little to the cardiovascular risks of surgery.[163] If possible, however, hypertension should be well controlled by means of medications before anesthesia and surgery to reduce the

990

TABLE 29-10 -- CAUSES OF INADEQUATE RESPONSIVENESS TO THERAPY Pseudoresistance "White coat" or office elevations Pseudohypertension in the elderly Nonadherence to Therapy Side effects of medication Cost of medication Lack of consistent and continuous primary care Inconvenient and chaotic dosing schedules Instructions not understood Inadequate patient education Organic brain syndrome (e.g., memory deficit) Drug-Related Causes Doses too low Inappropriate combinations (e.g., two centrally acting adrenergic inhibitors) Rapid inactivation (e.g., hydralazine) Drug interactions Nonsteroidal antiinflammatory drug Sympathomimetics Nasal decongestants Appetite suppressants Cocaine Caffeine Antidepressants (MAO inhibitors, tricyclics)

Oral contraceptives Adrenal steroids Licorice (chewing tobacco) Cyclosporine Erythropoietin Cholestyramine

Excessive volume contraction with stimulation of rennin-aldosterone Hypokalemia (usually diuretic induced) Rebound after clonidine withdrawal Associated Conditions Smoking Increasing obesity Sleep apnea Insulin resistance/hyperinsulinemia Ethanol intake more than 1 ounce/day (>3 portions) Anxiety-induced hyperventilation or panic attacks Chronic pain Intense vasoconstriction (Raynaud's, arteritis) Secondary Hypertension Renal insufficiency Renovascular hypertension Pheochromocytoma Primary aldosteronism Volume Overload Excess sodium intake Progressive renal damage (nephrosclerosis) Fluid retention due to reduction of blood pressure Inadequate diuretic therapy Modified from Joint National Committee, Sixth Report of the Joint National Committee on detection, evaluation, and treatment of high blood pressure (JNC VI). Arch Intern Med 157:2413, 1997. Copyright 1997 American Medical Association. risk of myocardial ischemia.[164] Therefore, patients taking antihypertensive medications should continue these drugs, as long as the anesthesiologist is aware of their use and takes reasonable precautions to prevent wide swings in pressure. The very short-acting beta blocker esmolol has been successful in preventing surges in blood pressure during intubation,[118] and the use of atenolol protected coronary patients undergoing noncardiac surgery.[119] Hypertension is often observed during and immediately after coronary bypass surgery (see p. 965 ); various intravenous agents have been successfully used to lower the pressure. Nitroprusside has been the usual choice during the postoperative period, but toxicity, often in the form of loss of consciousness and cyanide or thiocyanate toxicity, may develop in those who are critically ill and given the drug for prolonged periods. Esmolol, labetalol, or nicardipine may be a better choice.[165] HYPERTENSIVE CHILDREN (see also p. 956 and Chap. 45) .

Almost nothing is known about the effects of various antihypertensive medications given to children over long periods. In the absence of adequate data, an approach similar to that advocated for adults is advised.[166] Emphasis should be placed on weight reduction in hypertensive children who are obese, in the hope of attempting to control

hypertension without the need for drug therapy. HYPERTENSION DURING PREGNANCY.

This topic is discussed in Chapter 65 . HYPERTENSION IN THE ELDERLY.

As noted on page 957 , a few elderly persons may have high blood pressure as measured by the sphygmomanometer but may have less or no hypertension when direct intraarterial readings are made, i.e., pseudohypertension due to rigid arteries that do not collapse under the cuff. If either the systolic pressure alone or both systolic and diastolic levels are elevated, careful lowering of blood pressure with either diuretics[5] or dihydropyridine calcium antagonists[22] has been unequivocally documented to reduce cardiovascular morbidity in older hypertensive patients extending to those older than 80 years.[11] Care is needed because they may have a number of problems with the medications (Table 29-11) . In view of the reduced effectiveness of the baroceptor reflex and the failure of peripheral resistance to rise appropriately with standing,[167] drugs with a propensity to cause postural hypotension should be avoided, and all drugs should be given in slowly increasing doses to prevent excessive lowering of the pressure. For those who start with systolic pressures exceeding 160 mm Hg, the goal of therapy should be a level around 140 mm Hg with little concern about further reductions in already low diastolic levels.[167A] PATIENTS WITH HYPERTENSION AND DIABETES.

Special attention should be given to diabetic patients with hypertension. The two commonly coexist and multiply the cardiovascular risks of each alone. Fortunately, evidence from several trials now documents the protection provided by intensive control of hypertension, preferably in concert with management of the diabetes and the dyslipidemia that commonly accompanies the two.[24] [32] [85] [152] Most diabetic hypertensive patients need two or more antihypertensive drugs to bring their pressure to below 130/85 mm Hg, which is likely the highest level that should be tolerated. An ACE inhibitor should be included if proteinuria is present. A diuretic and a beta blocker are appropriate, and a long-acting dihydropyridine will likely be required.[104A] Concerns about possible adverse effects of calcium antagonists in diabetic patients[168] have been absolved by their TABLE 29-11 -- FACTORS THAT MIGHT CONTRIBUTE TO INCREASED RISK OF PHARMACOLOGICAL TREATMENT OF HYPERTENSION IN THE ELDERLY FACTORS POTENTIAL COMPLICATIONS

Diminished baroreceptor activity

Orthostatic hypotension

Decreased intravascular volume

Orthostatic hypotension, dehydration

Sensitivity to hypokalemia

Arrhythmia, muscle weakness

Decreased renal and hepatic function

Drug accumulation

Polypharmacy

Drug interaction

Central nervous system changes

Depression, confusion

991

even greater protective effects in diabetic than nondiabetic persons, [24] [32] including those with nephropathy.[169] HYPERTENSIVE PATIENTS WITH IMPOTENCE.

Erectile dysfunction is common in hypertensive patients, even more so in those who are also diabetic.[170] The problem may be exacerbated by diuretic therapy, even in appropriately low doses.[100] Fortunately, sildenafil usually returns erectile ability, but caution is advised with antihypertensive drugs.[171] The potential for hypotension, well recognized with concomitant nitrate therapy, may also appear with other vasodilators, although to a lesser degree. HYPERTENSION WITH CONGESTIVE HEART FAILURE.

Cardiac output may fall so markedly in hypertensive patients who are in heart failure with systolic dysfunction that their blood pressure is reduced, obscuring the degree of hypertension; often, however, the DBP is raised by intense vasoconstriction while the systolic pressure falls as a result of the reduced stroke volume. Lowering the blood pressure may, by itself, relieve the heart failure. Chronic unloading has been most efficiently accomplished with ACE inhibitors, and beta blockers have been shown to further reduce morbidity and mortality in ACE inhibitor-treated patients in heart failure.[172] Caution is needed for those elderly hypertensive patients with diastolic dysfunction related to marked left ventricular hypertrophy, because unloaders may worsen their status, whereas beta blockers or calcium antagonists may be beneficial. As noted in Chapter 28 , left ventricular hypertrophy is frequently found by echocardiography, even in patients with mild hypertension. All antihypertensive drugs except direct vasodilators have been shown to regress left ventricular hypertrophy and regression may continue for as long as 5 years of treatment. [173] HYPERTENSION WITH ISCHEMIC HEART DISEASE.

The coexistence of ischemic heart disease makes antihypertensive therapy even more

essential, because relief of the hypertension may ameliorate the coronary disease. Beta blockers and calcium antagonists are particularly useful if angina or arrhythmias are present. Caution is needed to avoid decreased coronary perfusion that may be responsible for the J curve seen in several trials[32] (see p. 975 ). The often markedly high levels of blood pressure during the early phase of an acute myocardial infarction may reflect sympathetic nervous hyperreactivity to pain. Antihypertensive drugs that do not decrease cardiac output may be cautiously utilized in the immediate postinfarction period, whereas beta blockers[174] and ACE inhibitors[175] have been shown to provide long-term benefit. THERAPY FOR HYPERTENSIVE CRISES When DBP exceeds 140 mm Hg, rapidly progressive damage to the arterial vasculature is demonstrable experimentally, and a surge of cerebral blood flow may rapidly lead to encephalopathy ( p. 966 ). If such high pressures persist or if there are any signs of encephalopathy, the pressures should be lowered using parenteral agents in those patients considered to be in immediate danger or with oral agents in those who are alert and in no other acute distress. A number of drugs for this purpose are currently available (Table 29-12) . If diastolic pressure exceeds 140 mm Hg and the patient has any complications, such as an aortic dissection, a constant infusion of nitroprusside is most effective and almost always lowers the pressure to the desired level. Constant monitoring with an intraarterial line is mandatory because a slightly excessive dose may lower the pressure abruptly to levels that induce shock. The potency and rapidity of action of nitroprusside have made it the treatment of choice for life-threatening hypertension. However, nitroprusside acts as a venous and arteriolar dilator, so that venous return and cardiac output are lowered and intracranial pressures may increase. Therefore, other parenteral agents are being more widely used. These include labetalol and the calcium antagonist nicardipine.[165] With any of these agents, intravenous furosemide is often needed to lower the blood pressure further and prevent retention of salt and water. Diuretics should not be given if volume depletion is initially present. For patients in less immediate danger, oral therapy may be used. Almost every drug has been used and most will, with repeated doses, reduce high pressures. The prior preference for liquid nifedipine by mouth or sublingually has been deflated because of occasional ischemic complications from too rapid reduction in blood pressure.[137] Oral doses of other short-acting formulations may be used, including furosemide, propranolol, captopril, or felodipine. A safer course for any patients, particularly if their current high pressures are simply a reflection of stopping previously effective oral medication and they are asymptomatic, is simply to restart that medication and monitor their response TABLE 29-12 -- PARENTERAL DRUGS FOR TREATMENT OF HYPERTENSIVE EMERGENCY (IN ORDER OF RAPIDITY OF ACTION)

DRUG

DOSAGE

ONSET OF ACTION

ADVERSE EFFECTS

Vasodilators Nitroprusside (Nipride, Nitropress)

0.25-10 mug/kg/min Instantaneous as IV infusion

Nausea, vomiting, muscle twitching, sweating, thiocyanate intoxication

Nitroglycerin

5-100 mug/min as IV infusion

2-5 min

Tachycardia, flushing, headache, vomiting, methemoglobinemia

Nicardipine (Cardene)

5-15 mg/hr IV

5-10 min

Tachycardia, headache, flushing, local phlebitis

Hydralazine (Apresoline)

10-20 mg IV 10-50 mg IM

10-20 min 20-30 min

Tachycardia, flushing, headache, vomiting, aggravation of angina

Enalapril (Vasotec IV)

1.25-5 mg q 6 hr

15 min

Precipitous fall in blood pressure in high renin states; response variable

Fenoldopam (Corlopam)

0.1-0.3 mug/kg/min

1000 mg/dl). Affected individuals do not necessarily have increased coronary risk, but they do have recurrent bouts of pancreatitis and eruptive xanthomas. Interestingly, severe hypertriglyceridemia may also be associated with xerostomia and xerophthalmia and with abnormalities in behavior. The hyperchylomicronemia results from a markedly reduced or absent LPL activity or, more rarely, by the absence of its activator, apo CII (see Table 31-3 , Fig. 31-4 ,2). [50] [51] These deficiencies lead to a lack of hydrolysis of chylomicrons and VLDL and to accumulation of these lipoproteins in plasma, especially in the postprandial phase. Extreme elevations of plasma triglycerides of more than 11.3 mmol/liter (>10,000 mg/dl) can occur. The plasma from a patient with very high triglyceride levels is milky white; and after a specimen stands overnight in a refrigerator, a clear band of chylomicrons appears at its top. The prevalence of mutations at the LPL gene locus are relatively frequent in populations with a founder effect (see also Chap. 56) . Multiple mutations at the LPL gene locus have been identified, with LPL188 , LPLAsn291Ser , and LPL207 being frequently associated with hyperchylomicronemia. There are at least 60 LPL mutations that cause LPL deficiency.[52] Heterozygotes for the disorder tend to have an increase in fasting plasma triglyceride levels and smaller, denser LDL particles. Many patients with complete LPL deficiency present in childhood with failure to thrive and recurrent bouts of pancreatitis. Consistent with the importance of the role of LPL, mice deficient in this enzyme have a lethal phenotype.[53] Treatment of acute pancreatitis in patients with familial hyperchylomicronemia consists of intravenous hydration and avoidance of fat in the diet (including in parenteral

nutrition). Rarely, plasma filtration may be required. Chronic treatment includes avoidance of alcohol and dietary fats. The use of short-chain fatty acids (which are not incorporated in chylomicrons) can make the diet more palatable. TYPE III HYPERLIPOPROTEINEMIA

Type III hyperlipoproteinemia, also referred to as dysbetalipoproteinemia or "broad beta disease," is a rare genetic lipoprotein disorder characterized by an accumulation in plasma of remnant lipoprotein particles.[54] Agarose gel electrophoresis of the lipoproteins yields a typical pattern of a broad band between the pre-beta (VLDL) and beta (LDL) lipoproteins, hence its name. Affected individuals clearly have increased cardiovascular risk. Clinical features include tuberous xanthomas and palmar striated xanthomas, which are pathognomonic of the disease. The total plasma cholesterol level is increased, as are triglyceride levels; the HDL-C value is reduced. Remnant lipoproteins (partly catabolized chylomicrons and VLDL) accumulate in plasma and are enriched in cholesterol esters. The defect is due to abnormal apo E that does not bind to hepatic receptors using apo E as a ligand, initially the LDL receptor (see Fig. 31-4 ,3). Patients with type III hyperlipoproteinemia have increased ratio of VLDL-C to triglycerides, normally less than 0.7 in mmol/liter (< 0.30 in mg/dl), owing to cholesteryl ester enrichment of remnant particles. The diagnosis includes plasma ultracentrifugation for lipoprotein separation, lipoprotein electrophoresis, and apo E phenotyping or genotyping. There are three common alleles for apo E: apo E2, E3, and E4. Patients with type III hyperlipoproteinemia have the apo E2/2 phenotype or genotype. The apo E2 allele has markedly decreased binding to the apo B:E (LDL) receptor. Normal populations have a prevalence of the apo E2/2 genotype of 0.7 to 1.0 percent. Type III hyperlipoproteinemia is only seen in approximately 1 percent of subjects bearing the apo E2/2 phenotype. The reasons for the relative rarity of type III dyslipoproteinemia (or low penetrance of the E2/2 genotype) are not fully understood. A second "hit" may enable the full expression of the disorder. Other rare mutations of the apo E gene can also cause type III hyperlipoproteinemia.[55] Apo E-deficient mice currently serve as one useful model for the study of atherosclerosis. Type III dyslipoproteinemia generally responds well to dietary therapy and to correction of other metabolic abnormalities (diabetes, obesity). In some cases it requires drug therapy, such as with fibric acid derivatives or statins. FAMILIAL COMBINED HYPERLIPIDEMIA.

One of the most common familial lipoprotein disorders is familial combined hyperlipoproteinemia (FCH). Described initially in survivors of myocardial infarction,[56] FCH has undergone several definitions since its original description. The presence in several members of the same family of elevated total cholesterol and/or triglycerides based on arbitrary cut-points defines FCH. The disorder must be identified in at least one first-degree relative for a diagnosis of FCH. The biochemical abnormalities include the elevation of plasma total and LDL-C (> 90th or 95th percentile), and/or an elevation of plasma triglycerides (> 90th to 95th percentile), a type IIb lipoprotein phenotype, a reduction in HDL-C, and elevation in apo B levels; small, dense LDL particles are frequently seen. Measurement of LDL-C and, in some cases, apo B levels can further

characterize this disorder. Because of the lack of a clear-cut clinical or biochemical marker, there is considerable overlap between FCH, familial dyslipidemic hypertension, the insulin-resistance metabolic syndrome, and hyperapobetalipoproteinemia.

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There are few clinical features of FCH; corneal arcus, xanthomas, and xanthelasmas occur infrequently. The underlying metabolic disorder appears to be hepatic overproduction of apo B-containing lipoproteins, delayed postprandial triglyceride-rich lipoprotein clearance, and increased flux of free fatty acids (FFA) to the liver. Experimental data have shown that hepatic apo B secretion is substrate driven, the most important substrates being FFA and cholesteryl esters. The increased delivery of FFA to the liver that occurs in states of insulin resistance augments hepatic apo B secretion. Genetic heterogeneity probably underlies FCH. The prevalence of FCH is reported at approximately 1:50 and accounts for 10 to 20 percent of patients with premature coronary artery disease.[57] FCH has complex genetics. Initially considered to be an autosomal codominant trait, a more complex mode of inheritance may pertain. Phenotypical expression of the disease varies with gender, age, diet, and comorbid states such as obesity and lack of exercise. Initial reports of linkage with the apo AI-CIII-AIV and LPL genes have not been substantiated. A novel locus on chromosome 1 in Finnish families appears promising in the identification of genes related to FCH.[58] Recent reports of the acylation stimulating protein (ASP) pathway suggests that abnormal peripheral uptake of FFA may underlie some cases of FCH and the insulin-resistance metabolic syndrome (see Fig. 31-3 D). ASP regulates FFA uptake by tissues. According to this scheme, increased flux of FFAs to the liver caused by this decreased uptake and utilization at the periphery drives hepatic apo B-containing lipoprotein assembly and secretion.[59] Abnormalities of HDL Metabolism

Observational studies have consistently linked a reduced plasma level of HDL-C to the development or presence of coronary artery disease. Most cases of reduced HDL-C result secondarily from elevated plasma triglycerides or apo B levels. These abnormalities often cluster with other features of the insulin-resistant metabolic syndrome (see also Chap. 63) . Familial hyperchylomicronemia, familial hypertriglyceridemia, and FCH are all associated with reduced HDL-C levels. Primary forms of low HDL-C, although less common, also are associated with premature coronary artery disease. Close study of these abnormalities has shed new light on the complex metabolism of HDL particles. Genetic disorders can cause either decreased production of HDL or abnormal maturation and increased catabolism of HDL or its primary apoprotein, AI. Primary defects affecting production of HDL particles consist predominantly in apo

AI-CIII-AIV gene defects. There are approximately a dozen reported mutations affecting the structure of apo AI[38] [60] with a marked reduction in HDL-C levels. Not all these defects cause premature cardiovascular disease. Clinical presentations can vary from extensive, atypical xanthomatosis and corneal infiltration of lipids to no manifestations. The treatment of these apo AI gene defects is generally unsuccessful in raising HDL-C levels. Other mutations of apo AI accelerate apo AI catabolism and may not be linked with cardiovascular disease. One such mutation, apo AIMilano (apo AIArg173Cys ), may be associated with longevity.[60] Genetic defects in the HDL-processing enzymes give rise to interesting phenotypes. Deficiencies of LCAT, which catalyzes the formation of cholesteryl esters in plasma, cause corneal infiltration of neutral lipids and hematological abnormalities because of abnormal constitution of red blood cell membranes. LCAT deficiency can cause an entity called "fish eye disease" because of the characteristic pattern of corneal infiltration observed in affected individuals.[61] Patients with absent CETP have very elevated HDL-C levels, enriched in cholesteryl esters.[62] Because CETP facilitates the transfer of HDL cholesteryl esters into triglyceride-rich lipoproteins, a deficiency of this enzyme causes accumulation of cholesteryl esters within HDL particles. Despite the high HDL levels, CETP may not afford protection against coronary artery disease.[63] A rare disorder of HDL deficiency was first identified in a proband from the island of Tangier in the Chesapeake Bay in the United States. The proband has markedly enlarged yellow tonsils and a near absence of HDL-C. His sister was also affected, and the entity was named Tangier disease.[64] Since then, at least 50 cases have been reported worldwide.[65] The cellular defect in Tangier disease has been identified as a reduced cellular cholesterol efflux in skin fibroblasts from affected subjects. [36] A more common entity, familial HDL deficiency, also results from decreased cellular cholesterol efflux. The genetic defect in Tangier disease and in familial HDL deficiency has been identified as a result of mutations of ABC1, which encodes CERP (see Fig. 31-3 C). [33] [34] [35]

OTHER CHOLESTEROL TRANSPORT DEFECTS

Niemann-Pick disease type C is a disorder of lysosomal cholesterol transport. Mental retardation and neurological manifestations occur frequently in patients with Niemann-Pick disease type C. The cellular phenotype includes markedly decreased (acid) sphingomyelinase activity, reduced cholesterol esterification, and a cellular cholesterol transport defect involving the Golgi apparatus. Unlike Tangier disease/familial HDL deficiency, the cellular defect in Niemann-Pick disease type C appears therefore to be proximal to the transport of cholesterol to the plasma membrane. The gene for Niemann-Pick disease type C (NPC1), mapped to the chromosomal location 18q21, encodes a 1278-amino acid protein of as yet unknown function. The NPC1 gene product shares homology with the morphogen receptor "patched" and the SREBP cleavage activating protein (SCAP).[66] [67] Secondary Causes of Dyslipidemia

Several clinical disorders secondarily alter lipoprotein status (Table 31-5) .[68] HORMONAL CAUSES OF DYSLIPIDEMIA (see also Chap. 64) .

Hypothyroidism often causes elevated levels of LDL-C, triglycerides, or both. An elevated thyroid stimulating hormone (TSH) value is key to the diagnosis, and the lipoprotein abnormalities often revert to normal once the thyroid status is corrected. Rarely, hypothyroidism may uncover a genetic lipoprotein disorder such as type III hyperlipidemia. A TSH level should be obtained on all patients with unexplained elevations in triglyceride levels. Estrogens can increase plasma triglyceride levels and HDL-C owing to increases in hepatic VLDL secretion and apo AI secretion (see also Chap. 58) . In postmenopausal women, estrogens may reduce LDL-C by 0-15%. Rarely, pregnancy, in a woman with LPL deficiency, severely increases plasma triglyceride levels. Such cases present a serious threat to mother and child and must be referred to specialized centers. Male sex hormones and anabolic steroids may increase hepatic lipase activity and have been used in the treatment of hypertriglyceridemia in men. Growth hormone use reduces LDL-C and increases TABLE 31-5 -- SECONDARY CAUSES OF DYSLIPOPROTEINEMIAS Metabolic Diabetes Lipodystrophy Glycogen storage disorders Renal Chronic renal failure Glomerulonephritis Nephrotic syndrome Liver Disease Obstructive liver disease Cirrhosis Hormonal Estrogens Progesterones Growth hormone Thyroid disorders (hypothyroidism) Lifestyle

Physical inactivity Obesity Diet rich in fats, saturated fats Alcohol intake Medications Immunosuppressive agents Corticosteroids Retinoids Highly active antiretroviral therapy Thiazides Beta-adrenergic blockers

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HDL-C but is not recommended in the treatment of lipoprotein disorders. METABOLIC CAUSES OF DYSLIPIDEMIA.

The constellation of metabolic abnormalities seen in the insulin-resistance metabolic syndrome currently constitutes the most frequent secondary cause of dyslipidemia (see also Chap. 63) . The findings of increased visceral fat (abdominal obesity), elevated blood pressure, and peripheral insulin resistance frequently cluster with increased plasma triglyceride levels and a reduced HDL-C level. Elevated plasma triglyceride levels and a low HDL-C value often accompany overt diabetes, especially type II adult-onset diabetes.[69] These abnormalities have prognostic implications in patients with type II diabetes. Although type II diabetics often do not have marked elevations in LDL-C levels, those with coronary artery disease benefit from lipid-lowering therapy with a statin.[70] One recent angiographic trial (Flu Diabetes Atherosclerosis Intervention Study [DAIS]) showed slowed progression in diabetic patients treated with a fibric acid derivative, fenofibrate, which lowered triglyceride levels and raised HDL-C levels.[71] Poorly controlled diabetes, obesity, and moderate to severe hyperglycemia can yield severe hypertriglyceridemia with chylomicronemia and increased VLDL. Subjects with juvenile diabetes may also present with severe hypertriglyceridemia when the diabetes is poorly controlled. Familial lipodystrophy (complete or partial) may be associated with increased VLDL secretion. In glycogen storage disorders, elevated plasma triglyceride levels are often encountered. RENAL DISORDERS AND DYSLIPIDEMIA.

Glomerulonephritis or protein-losing nephropathies can cause a marked increase in secretion of hepatic lipoproteins, elevating LDL-C levels, which may approach the levels seen in FH.[72] [73] In contrast, patients with chronic renal failure have a pattern of hypertriglyceridemia with reduced HDL-C. Patients on hemodialysis or chronic ambulatory peritoneal dialysis also exhibit similar lipoprotein changes. Many

hemodialysis patients have elevations in Lp(a). After organ transplantation, the immunosuppressive regimen (glucocorticoids and systemic immunosuppressive drugs) can contribute to elevation in triglyceride levels and a reduced HDL-C level. LIVER DISEASE AND DYSLIPIDEMIA.

Obstructive liver disease, especially primary biliary cirrhosis, may lead to the formation of an abnormal lipoprotein termed lipoprotein-x (Lp-x).[74] This type of lipoprotein is found in LCAT deficiency and consists of an LDL-like particle, but with a marked reduction in cholesteryl esters. Extensive xanthoma formation on the face and palmar areas can result from accumulation of Lp-x. DYSLIPIDEMIA ASSOCIATED WITH THERAPY FOR ACQUIRED IMMUNODEFICIENCY SYNDROME (See also Chap. 68) .

The introduction of inhibitors of a major protease of human immunodeficiency virus-1 (HIV-1) has markedly prolonged the survival of infected individuals.[75] Although HIV protease inhibitors have emerged as the cornerstone of highly active antiretroviral therapy (HAART), these agents can cause secondary dyslipidemia.[76] [77] Treatment with HAART results in increased levels of triglyceride-rich lipoprotein particles, such as VLDL.[78] In addition to the rise in total cholesterol and triglyceride levels, HAART causes a concomitant decrease in HDL levels. Reminiscent of the diabetic dyslipidemic syndrome, these changes in lipoprotein profile go hand in hand with hyperinsulinemia and insulin resistance.[79] Moreover, there is a striking and prevalent association of HAART with lipodystrophy. Specifically, patients receiving HAART often have a decreased peripheral accumulation of adipose tissue, while central adiposity increases. Although in most instances, the lipodystrophy is mild to moderate, more striking alterations can occur, including development of a "buffalo hump."[80] Potential clinical consequences of HAART-associated dyslipidemia may include premature atherosclerosis and pancreatitis due to hypertriglyceridemia. The mechanism of HAART-associated dyslipidemia remains obscure. Recent metabolic studies have shown maintained levels of LPL but decreased levels of hepatic lipase, and evidence for increased production of VLDL. Interestingly, the HIV protease active site has homology to two receptors involved in lipid metabolism.[81] The lipoprotein-related receptor has regions of approximately 60 percent sequence similarity with the HIV protease. Thus, HIV protease inhibitors might interfere with the function of this remnant receptor involved in clearing certain triglyceride-rich lipoprotein particles. The HIV protease also shares sequence similarity with regions of a retinoid binding protein known as CRAB1.[81] [82] By binding to CRAB1, HIV protease inhibitors might interfere with the synthesis of cis-9-retinoic acid. The retinoic acids are, of course, classic ligands for the retinoid X receptor (RXR). When liganded RXR pairs with another nuclear receptor, PPAR gamma, and forms an active transcription factor known to control adipocyte differentiation and insulin sensitivity.[83] Thus, the HIV protease inhibitors might interfere with the activation of these transcription factors and contribute to the lipodystrophy and insulin resistance.

Management.

The treatment of HAART-associated dyslipidemia requires control of triglyceride levels, particularly in patients with or at risk for pancreatitis. Treatment with fibric acid derivatives may help in this regard. No systematic information exists yet regarding the effect of lipid-lowering therapy on outcomes in individuals with HAART-associated dyslipidemia. However, reports of management of this dyslipidemia with fibric acid derivatives alone, or in combination with HMG CoA reductase inhibitors, have appeared. Because agents included in HAART can interfere with the metabolism of concomitantly administered drugs due to changes in cytochrome p450 isoform function, addition of lipid-lowering agents to HAART requires careful consideration of potential drug interactions. OTHER MEDICATIONS.

Several medications commonly cause alterations in lipoproteins.[68] Thiazide diuretics can increase plasma triglyceride levels. Beta blockers, especially the non-beta1 -selective agents, increase triglycerides and lower HDL-C levels. Retinoic acid can increase triglyceride levels, sometimes dramatically. Corticosteroids and immunosuppressive agents can increase plasma triglyceride levels.[84] Because transplantation recipients and patients on this class of drugs generally have an increase in cardiovascular risk, this secondary hyperlipidemia may warrant treatment (see also Chap. 30) .[85] Estrogens can increase plasma HDL-C significantly and may also increase triglyceride concentrations, sometimes substantially.[86] [87] LIFESTYLE FACTORS CONTRIBUTING TO DYSLIPIDEMIA.

Factors contributing to obesity, such as an imbalance between caloric intake and energy expenditure, lack of physical activity, and a diet rich in saturated fats and refined sugars, contribute in large part to the lipid and lipoprotein lipid levels within a population. In clinical practice, many dyslipoproteinemias other than the genetic forms mentioned earlier share important environmental components. Lifestyle changes (diet, exercise, reduction of abdominal obesity) remain the cornerstone of the treatment of most dyslipidemias. (See later and Chap. 32 for more information on exercise and obesity.) The effects of marked alterations in lifestyle,[88] reduction in dietary fats, especially saturated fats,[89] and exercise[90] can improve cardiovascular prognosis (see later and Chap. 32) . Translating these findings into practice, however, has been more difficult. For instance, dietary manipulations as performed in a physician's office lead to relatively small reductions in plasma lipid and lipoprotein cholesterol levels.[91] Management of Lipoprotein Disorders GENERAL APPROACHES.

Cardiologists must consider evaluation and management of dyslipidemia an integral part

of their practice. Two major questions confront the

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clinician treating patients with lipoprotein disorders. First, are there secondary causes for the dyslipoproteinemia and, second, what risk does this disorder have for the patient's health? The clinical evaluation should include a thorough history, including a complete family history that may reveal clues about genetic etiology and genetic susceptibility to cardiovascular disease. Most patients with dyslipoproteinemias have few symptoms. Exceptions include those with severe hypertriglyceridemia, who may present with acute pancreatitis, and those with familial lipoprotein disorders, who have cutaneous manifestations (xanthomas, xanthelasmas). Other risk factors should be sought (cigarette smoking, diabetes) along with secondary causes (diet, physical activity, alcohol intake). Concomitant medication use should be investigated; alternative treatments should be considered that avoid alterations in the lipid profile. The physical examination should include a search for xanthomas (in extensor tendons, including hands, elbows, knees, Achilles' tendons, as well as palmar xanthomas), the presence of xanthelasmas, and corneal arcus, corneal opacifications. Blood pressure, waist circumference, weight, and height should be recorded, and signs of vascular compromise must be carefully examined. A complete cardiovascular examination must be performed. The diagnosis of lipoprotein disorders is based on laboratory measurements (Table 31-6) . The lipid profile generally suffices for most lipoprotein disorders, and specialized laboratories can refine the diagnosis and provide expertise for extreme cases. Additional tests (e.g., measurement of apolipoprotein levels or of LDL particle size) increase cost and may not add predictive power beyond that of the lipid profile but may help to refine the diagnosis. It is advisable to stop all lipid-lowering therapy for 1 month before measuring a lipid profile during initial evaluation. Except in severe hypertriglyceridemia, this measure is unlikely to have a clinically significant adverse effect. At least two lipid profiles should be obtained, and secondary causes should be explored by the measurement of TSH and glucose. Baseline aspartate and alanine aminotransferases and creatinine kinase should also be obtained in candidates for drug therapy. SPECIFIC TREATMENTS.

The therapeutic options consist of lifestyle modifications, treatment of secondary causes, if possible, diet, and medications (see Chap. 33 for an extensive discussion of pharmacotherapy). The diet should have three objectives: (1) it should allow the patient to reach and maintain ideal body weight; (2) it should provide a well-balanced diet with fruits, vegetables, and grains; and (3) it should be restricted in saturated fats and refined carbohydrates.[92] The services of a professional dietitian prove valuable in this regard. Present guidelines recommend a diet in which protein intake represents 15 to 20 percent of calories and fats represent 25 to 30 percent (with only one third from

saturated fats).[93] The remaining calories are obtained from carbohydrates. Cholesterol intake is limited to less than 300 mg/d. Alcohol is not part of the current recommendations, although up to 2 drinks per day is associated with decreased cardiovascular deaths in many studies. The high cost of alcohol-related accidents, violent deaths, and liver disease, however, makes any recommendation regarding alcohol intake controversial. Although dietary changes should be instituted in most if not all the clinically relevant dyslipidemias, medications should be concomitantly initiated along with dietary changes in high-risk subjects, because in many cases the patient's diet may be insufficient to reach target levels. Chapter 33 reviews in detail the evidence base supporting the use of lipid-lowering interventions (pharmacological and nonpharmacological) in clinical trials. This section is provided as a "how to" guide to the use of currently available lipid-lowering agents.[68] RESINS.

The bile acid-binding resins act to interrupt the enterohepatic circulation of bile acids by inhibiting their reabsorbtion in the intestine (bile acids that contain cholesterol are more than 90 percent reabsorbed through this pathway). Their main indication is as adjunctive therapy in patients with severe hypercholesterolemia due to increased LDL-C. Because bile acid binding resins are not absorbed systemically (they remain in the intestine and are eliminated in the stool), they are considered safe in children. Cholestyramine (Questran) is used in 9-gm unit doses (containing 4 grams of anhydrous resin) as powder, and colestipol (Colestid) is used in 5-gm unit doses; a 1-gm tablet of colestipol is available. Effective doses range from two to six unit doses per day, always taken with meals. The side effects are predominantly gastrointestinal, with constipation, a sensation of fullness, and gastrointestinal discomfort being the most important ones. Hypertriglyceridemia can result from the use of these drugs. Decreased drug absorption dictates careful scheduling of medications 1 hour before or 3 hours after taking bile acid-binding resins. Bile acid-binding resins can be used in combination with statins in cases of severe hypercholesterolemia. HMG CoA REDUCTASE INHIBITORS (STATINS).

The development of the statins has led to a further validation of the lipid hypothesis. Their target is the rate-limiting enzyme for cholesterol synthesis. Under treatment, maintenance of cellular cholesterol homeostasis involves increased expression of the LDL-R and decreased rate of cholesteryl ester formation. These changes increase LDL-C clearance from plasma and decrease hepatic production of VLDL and LDL. The statins are generally very well tolerated; side effects include hepatotoxicity and myositis, which necessitate discontinuation of the drug in approximately 1 percent of patients. The currently available drugs include fluvastatin (Lescol), 20 to 80 mg/d; lovastatin (Mevacor), 20 to 80 mg/d; pravastatin (Pravachol), 20 to 40 mg/day; simvastatin (Zocor) 10 to 80 mg/d; atorvastatin (Lipitor) 10 to 80 mg/d; and cerivastatin (Baycol), 0.2 to 0.4 mg/d. There is considerable debate regarding the degree to which these drugs exert beneficial effects on cellular function independent from their effects on cholesterol

TABLE 31-6 -- LABORATORY TESTS FOR THE DIAGNOSIS OF LIPOPROTEIN DISORDERS LIPID MAY HELP IN SPECIALIZED RESEARCH PROFILE DIAGNOSIS CENTERS TOOLS Cholesterol

Lipoprotein separation by LDL particle size UTC

Triglycerides

Apo B

LPL assay

HDL-C

Apo AI

LCAT assay

Apo E genotype/phenotype

Apo E levels

Lp(a)

Apolipoprotein separation by PAGE

LDL-C

*

Molecular diagnosis

LDL-R assay Apo CII, CIII PAGE=polyacrylamide gel electrophoresis. Ultracentrifugation. *Calculated as LDL-C=Cholesterol - (Triglycerides/2.2+HDL-C) in mmol/liter (or triglycerides divided by 5 in mg/dl); valid for triglycerides < 4.5 mmol/liter ( 100 mumol/liter) and can have premature atherothrombosis. The mechanisms that account for these effects remain uncertain but may include endothelial toxicity, accelerated oxidation of LDL-C, impairment of endothelial-derived relaxing factor, and reduced flow-mediated arterial vasodilation.[225] [226] [227] [228] In contrast to severe hyperhomocystinemia, mild to moderate elevations of homocysteine (plasma levels > 15 mumol/liter) are common in general populations, primarily due to insufficient dietary intake of folic acid.[229] Other patient groups that tend to have elevated homocysteine levels include those with common polymorphisms in the methylene tetrahydrofolate reductase gene (MTHFR), those receiving folate antagonists

such as methotrexate and carbamazepine, and those with impaired homocysteine metabolism due to hypothyroidism or to renal insufficiency.[230] [231] In most clinical settings, total plasma homocysteine (the combination of free homocysteine, bound homocystine, and mixed disulfides) is measured by high-performance liquid chromatography, although reliable and less expensive immunoassay

Figure 31-7 Relative risks of future myocardial infarction among apparently healthy middle aged men according to baseline levels of lipoprotein(a) (Lp[a]), D -dimer, total plasma homocysteine (tHCY), total cholesterol (TC), fibrinogen, soluble intercellular adhesion molecule type-1 (sICAM-1), tissue type plasminogen activator antigen (tPA:ag), the total to HDL cholesterol ratio (TC:HDLC), interleukin-6 (IL-6), high sensitivity C reactive protein (hs-CRP), and the combination of hs-CRP and the TC:HDLC ratio. For consistency, risks are computed for those in the top quartile compared with the bottom quartile. (From Ridker PM: Novel risk factors and markers for coronary disease. Adv Intern Med 45:391-418, 2000.)

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TABLE 31-7 -- ASSESSMENT OF THE CLINICAL UTILITY OF NOVEL MARKERS OF CARDIOVASCULAR RISK MARKER ASSAY PROSPECTIVE ADDITIVE TO TOTAL CONDITIONS STUDIES AND HIGH-DENSITY STANDARDIZED? CONSISTENT? LIPOPROTEIN CHOLESTEROL? Lipoprotein(a)

No

Yes/no

Yes/no

Total homocysteine Yes

Yes/no

Yes/no

Tissue-type plasminogen activator and plasminogen activator inhibitor

Yes/no

Yes

Yes/no

Fibrinogen

Yes/no

Yes

Yes

High-sensitivity C-reactive protein

Yes

Yes

Yes

From Ridker PM: Evaluating novel cardiovascular risk factors: Can we better predict heart attacks? Ann Intern Med 130:933-937, 1999. techniques now exist. Although a nonfasting evaluation of total plasma homocysteine suffices for most clinical purposes, measurement of homocysteine levels 2 to 6 hours after ingestion of an oral methionine load (0.1 gm/kg body mass) can identify individuals with impaired homocysteine metabolism despite normal fasting levels.

A large series of cross-sectional and retrospective studies indicate a positive relationship between mild to moderate hyperhomocystinemia and atherosclerosis; on average, those with plasma levels above 15 mumol/liter appear to have a relative risk one and one-half to two times higher than individuals with lower levels.[232] [233] However, because homocysteine levels increase after myocardial infarction and stroke,[234] [235] such data cannot be used to establish a cause-and-effect relationship. By contrast, prospective epidemiological studies (where homocysteine levels are ascertained before the onset of cardiovascular events) have provided mixed data. For example, although positive prospective studies have been reported among apparently healthy middle-aged men[236] [237] [238] and women[239] [240] as well as among those with known coronary atherosclerosis,[241] it is important to recognize that several high-quality prospective studies have found no relationship between baseline homocysteine levels and subsequent vascular risk.[242] [243] [244] Furthermore, although some studies have found positive associations both among those taking and not taking multivitamins,[239] this effect lacks consistency. Finally, in some of the "positive" cohort studies, no evidence of association was seen with longer-term follow-up.[245] Thus, prospective studies of hyperhomocystinemia do not provide consistent evidence of association (Fig. 31-8). Moreover, the width of the 95 percent confidence intervals in these studies indicates a modest magnitude of any true increase in risk associated with homocysteine, perhaps limited to those individuals with markedly elevated levels. Due in part to this lack of compelling epidemiological data, current recommendations from both the American Heart Association and the American College of Cardiology do not recommend population-based screening for homocysteine.[230] The observation that mutation in the MTHFR gene leads to hyperhomocysteinemia but not to increased vascular risk also reduces enthusiasm for screening, at least from a genetic perspective. [246]

Recent fortification of the United States food supply with folate to reduce the risk of neural tube defects[247] also complicates clinical issues in terms of screening for hyperhomocystinemia. Since its initiation in 1992, the addition

Figure 31-8 Prospective studies of homocysteine as a risk factor for future cardiovascular events in populations free of clinical disease. PHS = Physicians' Health Study; MRFIT = Multiple Risk Factor Intervention Trial; BUPA = British United Provident Association; ARIC = Atherosclerosis Risk in Communities; WHS = Women's Health Study. (From Ridker PM: Novel risk factors and markers for coronary disease. Adv Intern Med 45:391-418, 2000.)

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of small amounts of folic acid to enriched flour and grain products has resulted in a 9 to 10 percent drop in mean population homocysteine levels and an almost 50 percent drop in the number of individuals with homocysteine levels within the moderately elevated range.[248] Thus, the number of individuals potentially identifiable by general screening

has decreased considerably over just a few years. In some patient groups, such as those with premature atherosclerosis, an absence of other risk factors or in the setting of renal failure, homocysteine screening may have increased utility. Folic acid, given in doses of up to 400 mug/d, can be expected to reduce homocysteine levels approximately 25 percent, whereas the addition of vitamin B12 will likely reduce levels another 7 percent.[249] Because this therapy is inexpensive and has low toxicity in the absence of vitamin B12 deficiency, vitamin supplementation may be a more cost-effective approach for high-risk groups than screening.[230] No randomized trial data are available that demonstrate that reducing homocysteine levels reduces coronary risk. Fibrinogen

Plasma fibrinogen critically influences platelet aggregation and blood viscosity, interacts with plasminogen binding, and in combination with thrombin mediates the final step in clot formation.[250] In addition, fibrinogen associates positively with age, obesity, smoking, diabetes, and LDL-C and inversely with HDL-C, alcohol use, physical activity, and exercise level.[251] [252] Given these relationships, it is not surprising that fibrinogen was among the first "novel" risk factors to be evaluated in epidemiological studies. Early reports from the Gothenburg,[253] Northwick Park,[254] and Framingham[255] heart studies all found significant positive associations between fibrinogen and future risk of cardiovascular events. A series of prospective studies have since confirmed these results,[256] [257] [258] [259] [260] [261] and a recent meta-analysis indicates that the relative risk of future cardiovascular events is 1.8 times higher for individuals in the top as compared with the bottom tertile of baseline fibrinogen concentration.[262] Women may have higher risks, although confounding by the effects of hormone replacement therapy limit interpretation of available studies.[263] Plasma viscosity, determined in part by fibrinogen level, also predicts cardiovascular risk.[264] [265] Due to the consistency of these data, many consider fibrinogen an independent marker of risk for coronary heart disease.[266] However, two issues have limited clinical screening for fibinogen to improve risk prediction: (1) inadequate standardization between competing laboratory techniques and (2) wide intraindividual variation in plasma levels over time.[267] In addition, because smoking and estrogen replacement therapy appear to have opposite effects on fibrinogen levels,[127] [268] [269] care must be taken when interpreting results for these subgroups. Furthermore, the magnitude to which fibrinogen assessment improves coronary risk prediction models has varied widely in different studies[270] [271] Despite major genetic determinants of fibrinogen concentration,[272] [273] substantial variation in plasma levels results from environmental factors. Smoking cessation, increased exercise, and weight loss can reduce fibrinogen concentration. Fibric acid derivatives also reduce fibrinogen, apparently through a PPAR-alpha mechanism.[274] [275] However, results of the Bezafibrate Infarction Prevention Trial do not show a significant

decrease in vascular risk despite an overall 9 percent reduction in fibrinogen due to drug administration.[276] Furthermore, although hormone replacement therapy also reduces fibrinogen levels, this effect did not translate into a net clinical benefit among participants in HERS.[217] Fibrinogen elevation occurs as part of the acute-phase response and may thus be associated with risk owing to its role as a marker of systemic inflammation. However, as is reviewed later in this chapter, other markers of inflammation such as hs-CRP appear to be more powerful than fibrinogen in terms of risk prediction Lipoprotein(a)

As described on page 1017 , Lp(a) consists of an LDL particle with its apo B-100 component linked by a disulfide bridge to apo(a), a variable length protein that has sequence homology to plasminogen.[47] The apo(a) component of Lp(a) is a complex molecule composed in part of varying numbers of cysteine-rich kringle repeats that result in great heterogeneity. Plasma Lp(a) concentrations vary inversely with apo(a) isoform size but may vary even within isoform size based on differential levels of production.[277] Underlying its molecular complexity, more than 25 heritable isoforms of Lp(a) exist.[47] This molecular variability has clinical import because Lp(a) levels vary widely across ethnic groups. Although the normal function of Lp(a) is unknown, the close homology between Lp(a) and plasminogen has raised the possibility that this unusual lipoprotein may inhibit endogenous fibrinolysis by competing with plasminogen for binding on the endothelial surface.[278] More recent data demonstrate accumulation of Lp(a) and co-localization with fibrin within atherosclerotic lesions, both in stable patients and among those with unstable angina pectoris.[279] [280] Apo(a) may also induce monocyte chemotactic activity in the vascular endothelium,[281] whereas Lp(a) may increase release of PAI.[282] Thus, several mechanisms may contribute to a role for Lp(a) in atherothrombosis. Many retrospective and cross-sectional studies suggest a positive association between Lp(a) and vascular risk. However, as in the case of homocysteine, levels of Lp(a) increase after acute ischemia and such studies cannot reliably determine causality. Prospective studies of Lp(a) avoid this bias but have not always found consistent evidence of association. For example, although several prospective studies employing plasma based assays for either apo(a) or for Lp(a) mass concentration have reported a positive, graded association,[258] [283] [284] [285] several other well-designed prospective studies have not demonstrated these effects.[286] [287] [288] [289] Electrophoretic detection of pre-beta-lipoprotein, a surrogate for Lp(a), has also been associated with increased vascular risk.[290] [291] However, these studies reported inconsistent data between men and women and between the endpoints of myocardial infarction and stroke. Thus, available prospective studies do not establish the importance of Lp (a) as a marker for all future cardiovascular events or whether any increased risk is restricted to those with the highest levels or an absence of other traditional risk factors. Beyond these considerations, several practical issues limit the utility of Lp (a) screening. First, commercially available tests for Lp(a) lack sufficient standardization and there

remains no consensus among clinical chemists on how best to measure this highly polymorphic molecule. This issue hampers reproducibility between laboratories, greatly reducing clinical efficacy.[292] Second, Lp(a) levels vary widely among different racial groups, with the African-American population tending to have more individuals in the higher range.[293] Scant evidence establishes the predictive value of Lp(a) for many ethnic groups, including African-Americans.[294] Similarly, the predictive value of Lp(a) in women is controversial.[295] Third, even in the positive studies of Lp(a), it is unclear whether evaluation of this lipoprotein adds to the predictive value of total and HDL-C. Indeed, LDL reduction markedly reduces any adverse hazard associated with Lp(a).[296]

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Whereas niacin can modestly reduce Lp(a) levels, specific Lp(a)-lowering therapies are not available. For all of these reasons, most authorities do not recommend general Lp(a) screening.[297] However, as with homocysteine, special situations may warrant Lp(a) evaluation, such as young individuals who have suffered infarction yet who appear to lack other traditional risk factors. Markers of Fibrinolytic Function (PAI-1, t-PA, Clot Lysis, and

D

-Dimer)Impaired fibrinolysis can result from an imbalance between the clot-dissolving enyzmes tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA) and their endogenous inhibitors, primarily PAI-1. Plasma levels of PAI-1 peak in the morning whereas concentrations of t-PA demonstrate a less prominent circadian variation.[298] On this basis, a relative hypofibrinolytic state may prevail in the morning that, along with increased platelet reactivity, may contribute to the increased risk of myocardial infarction seen in this time period.[299] Visceral obesity yields enhanced PAI-1 production from adipocytes, and thus impaired fibrinolysis may help explain how weight gain and obesity influence atherothrombosis.[300] [301] [302] Individuals with the insulin resistance syndrome commonly have impaired fibrinolysis.[303] [304] Clinically, patients with isolated PAI-1 deficiencies have excess rates of hemorrhage whereas animals with genetically mediated PAI-1 excess may develop spontaneous thrombosis.[305] [305A] However, a role for either t-PA or PAI-1 in the development of venous thrombosis remains controversial because retrospective studies may fail to account for acute-phase effects [306] and available prospective studies have not provided consistent evidence of association.[307] By contrast, a highly consistent series of prospective studies have linked abnormalities of fibrinolysis to increased risk of arterial thrombosis. For example, prospective associations exist between PAI-1 antigen and activity levels and the risk of first and recurrent myocardial infarction.[251] [271] [308] [309] Perhaps paradoxically, individuals at risk for future coronary as well as cerebral thrombosis consistently have elevated levels of circulating t-PA antigen.[304] [310] [311] [312] [313] These latter effects may represent evidence of underlying endothelial dysfunction among individuals at risk or of direct relationships between t-PA and PAI-1, or they may represent a biological response to impaired

fibrinolysis. In this regard, reduced clot lysis time, an overall indicator of net fibrinolytic function, also predicts coronary risk.[314] Finally, several studies indicate that levels of D-dimer, a peptide released by plasmin's action on fibrin, also predict myocardial infraction, peripheral atherothrombosis, and recurrent coronary events.[315] [316] [317] Despite these data, the clinical use of fibrinolytic markers to determine coronary risk may offer little marginal value. Direct measurement of PAI-1 activity is difficult in clinical settings and requires special anticoagulants and precise phlebotomy techniques to avoid degranulation of platelets, a rich source of PAI-1. In addition, these markers, particularly PAI-1, have wide circadian variation. Furthermore, few data indicate that assessment of fibrinolytic markers adds substantially to clinical risk prediction models.[3] The recognition that fibrinolytic function contributes to atherothrombotic risk has nonetheless yielded several practical clinical applications. For example, PAI-1-resistant thrombolytic agents may provide a means to increase the efficacy of fibrinolytic therapy for acute myocardial infarction. Furthermore, the renin-angiotensin system plays an important role in the regulation of fibrinolysis, and at least two randomized trials have shown the ability of angiotensin-converting enzyme inhibitors to influence favorably the balance between t-PA and PAI-1.[318] [319] Finally, genetic polymorphism in the promoter of the PAI-1 gene appears to be associated with elevated levels of PAI-1 expression,[320] [321] although whether this increases risk of myocardial infarction remains uncertain.[322] [323]

Markers of Inflammation (hs-CRP, ICAM-1, and IL-6) INFLAMMATION CHARACTERIZES ALL PHASES OF ATHEROSCLEROSIS.

As reviewed in Chapter 30 , inflammation characterizes all phases of atherosclerosis.[324] [325] Formation of the fatty streak, the earliest phase of atherogenesis, involves recruitment of leukocytes due to expression of leukocyte adhesion molecules on endothelial cells in turn triggered by primary proinflammatory cytokines such as interleukin (IL)-1 or tumor necrosis factor-alpha. Subsequent migration of inflammatory cells into the subendothelial space requires chemotaxis controlled by chemokines induced by the primary cytokines.[326] Mononuclear cells within this initial infiltrate as well as intrinsic vascular cells subsequently release growth factors that stimulate proliferation of the smooth muscle cells and hence the progression of plaques. Finally, the thrombotic complications of plaques often involve physical disruption, usually associated with signs of inflammation.[327] [328] Other proinflammatory cytokines such as CD154 (CD40 ligand) can induce tissue factor procoagulant expression and promote thrombus

Figure 31-9 Pathways by which vascular and extravascular sources of inflammation result in circulating levels of inflammatory markers associated with atherothrombosis. CRP=C-reactive protein; HSP=heat shock protein; ICAM-1=intercellular adhesion molecule-1; IL-1 = interleukin-1; SAA=serum amyloid A; TNF-alpha = tumor necrosis factor-alpha. (Adapted from Libby P, Ridker PM: Novel inflammatory markers of coronary risk: Theory versus practice Circulation 100:1148-1150, 1999. Copyright 1999, American

Heart Association.)

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Figure 31-10 (Figure Not Available) Baseline plasma concentration of hs-CRP and the risk of future cardiovascular events among apparently healthy men and women. CHS/RHPP=Cardiovascular Health Study/Rural Health Promotion Project; Helsinki=Helsinki Heart Study; MONICA=Monitoring trends and determinants in Cardiovascular disease; MRFIT=Multiple Risk Factor Intervention Trial; PHS=Physician's Health Study; WHS=Women's Health Study.

formation.[329] Thus, the inflammatory response participates in every stage of atherothrombosis. The primary proinflammatory cytokines IL-1 and tumor necrosis factor-alpha induce, in turn, the expression of another cytokine, IL-6. We have dubbed IL-6 a "messenger" cytokine because it can act remotely to change the program of protein synthesis in the liver from "housekeeping" proteins (e.g., albumin) to a family of proteins known collectively as acute-phase reactants. In this manner, local inflammation (in this case, the artery wall) can produce a reflection in the peripheral blood. We envisage this cytokine cascade orchestrating the expression of effector molecules (e.g., the adhesion molecules) as a biochemical pathway, similar to those encountered in intermediary metabolism (Fig. 31-9) . MARKERS OF INFLAMMATION PREDICT FUTURE RISK OF VASCULAR EVENTS.

Given this underlying pathophysiology, it is not surprising that several markers of low-grade systemic inflammation have also proven useful for cardiovascular risk prediction.[330] [331] These markers include nonspecific acute-phase reactants such as hs-CRP, adhesion molecules such as ICAM-1, which are involved in mononuclear cell attachment to the vascular endothelium, and cytokines such as IL-6 and tumor necrosis factor. Each of these inflammatory markers can be measured in plasma and may thus provide a window on the inflammatory processes at the level of the arterial wall. It remains unclear to what extent the acute-phase reactants serve merely as markers or themselves act as effectors of pathological responses. A large body of consistent evidence validates the use of acute-phase reactants such as CRP and serum amyloid A as markers of risk (see later). The evidence regarding their roles as direct mediators of pathology remains much more speculative. Nonetheless, CRP may activate complement and thus participate in sustaining inflammation. Serum amyloid A can bind to HDL particles, perhaps rendering them less protective against vascular inflammation.[332] Fibrinogen, another acute-phase protein, clearly can participate in coagulation, as discussed earlier. Among the inflammatory markers, hs-CRP will likely prove the most clinically useful because it is easy and inexpensive to measure with commercial assays.[333] CRP has proven to have strong predictive value both among currently healthy men [334] [334A] [334B] and women[331] [335] as well as among the elderly,[336] high-risk smokers,[337] those with

stable[338] and unstable angina pectoris,[339] [340] and those with prior myocardial infarction.[341] In these studies, individuals with hs-CRP levels in the upper quartile had relative risks of future vascular events three to four times higher than individuals with lower levels, effects that were independent of all other traditional cardiovascular risk factors (Fig. 31-10) (Figure Not Available) . Moreover, plasma levels of hs-CRP appear to add to the predictive value of plasma lipid measurements, and thus may provide an improved method to determine future vascular risk[342] (Fig. 31-11) . In one recent large-scale prospective evaluation of 12 different inflammatory and lipid markers of risk, hs-CRP proved to be the single best predictor of future vascular thrombosis.[331] Moreover, in multivariate analysis, only hs-CRP or the total cholesterol:HDL-C ratio independently predicted risk. Importantly, levels of hs-CRP as well as the

Figure 31-11 Relative risks for future myocardial infarction among currently healthy men according to baseline tertile of the total to HDL-cholesterol ratio and to baseline tertile of hs-CRP. From Ridker PM, Glynn R, Hennekens CH: C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 97:2007-2011, 1998. Copyright 1998, American Heart Association.)

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inflammatory markers serum amyloid A, soluble ICAM-1, and IL-6 all predicted future vascular risk. Interestingly, these variables establish increased risk even among those with LDL-C levels below 130 mg/dl, the threshold for pharmacotherapy mandated by National Cholesterol Education Program (NCEP) Adult Treatment Program-2 (ATP-2) guidelines (Fig. 31-12) . [331] Thus, the clinical use of inflammatory markers may help to identify individuals at higher risk for myocardial infarction despite not meeting criteria for treatment based on the lipid profile. For many clinicians, it may seem surprising that markers of inflammation such as CRP have such potent predictive value. After all, as a classic acute-phase reactant, levels of CRP increase several hundredfold in response to injury or infection and increase with a variety of inflammatory stimuli.[343] However, as long as hs-CRP is not measured within 2 to 3 weeks of an acute inflammatory stimulus (e.g., intercurrent infection), levels in a given individual are quite stable over long periods. TREATMENTS CAN MODIFY MARKERS OF INFLAMMATION.

Evidence also suggests that hs-CRP may represent a modifiable risk marker. In a randomized trial of low-dose aspirin, the relative efficacy of this agent in decreasing coronary risk was greatest among those with evidence of low-grade inflammation as determined by hs-CRP but was sequentially smaller as levels of hs-CRP declined, data

that suggest potentially important antiinflammatory effects for aspirin. [334] Similarly, in the Cholesterol and Recurrent Events (CARE) trial, the attributable risk reduction associated with pravastatin was greater among individuals with a persistent inflammatory response as determined by hs-CRP, such that statin therapy attenuated almost completely the elevated risk associated with inflammation.[341] Moreover, therapy with pravastatin in the CARE trial significantly reduced levels of hs-CRP over a 5-year period.[344] This finding corroborates in humans experimental studies that suggest that lipid lowering attenuates inflammation[345] [346] and that the use of statins reduces macrophage content and activity within atheromatous plaque.[347] [348] [349] Thus, lipid lowering by statins appears to mitigate the inflammatory processes that undermine plaque stability. Nonpharmacological methods to reduce hs-CRP include weight reduction and exercise.[350] [351] By contrast, cross-sectional[352] [353] and randomized data indicate that hormone replacement therapy may augment levels of hs-CRP.[354] MECHANISMS OF INFLAMMATORY MARKER ELEVATIONS.

Although the mechanisms underlying CRP as a risk factor remain uncertain, the low-grade inflammation detected by hs-CRP probably serves as an indirect marker of an enhanced cytokine[355] response to a variety of inflammatory stimuli that ultimately proves critical both for plaque progression and plaque rupture (see Fig. 31-9. Plasma levels of the "messenger" cytokine IL-6 , the primary driver of hepatic CRP synthesis, also predict future myocardial infarction among currently healthy men[356] as well as total mortality in the elderly.[357] Furthermore, individuals with

Figure 31-12 The value of hs-CRP, serum amyloid A (SAA), soluble intercellular adhesion molecule (sICAM-1), and interleukin-6 as predictors of future vascular risk among women with high, medium, and low levels of total cholesterol. (From Ridker PM, Hennekens CH, Buring JE, et al: C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 342:836-843, 2000.)

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acute coronary syndromes have elevated levels of IL-6, and this cytokine has both short- and long-term prognostic value among those with and without overt plaque rupture.[358] [359] Upstream effectors of IL-6 production also serve as markers of future vascular risk. Individuals with increased vascular risk also have elevated levels of tumor necrosis factor-alpha and IL-1 isoforms, which in turn may stimulate IL-6 expression. [359] [360] Cellular adhesion molecules responsible for recruitment of monocytes into the intima also appear to have a predictive role in vascular disease. In particular, those at risk for future coronary artery disease and stroke have elevated levels of soluble forms of ICAM-1 at baseline.[331] [361] [362] Soluble forms of other adhesion molecules that reflect endothelial activation or platelet adhesion may also indicate vascular disease progression.[129]

Sources of stimuli for the smoldering inflammatory response include not only the vessel wall itself but also extravascular sites. Extravascular foci of chronic infection might include the gingiva, the bronchi, the urinary tract (including the prostate), or diverticular disease. Chronic infection with agents such as Chlamydia pneumoniae, Helicobacter pylori, herpes simplex virus, or cytomegalovirus can lead to systemic inflammation. Such observations have heightened interest in the hypothesis that infection may contribute to coronary risk[363] [364] (see also Chap. 30) . Several cross-sectional and retrospective studies that suggest an increased prevalence of infection among individuals with known coronary disease support this hypothesis.[365] [366] [367] In addition, several studies have identified Chlamydia species[368] [369] as well as viral particles[367] [370] in atheromatous lesions. On the other hand, interpreting these data requires considerable caution. First, retrospective studies are prone to considerable confounding and the presence of infection may represent a result rather than a cause of atherosclerotic disease.[371] For example, several large-scale prospective studies have not found evidence that prior exposure to either Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, or herpes viruses is associated with increased risk of future cardiovascular events.[372] [373] [374] [375] [376] Furthermore, recovery of infectious particles within atheromatous plaque does not prove causation but may simply represent an innocent commensal colonization. It is thus uncertain whether infection plays an important etiological role in atherthrombosis. Available clinical trials of antibiotic therapy have been underpowered to demonstrate either a true benefit or a meaningful null result. It is important to recognize, however, several mechanisms by which infection might contribute to plaque instability. For example, Chlamydia species have been reported to induce macrophage foam cell formation and increase procoagulant activity.[377] [378] Human atheromas often contain chlamydial heat shock protein 60 (HSP-60), an effector of activation of macrophages, endothelium, and matrix metalloproteinase expression.[379] [380] [381] Ongoing large-scale clinical trials of antibiotic therapies in the setting of chronic and acute infarction will help resolve these controversies. Although the proximal stimuli remain unproven at this time, overwhelming evidence supports a major role for inflammation in atherosclerosis and establishes the clinical utility of measurement of the inflammatory response in identifying individuals at high risk for plaque rupture. FUTURE DIRECTIONS IN CORONARY RISK ASSESSMENT Although available data demonstrate the considerable potential of inflammatory markers such as hs-CRP to improve coronary risk prediction, determining the full utility of inflammatory markers as adjuncts to lipid screening in individual patients will require further clinical studies. The observation that elevated levels of CRP, IL-6, tumor necrosis factor, IL-1RA, and soluble ICAM-1 all associate with future vascular events provides a potent stimulus to consider targeted antiinflammatory therapies as a novel method to both treat and prevent vascular thrombosis. Aside from inflammatory markers, future strategies to detect vascular risk will likely take several forms. Imaging techniques including carotid and intravascular ultrasonography, electron-beam computed tomography (CT), and magnetic resonance imaging all hold

promise as methods to identify silent atheroma and perhaps vulnerable plaque.[330] Similarly, testing for endothelium-dependent vasodilation has proven highly effective in specialized research settings. However, each of these techniques requires carefully designed prospective evaluations to determine their clinical utility. Just as the extent of stenosis determined at coronary angiography does not necessarily predict plaque rupture, it is not at all certain that other imaging techniques will overcome this inherent limitation. For example, a recent study of coronary calcification as detected by electron-beam CT has found that this method does not predict accurately near-term vascular events, even in high-risk settings.[382] Furthermore, imaging studies and the consequences of false-positive testing can entrain considerable costs. Indeed, a recent American Heart Association position paper has advised against the use of electron-beam CT for coronary calcium scoring as a routine screening tool at present. An alternative approach to improving risk prediction would be expansion of current lipid screening algorithms to include other vascular markers with a firm pathophysiological basis such as homocysteine, LDL particle size, Lp(a), or hs-CRP. Advantages of this approach include relatively low cost, a recognition that such variables could add to simple lipid screening in assessing the risk of thrombotic complications of atheroma, and their firm basis in pathophysiology. Moreover, in contrast to imaging techniques, abundant prospective data already exist for many of these markers that can guide clinicians in their use. This approach seems promising because inflammatory markers appear to add to the predictive value of lipid screening and provide a window onto clinically relevant plaque biology. The "genomics revolution" mentioned earlier in relation to pharmacogenomics will also doubtless open new vistas of cardiovascular risk prediction. Over the next decade, considerable attention will focus on genetic detection of thrombotic risk. For venous thrombosis, genetic detection of factor V Leiden and of a common polymorphism in the promoter of the prothrombin gene have already entered clinical practice and have utility for targeting secondary prevention. In contrast, although family history contributes importantly to determining risk of myocardial infarction or stroke, studies of single gene polymorphisms and arterial thrombosis have proven disappointing, limiting enthusiasm for the use of genetic screening for abnormalities of hemostasis, thrombosis, and inflammation at present.[383] Nonetheless, screening of multiple loci and haplotyping hold the promise of better targeted pharmaceutical approaches based partly on genetic screening and will likely provide major avenues for coronary risk reduction in the future.

REFERENCES CONVENTIONAL ATHEROSCLEROTIC RISK FACTORS Wilson PW, D'Agostino RB, Levy D, et al: Prediction of coronary heart disease using risk factor categories. Circulation 97:1837-1847, 1998. 1.

D'Agostino RB, Russell MW, Huse DM, et al: Primary and subsequent coronary risk appraisal: New results from the Framingham study. Am Heart J 139:272-281, 2000. 2.

Ridker PM: Fibrinolytic and inflammatory markers for arterial occlusion: The evolving epidemiology of thrombosis and hemostasis. Thromb Haemost 78:53-59, 1997. 3.

1032

Rubins HB, Robins SJ, Collins D, et al: Distribution of lipids in 8,500 men with coronary artery disease. Department of Veterans Affairs HDL Intervention Trial Study Group. Am J Cardiol 75:1196-1201, 1995. 4.

5.

Brown MS, Goldstein JL: Heart attacks: Gone with the century? Science 272:629, 1996.

Murray CJ, Lopez AD: Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet 349:1269-1276, 1997. 6.

Johnson CL, Rifkind BM, Sempos CT, et al: Declining serum total cholesterol levels among US adults. The National Health and Nutrition Examination Surveys. JAMA 269:3002-3008, 1993. 7.

Burt VL, Culter JA, Higgins M, et al: Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population. Data from the health examination surveys, 1960 to 1991. Hypertension 26:60-69, 1995. 8.

Stampfer MJ, Hu FB, Manson JE, et al: Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med 343:16-22, 2000. 8A.

Stamler J, Stamler R, Neaton JD, et al: Low risk factor profile and long-term cardiovascular and noncardiovascular mortality and life expectancy: Findings for 5 large cohorts of young adult and middle-aged men and women. JAMA 282:2012-2018, 1999. 8B.

8C. Mosca

L, Grundy SM, Judelson D, et al: AA/ACC Scientific Statement: Guide to preventive cardiology in women. J Am Coll Cardiol 33:1751-1755, 1999.

DYSLIPIDEMIA Steinberg D: The cholesterol controversy is over: Why did it take so long? Circulation 80: 1070-1078, 1989. 9.

Anitschkow N, Chalatow S: On experimental cholesterin steatosis and its significance in the origin of some pathological processes (1913). Reprinted in Arteriosclerosis 3:178-182, 1983. 10.

Murray CJ, Lopez AD: Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet 349:1498-1504, 1997. 11.

Pearson T, Fuster V: 27th Bethesda Conference. Matching the Intensity of Risk Factor Management with the Hazard for Coronary Disease Events. J Am Coll Cardiol 27:957-1047, 1996. 12.

Kane JP, Kunitake ST: Isolation of plasma lipoproteins by ultracentrifugation and immunosorption. In Betteridge DJ, Illingworth DR, Shepherd J (eds): Lipoproteins in Health and Disease. New York, NY, Oxford University Press, 1999. 13.

14.

Assman G, Schulte H, von Eckardstein A, Huang Y: High-density lipoprotein cholesterol as a predictor

of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis 124:S11-S20, 1996. Keys A: Seven Countries: A multivariate analysis of death and coronary heart disease. Cambridge, Harvard University Press, 1980. 15.

Karanthanasis SK: Lipoprotein metabolism: High density lipoproteins. In Lusis AJ, Rotter RS, Sparkes RS (eds): Molecular Genetics of Coronary Artery Disease. Vol. 14. Candidate Genes and Processes in Atherosclerosis. Basel, Monographs in Human Genetics, 1992. 16.

Havel RJ, Kane JP: Structure and metabolism of plasma lipoproteins. In Scriver CR, Beaudet AL, Sly WS, et al. (eds): The Metabolic and Molecular Basis of Inherited Disease. New York, McGraw-Hill, 1995. 17.

Shumaker VN, Brown MS: Sequential flotation ultracentrifugation. Methods Enzymol 128:155-170, 1990. 18.

19.

Goldstein JL, Brown MS: Regulation of the mevalonate pathway. Nature 343: 425-430, 1990.

Hiltunen TP, Luoma JS, Nikkari T, et al: Expression of LDL receptor, VLDL receptor, LDL receptor-related protein, and scavenger receptor in rabbit atherosclerotic lesions: Marked induction of scavenger receptor and VLDL receptor expression during lesion development. Circulation 97:1079-1086, 1998. 20.

Nimpf J, Schneider WJ: The VLDL receptor: An LDL receptor relative with eight ligand binding repeats, LR8. Atherosclerosis 141:191-202, 1998. 21.

Herz J: Low-density lipoprotein receptor-related protein. In Betteridge D, Illingworth D, and Sheperd J (eds): Lipoproteins in Health and Disease. New York, Oxford University Press, 1999. 22.

Mann CJ, Troussard AA, Yen FT, et al: Inhibitory effects of specific apolipoprotein C-III isoforms on the binding of triglyceride-rich lipoproteins to the lipolysis-stimulated receptor. J Biol Chem 272:31348-31354, 1997. 23.

Krieger M: Type I and type II class A macrophage scavenger receptors. In Betteridge D, Illingworth D, Sheperd J (eds): Lipoproteins in Health and Disease. New York, Oxford University Press, 1999. 24.

25.

Libby P, Clinton SK: The role of macrophages in atherogenesis. Curr Opin Lipidol 4:355-363, 1993.

Sawamura T, Kume N, Aoyama T, et al: An endothelial receptor for oxidized low-density lipoprotein. Nature 386:73-77, 1997. 26.

Rigotti A, Krieger M: Getting a handle on "good" cholesterol with the high-density lipoprotein receptor. N Engl J Med 341:2011-2013, 1999. 27.

Fidge NH: High density lipoprotein receptors, binding proteins, and ligands. J Lipid Res 40:187-201, 1999. 28.

28A. Moestrup

SK, Kozyraki R: Cubilin, a high-density lipoprotein receptor. Curr Opin Lipidol 11:133-140,

2000. 28B. Hammad

SM, Barth JL, Knaak C, Argraves WS: Megalin acts in concert with cubulin to mediate endocytosis of high density lipoproteins. J Biol Chem 275:12003-12008, 2000.

Scott J, Navaratnam N, Carter C: Molecular modelling and the biosynthesis of apoliprotein B containing lipoproteins. Atherosclerosis 141:S17-24, 1998. 29.

Mahley RW, Ji ZS: Remnant lipoprotein metabolism: Key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E. J Lipid Res 40:1-16, 1999. 30.

Brown MS, Brown JL: The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89:331-340, 1997. 31.

Farese RV Jr: Acyl CoA:cholesterol acyltransferase genes and knockout mice. Curr Opin Lipidol 9:119-123, 1998. 32.

Rust S, Rosier M, Funke H, et al: Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 22:352-355, 1999. 33.

Brooks-Wilson A, Marcil M, Clee S, et al: Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet 22:336-345, 1999. 34.

Bodzioch M, Orso E, Klucken J, et al: The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 22:347-351, 1999. 35.

36.

Young SG, Fielding CJ: The ABCs of cholesterol efflux. Nat Genet 22:316-318, 1999.

Mackness MI, Mackness B, Durrington PN, et al: Paraoxonase and coronary heart disease. Curr Opin Lipidol 9:319-324, 1998. 37.

Genest JJ, Marcil M, Denis M, et al: High density liproteins in health and in disease. J Invest Med 47:31-42, 1999. 38.

39.

Havel RJ: Postprandial lipid metabolism: An overview. Proc Nutr Soc 56:659-666, 1997.

Grundy SM: Small LDL, atherogenic dyslipidemia, and the metabolic syndrome. Circulation 95:1-4, 1997. 40.

Wilson DJ, Gahan M, Haddad L, et al: A World Wide Web site for low-density lipoprotein receptor gene mutations in familial hypercholesterolemia: Sequence-based, tabular, and direct submission data handling. Am J Cardiol 81:1509-1511, 1998. 41.

Boren J, Lee I, Zhu W, et al: Identification of the low density lipoprotein receptor-binding site in apolipoprotein B100 and the modulation of its binding activity by the carboxyl terminus in familial defective apo-B100. J Clin Invest 101:1084-1093, 1998. 42.

Hansen PS, Defesche JC, Kastelein JJP, et al: Phenotypic variation in patients heterozygous for familial defective apoliprotein B (FDB) in three European countries. Arterioscler Thromb Vasc Biol 17:741-747, 1997. 43.

Narcisi TME, Shoulders CC, Chester SA, et al: Mutations of the microsomal tryglyceride-transfer-protein gene in aetalipoproteinemia. Am J Hum Genet 102:1298-1310, 1995. 44.

Salen G, Shefer S, Nguyen L, et al: Sitosterolemia. In Betteridge D, Illingworth D, Sheperd J (eds): Lipoproteins in Health and Disease. New York, Oxford University Press, 1999. 45.

Patel SB, Salen G, Hidaka H, et al: Mapping a gene involved in regulating dietary cholesterol absorption: The sitosterolemia locus is found at chromosome 2p21. J Clin Invest 102:1041-1044, 1998. 46.

47.

Hobbs HH, White AL: Lipoprotein (a): Intrigues and insights. Curr Opin Lipidol 10:225-236, 1999.

Duane WC: Cholesterol metabolism in familial hypertriglyceridemia: Effects of obesity versus triglyceride level. J Lab Clin Med 130:635-642, 1997. 48.

Sjarif DR, Sinke RJ, Duran M, et al: Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency. J Med Genet 35:650-656, 1998. 49.

Clark AG, Weiss KM, Nickerson DA, et al: Haplotype structure and population genetic inferences from nucleotide-sequence variation in human lipoprotein lipase. Am J Hum Genet 63:595-612, 1998. 50.

Feoli-Fonseca JC, Levy E, Godard M, et al: Familial lipoprotein lipase deficiency in infancy: Clinical, biochemical, and molecular study. J Pediatr 133:417-423, 1998. 51.

Santamarina-Fojo S: The familial chylomicronemia syndrome. Endocrinol Metab Clin North Am 27:551-567, 1998. 52.

Weinstock PH, Bisgaier CL, Aalto-Setala K, et al: Severe hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice: Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes. J Clin Invest 96:2555-2568, 1995. 53.

Mahley R, Rall S: Type III hyperlipoproteinemia (dysbetalipoproteinemia; remnant particle disease). In Betteridge D, Illingworth D, Sheperd J (eds): Lipoproteins in Health and Disease. New York, Oxford University Press, 1999. 54.

Welty FK, Lahoz C, Tucker KL, et al: Frequency of ApoB and ApoE gene mutations as causes of hypobetalipoproteinemia in the Framingham offspring population. Arterioscler Thromb Vasc Biol 18:1745-1751, 1998. 55.

Goldstein JL, Schrott HG, Hazzard WR, et al: Hyperlipidemia in coronary heart disease: II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest 52:1544-1568, 1973. 56.

Genest JJ Jr, Martin-Munley SS, McNamara JR, et al: Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation 85:2025-2033, 1992. 57.

1033

Pajukanta P, Terwilliger JD, Perola M, et al: Genome-wide scan for familial combined hyperlipidemia genes in Finnish families, suggesting multiple susceptibility loci influencing triglyceride, cholesterol, and apolipoprotein B levels. Am J Hum Genet 64:1453-1463, 1999. 58.

Cianflone KM, Maslowska MH, Sniderman AD: Impaired response of fibroblasts from patients with hyperapobetalipoproteinemia to acylation-stimulating protein. J Clin Invest 85:722-730, 1990. 59.

Calabresi L, Franceschini G: High density lipoprotein and coronary heart disease: Insights from mutations leading to low high density lipoprotein. Curr Opin Lipidol 8:219-224, 1997. 60.

Kuivenhoven JA, Pritchard H, Hill J, et al: The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes. J Lipid Res 38:191-205, 1997. 61.

Matzuzawa Y, Yamashita S: Choelsteryl ester protein deficiency. In Betteridge D, Illingworth D, Sheperd J (eds): Lipoproteins in Health and Disease. New York, Oxford University Press, 1999. 62.

Zhong S, Sharp DS, Grove JS, et al: Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. J Clin Invest 97:2917-2923, 1996. 63.

Assman G, von Eckardstein A, Brewer HBJ: Familial high density lipoprotein deficiency: Tangier disease. In Scriver CR, Beaudet AL, Sly WS, et al (eds): The Metabolic and Molecular Basis of Inherited Disease. New York, McGraw-Hill, 1995. 64.

Serfaty-Lacrosniere C, Civeira F, Lanzberg A, et al: Homozygous Tangier disease and cardiovascular disease. Atherosclerosis 107:85-98, 1994. 65.

Loftus SK, Morris JA, Carstea ED, et al: Murine model of Niemann-Pick C disease: Mutation in a cholesterol homeostasis gene. Science 277:232-235, 1997. 66.

Carstea ED, Morris JA, Coleman KG, et al: Niemann-Pick C1 disease gene: Homology to mediators of cholesterol homeostasis. Science 277:228-231, 1997. 67.

68.

Broeders N, Knoop C, Abramowicz D: Drug treatment of lipid. N Engl J Med 341:2020-2021, 1999.

Laakso M, Lehto S, Penttila I, et al: Lipids and lipoproteins predicting coronary heart disease mortality and morbidity in patients with non-insulin-dependent diabetes [see comments]. Circulation 88:1421-1430, 1993. 69.

Pyorala K, Pedersen TR, Kjekshus J, et al: Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease: A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 20:614-620, 1997. 70.

Steiner G, Stewart D, Hosking JD: Baseline characteristics of the study population in the Diabetes Atherosclerosis Intervention Study (DAIS). World Health Organization Collaborating Centre for the Study of Atherosclerosis in Diabetes. Am J Cardiol 84:1004-1010, 1999. 71.

Short C, Durrington P: Renal disorders. In Betteridge D, Illingworth D, Sheperd J (eds): Lipoproteins in Health and Disease. New York, Oxford University Press, 1999. 72.

Kamanna VS, Bassa BV, Kirschenbaum MA: Atherogenic lipoproteins and human disease: Extending concepts beyond the heart to the kidney. Curr Opin Nephrol Hypertens 6:205-211, 1997. 73.

74.

Miller JP: Dyslipoproteinaemia of liver disease. Clin Endocrinol Metab 4:807-832, 1990.

Rerkpattanapipat P, Wongpraparut N, Jacobs LE, et al: Cardiac manifestations of acquired immunodeficiency syndrome. Arch Intern Med 160:602-608, 2000. 75.

76.

Periard D, Telenti A, Sudre P, et al: Atherogenic dyslipidemia in HIV-infected individuals treated with

protease inhibitors. The Swiss HIV Cohort Study. Circulation 100:700-705, 1999. Echevarria KL, Hardin TC, Smith JA: Hyperlipidemia associated with protease inhibitor therapy. Ann Pharmacother 33:859-863, 1999. 77.

Purnell JQ, Zambon A, Knopp RH, et al: Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects. AIDS 14:51-57, 2000. 78.

Mulligan K, Grunfeld C, Tai VW, et al: Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection. J Acquir Immune Defic Syndr 23:35-43, 2000. 79.

Carr A, Samaras K, Thorisdottir A, et al: Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor- associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: A cohort study. Lancet 353:2093-2099, 1999. 80.

Carr A, Samaras K, Burton S, et al: A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 12:F51-58, 1998. 81.

Mathe G: Human obesity and thinness, hyperlipidemia, hyperglycemia, and insulin resistance associated with HIV1 protease inhibitors: Prevention by alternating several antiproteases in short sequences. Biomed Pharmacother 53:449-451, 1999. 82.

Barroso I, Gurnell M, Crowley VE, et al: Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402:880-883, 1999. 83.

Ballantyne CM, Radovancevic B, Farmer JA, et al: Hyperlipidemia after heart transplantation: Report of a 6-year experience, with treatment recommendations. J Am Coll Cardiol 19:1315-1321, 1992. 84.

Kobashigawa JA, Katznelson S, Laks H, et al: Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 333:621-627, 1995. 85.

Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA 273:199-208, 1995. 86.

Rossouw JE: Hormone replacement therapy and cardiovascular disease. Curr Opin Lipidol 10:429-434, 1999. 87.

Ornish D, Scherwitz LW, Billings JH, et al: Intensive lifestyle changes for reversal of coronary heart disease. JAMA 280:2001-2007, 1998. 88.

de Lorgeril M, Salen P, Martin JL, et al: Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: Final report of the Lyon Diet Heart Study. Circulation 99:779-785, 1999. 89.

Paffenbarger RS Jr, Hyde RT, Wing AL, et al: The association of changes in physical-activity level and other lifestyle characteristics with mortality among men. N Engl J Med 328:538-545, 1993. 90.

Genest JJ, Soulier V, Dufour R: Cholesterol-lowering in secondary prevention of CAD: Treat-to-target, percent reduction, or both? (Lessons learned from recent trials). Cardiovasc Dis Prevent 2:7-12, 1999. 91.

Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: Executive summary. Expert Panel on the Identification, Evaluation, and Treatment of Overweight in Adults. Am J Clin Nutr 68:899-917, 1998. 92.

Panel TE: Summary of the Second report of the National Cholesterol Education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel II). JAMA 269:3015-3023, 1993. 93.

Marx N, Sukhova GK, Collins T, et al: PPARalpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation 99:3125-3131, 1999. 94.

Genest J Jr, Nguyen NH, Theroux P, et al: Effect of micronized fenofibrate on plasma lipoprotein levels and hemostatic parameters of hypertriglyceridemic patients with low levels of high-density lipoprotein cholesterol in the fed and fasted state. J Cardiovasc Pharmacol 35:164-172, 2000. 95.

Guyton JR: Effect of niacin on atherosclerotic cardiovascular disease. Am J Cardiol 82:18U-23U; discussion 39U-41U, 1998. 96.

De Caterina R, Cybulsky MI, Clinton SK, et al: The omega-3 fatty acid docosahexaenoate reduces cytokine-induced expression of proatherogenic and proinflammatory proteins in human endothelial cells. Arterioscler Thromb 14:1829-1836, 1995. 97.

De Caterina R, Spiecker M, Solaini G, et al: The inhibition of endothelial activation by unsaturated fatty acids. Lipids 34 (Suppl): S191-S194, 1999. 98.

Tardif J-C, Cote G, Lesperance J, et al: Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. N Engl J Med Multivitamins and Probucol Study Group. 337:365-372, 1997. 99.

Moghadasian MH, Frohlich JJ: Effects of dietary phytosterols on cholesterol metabolism and atherosclerosis: Clinical and experimental evidence. Am J Med 107: 588-594, 1999. 100.

101.

Nguyen TT: The cholesterol-lowering action of plant stanol esters. J Nutr 129:2109-2112, 1999.

Gylling H, Radhakrishnan R, Miettinen TA: Reduction of serum cholesterol in postmenopausal women with previous myocardial infarction and cholesterol malabsorption induced by dietary sitostanol ester margarine: Women and dietary sitostanol. Circulation 96:4226-4231, 1997. 102.

Vuorio AF, Gylling H, Turtola H, et al: Stanol ester margarine alone and with simvastatin lowers serum cholesterol in families with familial hypercholesterolemia caused by the FH-North Katelia mutation. Arterioscler Thromb Vasc Biol 20:500-506, 2000. 103.

Position of the American Dietetic Association: Functional foods. J Am Diet Assoc 99: 1278-1285, 1999. 104.

105.

Havel RJ: Dietary supplement or drug? The case of cholestin. Am J Clin Nutr 69: 175-176, 1999.

Nishimura S, Sekiguchi M, Kano T, et al: Effects of intensive lipid lowering by low-density lipoprotein apheresis on regression of coronary atherosclerosis in patients with familial hypercholesterolemia: Japan Low-density Lipoprotein Apheresis Coronary Atherosclerosis Prospective Study (L-CAPS). Atherosclerosis 144:409-417, 1999. 106.

107.

Wilson JM, Grossman M, Raper SE, et al: Clinical protocol: Ex vivo gene therapy of familial

hypercholesterolemia. Hum Gene Ther 3:179-222, 1992. Wetterau JR, Aggerbeck LP, Bouma ME, et al: Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia Science 258:999-1001, 1992. 108.

Bocan TM, Krause BR, Rosebury WS, et al: The ACAT inhibitor avasimibe reduces macrophages and matrix metalloproteinase expression in atherosclerotic lesions of hypercholesterolemic rabbits. Arterioscler Thromb Vasc Biol 20:70-79, 2000. 109.

Kuivenhoven JA, Jukema JW, Zwinderman AH, et al: The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group. N Engl J Med 338: 86-93, 1998. 110.

Meyer MR, Tschanz JT, Norton MC, et al: APOE genotype predicts when--not whether--one is predisposed to develop Alzheimer disease. Nat Genet 19:321-322, 1998. 111.

SMOKING Centers for Disease Control: The Health Consequences of Smoking: Nicotine Addiction. A Report of the Surgeon General. Rockville, MD, U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, 1988. 112.

1034

Fiore MC: Trends in cigarette smoking in the United States: The epidemiology of tobacco use. Med Clin North Am 76:289-303, 1992. 113.

Wechsler H, Rigotti NA, Gledhill-Hoyt J, et al: Increased levels of cigarette use among college students: A cause for national. JAMA 280:1673-1678, 1998. 114.

Centers for Disease Control and Prevention: Incidence of initiation of cigarette smoking--United States, 1965-1996. Morbid Mortal Wkly Rep 47:837-840, 1998. 115.

116.

Wald NJ, Hackshaw AK: Cigarette smoking: An epidemiological overview. Br Med Bull 52:3-11, 1996.

117.

Peto R, Lopez AD, Boreham J, et al: Mortality from smoking worldwide. Br Med Bull 52:12-21, 1996.

Glantz SA, Parmley WW: Passive smoking and heart disease: Epidemiology, physiology, and biochemistry. Circulation 83:1-12, 1991. 118.

Kawachi I, Colditz GA, Speizer FE, et al: A prospective study of passive smoking and coronary heart disease. Circulation 95:2374-2379, 1997. 119.

Willett WC, Green A, Stampfer MJ, et al: Relative and absolute excess risks of coronary heart disease among women who smoke cigarettes. N Engl J Med 317:1303-1309, 1987. 120.

Wannamethee SG, Shaper AG, Whincup PH, et al: Smoking cessation and the risk of stroke in middle-aged men. JAMA 274:155-160, 1995. 121.

Howard G, Wagenknecht LE, Burke GL, et al: Cigarette smoking and progression of atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) Study. JAMA 279:119-124, 1998. 122.

Morrow JD, Frei B, Longmire AW, et al: Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers: Smoking as a cause of oxidative damage. N Engl J Med 332:1198-1203, 1995. 123.

Frei B, Forte TM, Ames BN, et al: Gas phase oxidants of cigarette smoke induce lipid peroxidation and changes in lipoprotein properties in human blood plasma. Protective effects of ascorbic acid. Biochem J 277:133-138, 1991. 124.

Zeiher AM, Schachinger V, Minners J: Long-term cigarette smoking impairs endothelium-dependent coronary arterial vasodilator function. Circulation 92:1094-1100, 1995. 125.

Celermajer DS, Sorensen KE, Georgakopoulos D, et al: Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation 88:2149-2155, 1993. 126.

Meade TW, Imeson J, Stirling Y: Effects of changes in smoking and other characteristics on clotting factors and the risk of ischaemic heart disease. Lancet 2:986-988, 1987. 127.

Tracy RP, Psaty BM, Macy E, et al: Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects. Arterioscler Thromb Vasc Biol 17:2167-2176, 1997. 128.

Blann AD, Steele C, McCollum CN: The influence of smoking on soluble adhesion molecules and endothelial cell markers. Thromb Res 85:433-438, 1997. 129.

Fusegawa Y, Goto S, Handa S, et al: Platelet spontaneous aggregation in platelet-rich plasma is increased in habitual smokers. Thromb Res 93:271-278, 1999. 130.

Adams MR, Jessup W, Celermajer DS: Cigarette smoking is associated with increased human monocyte adhesion to endothelial cells: Reversibility with oral L -arginine but not vitamin C. J Am Coll Cardiol 29:491-497, 1997. 131.

Sugiishi M, Takatsu F: Cigarette smoking is a major risk factor for coronary spasm. Circulation 87:76-79, 1993. 132.

Manson JE, Tosteson H, Ridker PM, et al: The primary prevention of myocardial infarction. N Engl J Med 326:1406-1416, 1992. 133.

Fiore MC, Smith SS, Jorenby DE, et al: The effectiveness of the nicotine patch for smoking cessation: A meta-analysis. JAMA 271:1940-1947, 1994. 134.

Silagy C, Mant D, Fowler G, et al: Meta-analysis on efficacy of nicotine replacement therapies in smoking cessation. Lancet 343:139-142, 1994. 135.

Krumholz HM, Cohen BJ, Tsevat J, et al: Cost-effectiveness of a smoking cessation program after myocardial infarction. J Am Coll Cardiol 22:1697-1702, 1993. 136.

Palmer JR, Rosenberg L, Shapiro S: "Low yield" cigarettes and the risk of nonfatal myocardial infarction in women. N Engl J Med 320:1569-1573, 1989. 137.

HYPERTENSION The Sixth Report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 157:2413-2446, 1997. 138.

MacMahon S, Peto R, Cutler J, et al: Blood pressure, stroke, and coronary heart disease: I. Prolonged differences in blood pressure: Prospective observational studies corrected for the regression dilution bias. Lancet 335:765-774, 1990. 139.

Neaton JD, Wentworth D: Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease: Overall findings and differences by age for 316,099 white men. Multiple Risk Factor Intervention Trial Research Group. Arch Intern Med. 152:56-64, 1992. 140.

O'Donnell CJ, Ridker PM, Glynn RJ, et al: Hypertension and borderline isolated systolic hypertension increase risks of cardiovascular disease and mortality in male physicians. Circulation 95:1132-1137, 1997. 141.

Mitchell GF, Moye LA, Braunwald E, et al: Sphygmomanometrically determined pulse pressure is a powerful independent predictor of recurrent events after myocardial infarction in patients with impaired left ventricular function. SAVE investigators. Survival and Ventricular Enlargement. Circulation 96:4254-4260, 1997. 142.

Collins R, Peto R, MacMahon S, et al: Blood pressure, stroke, and coronary heart disease: II. Short-term reductions in blood pressure: Overview of randomised drug trials in their epidemiological context. Lancet 335:827-838, 1990. 143.

Group SCR: Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA 265:3255-3264, 1991. 144.

Staessen JA, Fagard R, Thijs L, et al: Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 350:757-764, 1997. 145.

Whelton PK, Appel LJ, Espeland MA, et al: Sodium reduction and weight loss in the treatment of hypertension in older persons: A randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). TONE Collaborative Research. JAMA 279:839-846, 1998. 146.

27th Bethesda Conference. Matching the Intensity of Risk Factor Management with the Hazard for Coronary Disease Events. September 14-15, 1995. J Am Coll Cardiol 27:957-1047, 1996. 147.

INSULIN RESISTANCE AND DIABETES Gu K, Cowie CC, Harris MI: Mortality in adults with and without diabetes in a national cohort of the U.S. population, 1971-1993. Diabetes Care 21:1138-1145, 1998. 148.

Stein B, Weintraub WS, Gebhart SP, et al: Influence of diabetes mellitus on early and late outcome after percutaneous transluminal coronary angioplasty. Circulation 91:979-989, 1995. 149.

Kannel W, McGee D: Diabetes and glucose tolerance as risk factors for cardiovascular disease: The Framingham Study. Diabetes Care 2:120-126, 1979. 150.

Manson JE, Colditz GA, Stampfer MJ, et al: A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in women. Arch Intern Med 151:1141-1147, 1991. 151.

Barrett-Connor EL, Cohn BA, Wingard DL, et al: Why is diabetes mellitus a stronger risk factor for fatal ischemic heart disease in women than in men? The Rancho Bernardo Study. JAMA 265:627-631, 1991. 152.

153.

Nathan DM: Long-term complications of diabetes mellitus. N Engl J Med 328:1676-1685, 1993.

Despres JP, Lamarche B, Mauriege P, et al: Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 334:952-957, 1996. 154.

Reaven GM: Banting Lecture 1988. Role of insulin resistance in human disease. Nutrition 13:65; discussion 64, 66, 1997. 155.

Panahloo A, Yudkin JS: Diminished fibrinolysis in diabetes mellitus and its implication for diabetic vascular disease. J Cardiovasc Risk 4:91-99, 1997. 156.

Kannel WB, D'Agostino RB, Wilson PW, et al: Diabetes, fibrinogen, and risk of cardiovascular disease: The Framingham experience. Am Heart J 120:672-676, 1990. 157.

Wautier JL, Guillausseau PJ: Diabetes, advanced glycation endproducts and vascular disease. Vasc Med 3:131-137, 1998. 158.

Stehouwer CD, Nauta JJ, Zeldenrust GC, et al: Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus. Lancet 340:319-323, 1992. 159.

Johnstone MT, Creager SJ, Scales KM, et al: Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 88:2510-2516, 1993. 160.

Neil A, Hawkins M, Potok M, et al: A prospective population-based study of microalbuminuria as a predictor of mortality in NIDDM. Diabetes Care 16:996-1003, 1993. 161.

Valmadrid CT, Klein R, Moss SE, Klein BEK: The risk of cardiovascular disease mortality associated with microalbuminuria and gross proteinuria in persons with older onset diabetes mellitus. Arch Intern Med 160:1093-1100, 2000. 161A.

The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 329:977-986, 1993. 162.

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352:837-853, 1998. 163.

Liu S, Stampfer M, Manson JE, et al: A prospective study of dietary intake of carbohydrate, glycemic load, and risk of myocardial infarction in US women. Am J Clin Nutr 71:1455-1461, 2000. 163A.

EXERCISE AND OBESITY Fletcher GF, Blair SN, Blumenthal J, et al: Statement on exercise: Benefits and recommendations for physical activity programs for all Americans: A statement for health professionals by the Committee on Exercise and Cardiac Rehabilitation of the Council on Clinical Cardiology, American Heart Association. 164.

Circulation 86:340-344, 1992.

1035

Paffenbarger RS Jr, Hyde RT, Wing AL, et al: Physical activity, all-cause mortality, and longevity of college alumni. N Engl J Med 314:605-613, 1986. 165.

Sandvik L, Erikssen J, Thaulow E et al: Physical fitness as a predictor of mortality among healthy, middle-aged Norwegian men. N Engl J Med 328:533-537, 1993. 166.

Rosengren A, Wilhelmsen L: Physical activity protects against coronary death and deaths from all causes in middle-aged men: Evidence from a 20-year follow-up of the primary prevention study in Goteborg. Ann Epidemiol 7:69-75, 1997. 167.

Morris JM, Clayton DG, Everitt MG, et al: Exercise in leisure time: Coronary attack and death rates. Br Heart J 63:325-334, 1990. 167A.

Blair SN, Goodyear NN, Gibbons LW, Cooper KH: Physical fitness and incidence of hypertension in healthy normotensive men and women. JAMA 252:487-490, 1984. 167B.

Leon AS, Connett J, Jacobs DR Jr, Rauramaa R: Leisure-time physical activity levels and risk of coronary heart disease and death: The Multiple Risk Factor Intervention Trial. JAMA 258:2388-2395, 1987. 167C.

Ekelund LG, Haskell WL, Johnson JL, et al: Physical fitness as a prevention of cardiovascular mortalilty in asymptomatic North American men. N Engl J Med 319:1379-1384, 1988. 167D.

Wannamethee SG, Shaper AG, Walker M: Changes in physical activity, mortality, and incidence of coronary heart disease in older men. Lancet 351:1603-1608, 1998. 168.

Manson JE, Hu FB, Rich-Edwards JW, et al: A prospective study of walking as compared with vigorous exercise in the prevention of coronary heart disease in women. N Engl J Med 341:650-658, 1999. 169.

Lee IM, Paffenbarger RS Jr: Physical activity and stroke incidence: The Harvard Alumni Health Study. Stroke 29:2049-2054, 1998. 170.

Lee IM, Hennekens CH, Berger K, et al: Exercise and risk of stroke in male physicians. Stroke 30:1-6, 1999. 171.

Hahn RA, Teutsch SM, Rothenberg RB, et al: Excess deaths from nine chronic diseases in the United States, 1986. JAMA 264:2654-2659, 1990. 172.

Pate RR, Pratt M, Blair SN, et al: Physical activity and public health: A recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine. JAMA 273:402-407, 1995. 173.

Fletcher GF, Balady G, Froelicher VF, et al: Exercise standards: A statement for health care professionals from the American Heart Association. Circulation 91:580-615, 1995. 174.

Surgeon General's report on physical activity and health: From the Centers for Disease Control and Prevention. JAMA 276:522, 1996. 175.

Kokkinos PF, Narayan P, Colleran JA, et al: Effects of regular exercise on blood pressure and left ventricular hypertrophy in African-American men with severe hypertension. N Engl J Med 333:1462-1467, 1995. 176.

King AC, Haskell WL, Young DR, et al: Long-term effects of varying intensities and formats of physical activity on participation rates, fitness, and lipoproteins in men and women aged 50 to 65 years. Circulation 91:2596-2604, 1995. 177.

Helmrich SP, Ragland DR, Leung RW, et al: Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. N Engl J Med 325:147-152, 1991. 178.

Lynch J, Helmrich SP, Lakka TA, et al: Moderately intense physical activities and high levels of cardiorespiratory fitness reduce the risk of non-insulin-dependent diabetes mellitus in middle-aged men. Arch Intern Med 156:1307-1314, 1996. 179.

Clarkson P, Montgomery HE, Mullen MJ, et al: Exercise training enhances endothelial function in young men. J Am Coll Cardiol 33:1379-1385, 1999. 180.

Stratton JR, Chandler WL, Schwartz RS, et al: Effects of physical conditioning on fibrinolytic variables and fibrinogen in young and old healthy adults. Circulation 83:1692-1697, 1991. 181.

Kestin AS, Ellis PA, Barnard MR, et al: Effect of strenuous exercise on platelet activation state and reactivity. Circulation 88:1502-1511, 1993. 182.

Wood PD, Stefanick ML, Williams PT, et al: The effects on plasma lipoproteins of a prudent weight-reducing diet, with or without exercise, in overweight men and women. N Engl J Med 325:461-466, 1991. 183.

Manson JE, Colditz GA, Stampfer MJ, et al: A prospective study of obesity and risk of coronary heart disease in women. N Engl J Med 322:882-889, 1990. 184.

Rosengren A, Wedel H, Wilhelmsen L: Body weight and weight gain during adult life in men in relation to coronary heart disease and mortality: A prospective population study [see comments]. Eur Heart J 20:269-277, 1999. 185.

Willett WC, Manson JE, Stampfer MJ, et al: Weight, weight change, and coronary heart disease in women. Risk within the "normal" weight range. JAMA 273:461-465, 1995. 186.

Rexrode KM, Carey VJ, Hennekens CH, et al: Abdominal adiposity and coronary heart disease in women. JAMA 280:1843-1848, 1998. 187.

Rimm EB, Stampfer MJ, Giovannucci E, et al: Body size and fat distribution as predictors of coronary heart disease among middle-aged and older US men. Am J Epidemiol 141:1117-1127, 1995. 188.

Krauss RM, Winston M, Fletcher RN, Grundy SM: Obesity: Impact of cardiovascular disease. Circulation 98:1472-1476, 1998. 189.

MENTAL STRESS AND CARDIOVASCULAR RISK

Yeung AC, Vekshtein VI, Krantz DS, et al: The effect of atherosclerosis on the vasomotor response of coronary arteries to mental stress. N Engl J Med 325:1551-1556, 1991. 190.

Jiang W, Babyak M, Krantz DS, et al: Mental stress--induced myocardial ischemia and cardiac events. JAMA 275:1651-1656, 1996. 191.

Krantz DS, Santiago HT, Kop WJ, et al: Prognostic value of mental stress testing in coronary artery disease. Am J Cardiol 84:1292-1297, 1999. 192.

Leor J, Poole WK, Kloner RA: Sudden cardiac death triggered by an earthquake. N Engl J Med 334:413-419, 1996. 193.

Krantz DS, Sheps DS, Carney RM, et al: Effects of mental stress in patients with coronary artery disease. JAMA 283:1800-1802, 2000. 194.

Enhancing recovery in coronary heart disease patients (ENRICHD): Study design and methods. The ENRICHD investigators. Am Heart J 139:1-9, 2000. 195.

ESTROGEN STATUS Walsh BW, Schiff I, Rosner B, et al: Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 325:1196-1204, 1991. 196.

197.

Barrett-Connor E, Bush TL: Estrogen and coronary heart disease in JAMA 265:1861-1867, 1991.

Stampfer MJ, Colditz GA, Willett WC et al: Postmenopausal estrogen therapy and cardiovascular disease: Ten-year follow-up from the nurses' health study. N Engl J Med 325:756-762, 1991. 198.

Gerhard M, Ganz P: How do we explain the clinical benefits of estrogen? From bedside to bench. Circulation 92:5-8, 1995. 199.

Reis SE, Gloth ST, Blumenthal RS, et al: Ethinyl estradiol acutely attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women. Circulation 89:52-60, 1994. 200.

Lieberman EH, Gerhard MD, Uehata A, et al: Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. Ann Intern Med 121:936-941, 1994. 201.

Shwaery GT, Vita JA, Kenney JF Jr: Antioxidant protection of LDL by physiologic concentrations of estrogens is specific for 17-beta-estradiol. Atherosclerosis 138:255-262, 1998. 202.

Caulin-Glaser T, Farrell WJ, Pfau SE, et al: Modulation of circulating cellular adhesion molecules in postmenopausal women with coronary artery disease. J Am Coll Cardiol 31:1555-1560, 1998. 203.

Koh KK, Mincemoyer R, Bui MN, et al: Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women. N Engl J Med 336:683-690, 1997. 204.

Espeland MA, Hogan PE, Fineberg SE, et al: Effect of postmenopausal hormone therapy on glucose and insulin concentrations: PEPI Investigators. Postmenopausal Estrogen/Progestin Interventions. Diabetes Care 21:1589-1595, 1998. 205.

206.

Rosenberg L, Kaufman DW, Helmrich SP, et al: Myocardial infarction and cigarette smoking in

women younger than 50 years of age. JAMA 253:2965-2969, 1985. Lewis MA, Spitzer WO, Heinemann LA, et al: Third generation oral contraceptives and risk of myocardial infarction: An international case-control study. Transnational Research Group on Oral Contraceptives and the Health of Young Women. BMJ 312:88-90, 1996. 207.

Petitti DB, Sidney S, Bernstein A, et al: Stroke in users of low-dose oral contraceptives. N Engl J Med 335:8-15, 1996. 208.

Sidney S, Petitti DB, Quesenberry CP Jr, et al: Myocardial infarction in users of low-dose oral contraceptives. Obstet Gynecol 88:939-944, 1996. 209.

Grodstein F, Stampfer M: The epidemiology of coronary heart disease and estrogen replacement in postmenopausal women. Prog Cardiovasc Dis 38:199-210, 1995. 210.

Grady D, Rubin SM, Petitti DB, et al: Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 117:1016-1037, 1992. 211.

Grodstein F, Stampfer MJ, Manson JE, et al: Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 335:453-461, 1996. 212.

Grodstein F, Stampfer MJ, Colditz GA, et al: Postmenopausal hormone therapy and mortality. N Engl J Med 336:1769-1775, 1997. 213.

Matthews KA, Kuller LH, Wing RR, et al: Prior to use of estrogen replacement therapy, are users healthier than nonusers? Am J Epidemiol 143:971-978, 1996. 214.

Colditz GA, Hankinson SE, Hunter DJ, et al: The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 332:1589-1593, 1995. 215.

Col NF, Eckman MH, Karas RH, et al: Patient-specific decisions about hormone replacement therapy in postmenopausal women. JAMA 277:1140-1147, 1997. 216.

Hulley S, Grady D, Bush T, et al: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 280:605-613, 1998. 217.

Shlipak MG, Simon JA, Vittinghoff E, et al: Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause. JAMA 283:1845-1852, 2000. 218.

Delmas PD, Bjarnason NH, Mitlak BH, et al: Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 337:1641-1647, 1997. 219.

Walsh BW, Kuller LH, Wild RA, et al: Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 279:1445-1451, 1998. 220.

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NOVEL RISK FACTORS

Ridker P, Libby P: Nontraditional coronary risk factors and vascular biology: The frontiers of preventive cardiology. J Invest Med 46:338-350, 1998. 221.

Dawber TR, Meadors GF, Moore FE J: Epidemiological approaches to heart disease: The Framingham Study. Am J Public Health 41:279-286, 1951. 222.

Kannel WB, Dawber TR, AK: Factors of risk in the development of coronary heart diseases--six year follow-up experience: The Framingham Study. Ann Intern Med 55:33-50, 1961. 223.

Ridker PM: Evaluating novel cardiovascular risk factors: Can we better predict heart attacks? Ann Intern Med 130:933-937, 1999. 224.

HOMOCYSTEINE 225.

Welch GN, Loscalzo J: Homocysteine and atherothrombosis. N Engel J Med 338:1042-1050, 1998.

Tsai JC, Perrella MA, Yoshizumi M, et al: Promotion of vascular smooth muscle cell growth by homocysteine: A link to atherosclerosis. Proc Natl Acad Sci U S A 91:6369-6373, 1994. 226.

Stamler JS, Osborne JA, Jaraki O, et al: Adverse vascular effects of homocysteine are modulated by endothelium- derived relaxing factor and related oxides of nitrogen. J Clin Invest 91:308-318, 1993. 227.

Chambers JC, McGregor A, Jean-Marie J, et al: Acute hyperhomocysteinaemia and endothelial dysfunction. Lancet 351:36-37, 1998. 228.

Selhub J, Jacques PF, Wilson PW, et al: Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 270: 2693-2698, 1993. 229.

Malinow MR, Bostom AG, Krauss RM: Homocyst(e)ine, diet, and cardiovascular diseases: A statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 99:178-182, 1999. 230.

231.

Hankey GJ, Eikelboom JW: Homocysteine and vascular disease. Lancet 354:407-413, 1999.

Boushey CJ, Beresford SA, Omenn GS, et al: A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: Probable benefits of increasing folic acid intakes. JAMA 274:1049-1057, 1995. 232.

Graham IM, Daly LE, Refsum HM, et al: Plasma homocysteine as a risk factor for vascular disease: The European Concerted Action Project. JAMA 277:1775-1781, 1997. 233.

Egerton W, Silberberg J, Crooks R, et al: Serial measures of plasma homocyst(e)ine after acute myocardial infarction. Am J Cardiol 77:759-761, 1996. 234.

Lindgren A, Brattstrom L, Norrving B, et al: Plasma homocysteine in the acute and convalescent phases after stroke. Stroke 26:795-800, 1995. 235.

Stampfer MJ, Malinow MR, Willett WC, et al: A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 268:877-881, 1992. 236.

237.

Arnesen E, Refsum H, Bonaa KH, et al: Serum total homocysteine and coronary heart disease. Int J

Epidemiol 24:704-709, 1995. Wald NJ, Watt HC, Law MR, et al: Homocysteine and ischemic heart disease: Results of a prospective study with implications regarding prevention. Arch Intern Med 158:862-867, 1998. 238.

Ridker PM, Manson JE, Buring JE, et al: Homocysteine and risk of cardiovascular disease among postmenopausal women. JAMA 281:1817-1821, 1999. 239.

Bostom AG, Silbershatz H, Rosenberg IH, et al: Nonfasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women. Arch Intern Med 159:1077-1080, 1999. 240.

Nygard O, Nordrehaug JE, Refsum H, et al: Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 337:230-236, 1997. 241.

Evans RW, Shaten BJ, Hempel JD, et al: Homocyst(e)ine and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial. Arterioscler Thromb Vasc Biol 17:1947-1953, 1997. 242.

Alfthan G, Pekkanen J, Jauhiainen M, et al: Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis 106:9-19, 1994. 243.

Folsom AR, Nieto FJ, McGovern PG, et al: Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: The Atherosclerosis Risk in Communities (ARIC) study. Circulation 98:204-210, 1998. 244.

Chasan-Taber L, Selhub J, Rosenberg IH, et al: A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians. J Am Coll Nutr 15:136-143, 1996. 245.

Brattstrom L, Wilcken DE, Ohrvik J, et al: Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: The result of a meta-analysis. Circulation 98:2520-2526, 1998. 246.

Werler MM, Shapiro S, Mitchell AA: Periconceptional folic acid exposure and risk of occurrent neural tube defects. JAMA 269:1257-1261, 1993. 247.

Jacques PF, Selhub J, Bostom AG, et al: The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 340:1449-1454, 1999. 248.

Lowering blood homocysteine with folic acid based supplements: Meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. BMJ 316:894-898, 1998. 249.

FIBRINOGEN Ernst E, Resch KL: Fibrinogen as a cardiovascular risk factor: A meta-analysis and review of the literature. Ann Intern Med 118:956-963, 1993. 250.

Scarabin PY, Aillaud MF, Amouyel P, et al: Associations of fibrinogen, factor VII and PAI-1 with baseline findings among 10,500 male participants in a prospective study of myocardial infarction--the PRIME Study. Prospective Epidemiological Study of Myocardial Infarction. Thromb Haemost 80:749-756, 1998. 251.

252.

Margaglione M, Cappucci G, Colaizzo D, et al: Fibrinogen plasma levels in an apparently healthy

general population--relation to environmental and genetic determinants. Thromb Haemost 80:805-810, 1998. Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, et al: Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 311:501-505, 1984. 253.

Meade TW, Mellows S, Brozovic M, et al: Haemostatic function and ischaemic heart disease: Principal results of the Northwick Park Heart Study. Lancet 2:533-537, 1986. 254.

Kannel WB, Wolf PA, Castelli WP, et al: Fibrinogen and risk of cardiovascular disease: The Framingham Study. JAMA 258:1183-1186, 1987. 255.

Heinrich J, Balleisen L, Schulte H, et al: Fibrinogen and factor VII in the prediction of coronary risk: Results from the PROCAM study in healthy men. Arterioscler Thromb 14:54-59, 1994. 256.

Yarnell JW, Baker IA, Sweetnam PM, et al: Fibrinogen, viscosity, and white blood cell count are major risk factors for ischemic heart disease: The Caerphilly and Speedwell collaborative heart disease studies. Circulation 83:836-844, 1991. 257.

Cremer P, Nagel D, Labrot B, et al: Lipoprotein Lp(a) as predictor of myocardial infarction in comparison to fibrinogen, LDL cholesterol and other risk factors: Results from the prospective Gottingen Risk Incidence and Prevalence Study (GRIPS). Eur J Clin Invest 24:444-453, 1994. 258.

Ma J, Hennekens CH, Ridker PM, et al: A prospective study of fibrinogen and risk of myocardial infarction in the Physicians' Health Study. J Am Coll Cardiol 33:1347-1352, 1999. 259.

Wu KK, Folsom AR, Heiss G, et al: Association of coagulation factors and inhibitors with carotid artery atherosclerosis: Early results of the Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol 2:471-480, 1992. 260.

Tracy RP, Bovill EG, Yanez D, et al: Fibrinogen and factor VIII, but not factor VII, are associated with measures of subclinical cardiovascular disease in the elderly. Results from The Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 15:1269-1279, 1995. 261.

Danesh J, Collins R, Appleby P, et al: Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: Meta-analyses of prospective studies. JAMA 279:1477-1482, 1998. 262.

Woodward M, Lowe GD, Rumley A, et al: Fibrinogen as a risk factor for coronary heart disease and mortality in middle-aged men and women: The Scottish Heart Health Study. Eur Heart J 19:55-62, 1998. 263.

Sweetnam PM, Thomas HF, Yarnell JW, et al: Fibrinogen, viscosity and the 10-year incidence of ischaemic heart disease. Eur Heart J 17:1814-1820, 1996. 264.

Koenig W, Sund M, Filipiak B, et al: Plasma viscosity and the risk of coronary heart disease: Results from the MONICA-Augsburg Cohort Study, 1984 to 1992. Arterioscler Thromb Vasc Biol 18:768-772, 1998. 265.

Maresca G, Di Blasio A, Marchioli R, et al: Measuring plasma fibrinogen to predict stroke and myocardial infarction: An update. Arterioscler Thromb Vasc Biol 19:1368-1377, 1999. 266.

Rosenson RS, Tangney CC, Hafner JM: Intraindividual variability of fibrinogen levels and cardiovascular risk profile. Arterioscler Thromb 14:1928-1932, 1994. 267.

Kannel WB, D'Agostino RB, Belanger AJ: Fibrinogen, cigarette smoking, and risk of cardiovascular disease: Insights from the Framingham Study. Am Heart J 113:1006-1010, 1987. 268.

Nabulsi AA, Folsom AR, White A, et al: Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. The Atherosclerosis Risk in Communities Study Investigators. N Engl J Med 328:1069-1075, 1993. 269.

Folsom AR, Wu KK, Rosamond WD, et al: Prospective study of hemostatic factors and incidence of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 96:1102-1108, 1997. 270.

Thompson SG, Kienast J, Pyke SD, et al: Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med 332:635-641, 1995. 271.

Humphries SE: Genetic regulation of fibrinogen. Eur Heart J 16 (Suppl A):16-19; discussion 19-20, 1995. 272.

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Tybjaerg-Hansen A, Agerholm-Larsen B, Humphries SE, et al: A common mutation (G-455 A) in the beta-fibrinogen promoter is an independent predictor of plasma fibrinogen, but not of ischemic heart disease: A study of 9,127 individuals based on the Copenhagen City Heart Study. J Clin Invest 99:3034-3039, 1997. 273.

Kockx M, Gervois PP, Poulain P, et al: Fibrates suppress fibrinogen gene expression in rodents via activation of the peroxisome proliferator-activated receptor-alpha. Blood 93:2991-2998, 1999. 274.

Staels B, Koenig W, Habib A, et al: Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. Nature 393:790-793, 1998. 275.

Behar S: Lowering fibrinogen levels: Clinical update. BIP Study Group. Bezafibrate Infarction Prevention. Blood Coagul Fibrinolysis 10 (Suppl 1):S41-S43, 1999. 276.

LIPOPROTEIN(a) Rader DJ, Cain W, Ikewaki K, et al: The inverse association of plasma lipoprotein(a) concentrations with apolipoprotein(a) isoform size is not due to differences in Lp(a) catabolism but to differences in production rate. J Clin Invest 93:2758-2763, 1994. 277.

Hajjar KA, Gavish D, Breslow JL, et al: Lipoprotein(a) modulation of endothelial cell surface fibrinolysis and its potential role in atherosclerosis. Nature 339:303-305, 1989. 278.

Loscalzo J, Weinfeld M, Fless GM, et al: Lipoprotein(a), fibrin binding, and plasminogen activation. Arteriosclerosis 10:240-245, 1990. 279.

Dangas G, Mehran R, Harpel PC, et al: Lipoprotein(a) and inflammation in human coronary atheroma: Association with the severity of clinical presentation. J Am Coll Cardiol 32:2035-2042, 1998. 280.

Poon M, Zhang X, Dunsky KG, et al: Apolipoprotein(a) induces monocyte chemotactic activity in human vascular endothelial cells. Circulation 96:2514-2519, 1997. 281.

Etingin OR, Hajjar DP, Hajjar KA, et al: Lipoprotein(a) regulates plasminogen activator inhibitor-1 expression in endothelial cells: A potential mechanism in thrombogenesis. J Biol Chem 266:2459-2465, 1991. 282.

Schaefer EJ, Lamon-Fava S, Jenner JL, et al: Lipoprotein(a) levels and risk of coronary heart disease in men: The Lipid Research Clinics Coronary Primary Prevention Trial. JAMA 271:999-1003, 1994. 283.

Wald NJ, Law M, Watt HC, et al: Apolipoproteins and ischaemic heart disease: Implications for screening. Lancet 343:75-79, 1994. 284.

Wild SH, Fortmann SP, Marcovina SM: A prospective case-control study of lipoprotein(a) levels and apo(a) size and risk of coronary heart disease in Stanford Five-City Project participants. Arterioscler Thromb Vasc Biol 17:239-245, 1997. 285.

Ridker PM, Hennekens CH, Stampfer MJ: A prospective study of lipoprotein(a) and the risk of myocardial infarction. JAMA 270:2195-2199, 1993. 286.

Ridker PM, Stampfer MJ, Hennekens CH: Plasma concentration of lipoprotein(a) and the risk of future stroke. JAMA 273:1269-1273, 1995. 287.

Jauhiainen M, Koskinen P, Ehnholm C, et al: Lipoprotein(a) and coronary heart disease risk: A nested case-control study of the Helsinki Heart Study participants. Atherosclerosis 89:59-67, 1991. 288.

Cantin B, Gagnon F, Moorjani S, et al: Is lipoprotein(a) an independent risk factor for ischemic heart disease in men? The Quebec Cardiovascular Study. J Am Coll Cardiol 31:519-525, 1998. 289.

Bostom AG, Gagnon DR, Cupples LA, et al: A prospective investigation of elevated lipoprotein (a) detected by electrophoresis and cardiovascular disease in women: The Framingham Heart Study. Circulation 90:1688-1695, 1994. 290.

Nguyen TT, Ellefson RD, Hodge DO, et al: Predictive value of electrophoretically detected lipoprotein(a) for coronary heart disease and cerebrovascular disease in a community-based cohort of 9936 men and women. Circulation 96:1390-1397, 1997. 291.

Tate JR, Rifai N, Berg K, et al: International Federation of Clinical Chemistry standardization project for the measurement of lipoprotein(a). Phase I. Evaluation of the analytical performance of lipoprotein(a) assay systems and commercial calibrators. Clin Chem 44:1629-1640, 1998. 292.

Weiss SR, Bachorik PS, Becker LC, et al: Lipoprotein(a) and coronary heart disease risk factors in a racially mixed population: The Johns Hopkins Sibling Study. Ethn Dis 8:60-72, 1998. 293.

Moliterno DJ, Jokinen EV, Miserez AR, et al: No association between plasma lipoprotein(a) concentrations and the presence or absence of coronary atherosclerosis in African-Americans. Arterioscler Thromb Vasc Biol 15:850-855, 1995. 294.

Sunayama S, Daida H, Mokuno H, et al: Lack of increased coronary atherosclerotic risk due to elevated lipoprotein(a) in women > or = 55 years of age. Circulation 94:1263-1268, 1996. 295.

296.

Maher VM, Brown BG, Marcovina SM, et al: Effects of lowering elevated LDL cholesterol on the

cardiovascular risk of lipoprotein(a). JAMA 274:1771-1774, 1995. Fortmann SP, Marcovina SM: Lipoprotein(a), a clinically elusive lipoprotein particle [editorial; comment]. Circulation 95:295-296, 1997. 297.

MARKERS OF FIBRINOLYTIC FUNCTION (PAI-1, t-PA, CLOT LYSIS,

D

-DIMER)

Angleton P, Chandler WL, Schmer G: Diurnal variation of tissue-type plasminogen activator and its rapid inhibitor (PAI-1). Circulation 79:101-106, 1989. 298.

Tofler GH, Brezinski D, Schafer AI, et al: Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med 316:1514-1518, 1987. 299.

Shimomura I, Funahashi T, Takahashi M, et al: Enhanced expression of PAI-1 in visceral fat: Possible contributor to vascular disease in obesity. Nat Med 2:800-803, 1996. 300.

Alessi MC, Peiretti F, Morange P, et al: Production of plasminogen activator inhibitor 1 by human adipose tissue: Possible link between visceral fat accumulation and vascular disease. Diabetes 46:860-867, 1997. 301.

Lundgren CH, Brown SL, Nordt TK, et al: Elaboration of type-1 plasminogen activator inhibitor from adipocytes: A potential pathogenetic link between obesity and cardiovascular disease. Circulation 93:106-110, 1996. 302.

Potter van Loon BJ, Kluft C, Radder JK, et al: The cardiovascular risk factor plasminogen activator inhibitor type 1 is related to insulin resistance. Metabolism 42:945-949, 1993. 303.

Juhan-Vague I, Thompson SG, Jespersen J: Involvement of the hemostatic system in the insulin resistance syndrome: A study of 1500 patients with angina pectoris. The ECAT Angina Pectoris Study Group. Arterioscler Thromb 13:1865-1873, 1993. 304.

Fay WP, Shapiro AD, Shih JL, et al: Brief report: Complete deficiency of plasminogen-activator inhibitor type 1 due to a frame-shift mutation. N Engl J Med 327:1729-1733, 1992. 305.

Kohler HP, Grant PJ: Mechanisms of disease: Plasminogen-activator inhibitor type 1 and coronary artery disease. N Engl J Med 342:1792-1801, 2000. 305A.

Prins MH, Hirsh J: A critical review of the evidence supporting a relationship between impaired fibrinolytic activity and venous thromboembolism. Arch Intern Med 151:1721-1731, 1991. 306.

Ridker PM, Vaughan DE, Stampfer MJ, et al: Baseline fibrinolytic state and the risk of future venous thrombosis: A prospective study of endogenous tissue-type plasminogen activator and plasminogen activator inhibitor. Circulation 85:1822-1827, 1992. 307.

Hamsten A, Wiman B, de Faire U, et al: Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 313:1557-1563, 1985. 308.

Hamsten A, de Faire U, Walldius G, et al: Plasminogen activator inhibitor in plasma: Risk factor for recurrent myocardial infarction. Lancet 2:3-9, 1987. 309.

Jansson JH, Olofsson BO, Nilsson TK: Predictive value of tissue plasminogen activator mass concentration on long-term mortality in patients with coronary artery disease: A 7-year follow-up. 310.

Circulation 88:2030-2034, 1993. Ridker PM, Vaughan DE, Stampfer MJ, et al: Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 341:1165-1168, 1993. 311.

Ridker PM, Hennekens CH, Stampfer MJ, et al: Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet 343:940-943, 1994. 312.

Thogersen AM, Jansson JH, Boman K, et al: High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: Evidence for the fibrinolytic system as an independent primary risk factor. Circulation 98:2241-2247, 1998. 313.

Meade TW, Ruddock V, Stirling Y, et al: Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 342:1076-1079, 1993. 314.

Ridker PM, Hennekens CH, Cerskus A, et al: Plasma concentration of cross-linked fibrin degradation product ( D -dimer) and the risk of future myocardial infarction among apparently healthy men. Circulation 90:2236-2240, 1994. 315.

Fowkes FG, Lowe GD, Housley E, et al: Cross-linked fibrin degradation products, progression of peripheral arterial disease, and risk of coronary heart disease. Lancet 342:84-86, 1993. 316.

Moss AJ, Goldstein RE, Marder VJ, et al: Thrombogenic factors and recurrent coronary events. Circulation 99:2517-2522, 1999. 317.

Wright RA, Flapan AD, Alberti KG, et al: Effects of captopril therapy on endogenous fibrinolysis in men with recent, uncomplicated myocardial infarction. J Am Coll Cardiol 24:67-73, 1994. 318.

Vaughan DE, Rouleau JL, Ridker PM, et al: Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. HEART Study Investigators. Circulation 96:442-447, 1997. 319.

Dawson SJ, Wiman B, Hamsten A, et al: The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem 268:10739-10745, 1993. 320.

Eriksson P, Kallin B, van't Hooft FM, et al: Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci U S A 92:1851-1855, 1995. 321.

Ye S, Green FR, Scarabin PY, et al: The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with differences in plasma PAI-1 activity but not with risk of myocardial infarction in the ECTIM study. Etude Cas Temoins de l'infarctus du myocarde. Thromb Haemost 74:837-841, 1995. 322.

1038

Ridker PM, Hennekens CH, Lindpaintner K, et al: Arterial and venous thrombosis is not associated with the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor gene in a large cohort 323.

of US men. Circulation 95:59-62, 1997.

MARKERS OF INFLAMMATION 324.

Ross R: Atherosclerosis--an inflammatory disease. N Engl J Med 340:115-126, 1999.

325.

Libby P: The molecular bases of the acute coronary syndromes. Circulation 91:2844-2850, 1995.

Gu L, Okada Y, Clinton S, et al: Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low-density lipoprotein-deficient mice. Mol Cell 2:275-281, 1998. 326.

Moreno PR, Falk E, Palacios IF, et al: Macrophage infiltration in acute coronary syndromes: Implications for plaque rupture. Circulation 90:775-778, 1994. 327.

van der Wal AC, Becker AE, van der Loos CM, at al: Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 89:36-44, 1994. 328.

Mach F, Schoenbeck U, Bonnefoy JY, et al: Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of CD40: Induction of collagenase, stromelysin, and tissue factor. Circulation 96:396-399, 1997. 329.

Libby P, Ridker PM: Novel inflammatory markers of coronary risk: Theory versus practice. Circulation 100:1148-1150, 1999. 330.

Ridker PM, Hennekens CH, Buring JE, et al: C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 342:836-843, 2000. 331.

Van Lenten BJ, Hama SY, de Beer FC, et al: Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response: Loss of protective effect of HDL against LDL oxidation in aortic wall cell co-cultures. J Clin Invest 96:2758-2767, 1995. 332.

Rifai N, Tracy RP, Ridker PM: Clinical efficacy of an automated high-sensitivity C-reactive protein assay. Clin Chem 45:2136-2141, 1999. 333.

Ridker PM, Cushman M, Stampfer MJ, et al: Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 336:973-979, 1997. 334.

Koenig W, Sund M, Froelich M, et al: C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: Results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsberg Cohort Study, 1984 to 1992. Circulation 99:237-242, 1999. 334A.

Roivainen M, Viik-Kajander M, Palosuo T, et al: Infections, inflammation, and the risk of coronary heart disease. Circulation 101:252-257, 2000. 334B.

Ridker PM, Buring JE, Shih J, et al: Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 98:731-733, 1998. 335.

Tracy RP, Lemaitre RN, Psaty BM, et al: Relationship of C-reactive protein to risk of cardiovascular disease in the elderly: Results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol 17:1121-1127, 1997. 336.

Kuller LH, Tracy RP, Shaten J, et al: Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Multiple Risk Factor Intervention Trial. Am J Epidemiol 144:537-547, 1996. 337.

Haverkate F, Thompson SG, Pyke SD, et al: Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Lancet 349:462-466, 1997. 338.

Liuzzo G, Biasucci LM, Gallimore JR, et al: The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med 331:417-424, 1994. 339.

Morrow DA, Rifai N, Antman EM, et al: C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: A TIMI 11A substudy. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol 31:1460-1465, 1998. 340.

Ridker PM, Rifai N, Pfeffer MA, et al: Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation 98:839-844, 1998. 341.

Ridker PM, Glynn RJ, Hennekens CH: C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of fast myocardial infarction. Circulation 97:2007-2011, 1998. 342.

Pepys MG: The acute phase response and C-reactive protein. In Weatherall DJ, Ledingham JGG, Warrell DA (eds): Oxford Textbook of Medicine. Oxford, Oxford University Press, 1995. 343.

Ridker PM, Rifai N, Pfeffer MA, et al: Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 100:230-235, 1999. 344.

Aikawa M, Rabkin E, Okada Y, et al: Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma: A potential mechanism of lesion stabilization. Circulation 97:2433-2444, 1998. 345.

Aikawa M, Voglic SJ, Sugiyama S, et al: Dietary lipid lowering reduces tissue factor expression in rabbit atheroma. Circulation 100:1215-1222, 1999. 346.

Shiomi M, Ito T: Effect of cerivastatin sodium, a new inhibitor of HMG-CoA reductase, on plasma lipid levels, progression of atherosclerosis, and the lesional composition in the plaques of WHHL rabbits. Br J Pharmacol 126:961-968, 1999. 347.

Williams JK, Sukhova GK, Herrington DM, et al: Pravastatin has cholesterol-lowering independent effects on the artery wall of atherosclerotic monkeys. J Am Coll Cardiol 31:684-691, 1998. 348.

Bellosta S, Via D, Canavesi M, et al: HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages. Arterioscler Thromb Vasc Biol 18:1671-1678, 1998. 349.

Smith JK, Dykes R, Douglas JE, et al: Long-term exercise and atherogenic activity of blood mononuclear cells in persons at risk of developing ischemic heart disease. JAMA 281:1722-1727, 1999. 350.

Visser M, Bouter LM, McQuillan GM, et al: Elevated C-reactive protein levels in overweight and obese adults. JAMA 282:2131-2135, 1999. 351.

Cushman M, Meilahn EN, Psaty BM, et al: Hormone replacement therapy, inflammation, and hemostasis in elderly women. Arterioscler Thromb Vasc Biol 19:893-899, 1999. 352.

Ridker PM, Hennekens CH, Rifai N, et al: Hormone replacement therapy and increased plasma concentration of C-reactive protein. Circulation 100:713-716, 1999. 353.

Cushman M, Legault C, Barrett-Connor E, et al: Effect of postmenopausal hormones on inflammation-sensitive proteins: The Postmenopausal Estrogen/Progestin Interventions (PEPI) Study. Circulation 100:717-722, 1999. 354.

Maseri A: Inflammation, atherosclerosis, and ischemic events--exploring the hidden side of the moon. N Engl J Med 336:1014-1016, 1997. 355.

Ridker PM, Rifai N, Stampfer MJ, et al: Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101:1767-1772, 2000. 356.

Harris TB, Ferrucci L, Tracy RP, et al: Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med 106:506-512, 1999. 357.

Liuzzo G, Buffon A, Biasucci LM, et al: Enhanced inflammatory response to coronary angioplasty in patients with severe unstable angina. Circulation 98:2370-2376, 1998. 358.

Biasucci LM, Liuzzo G, Fantuzzi G, et al: Increasing levels of interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events. Circulation 99:2079-2084, 1999. 359.

Ridker PM, Rifai N, Pfeffer M, et al, for the Cholesterol and Recurrent Events (CARE) Investigators: Elevation of tumor necrosis factor and increased risk of recurrent coronary events following myocardial infarction. Circulation 101:2149-2153, 2000. 360.

Hwang SJ, Ballantyne CM, Sharrett AR, et al: Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: The Atherosclerosis Risk In Communities (ARIC) study. Circulation 96:4219-4225, 1997. 361.

Ridker PM, Hennekens CH, Roitman-Johnson B, et al: Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet 351:88-92, 1998. 362.

Danesh J, Collins R, Peto R: Chronic infections and coronary heart disease: Is there a link? Lancet 350:430-436, 1997. 363.

Libby P, Egan D, Skarlatos S: Roles of infectious agents in atherosclerosis and restenosis: An assessment of the evidence and need for future research. Circulation 96:4095-4103, 1997. 364.

Saikku P, Leinonen M, Mattila K, et al: Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet 2:983-986, 1988. 365.

Mendall MA, Goggin PM, Molineaux N, et al: Relation of Helicobacter pylori infection and coronary heart disease. Br Heart J 71:437-439, 1994. 366.

Melnick JL, Adam E, DeBakey ME: Possible role of cytomegalovirus in atherogenesis. JAMA 263:2204-2207, 1990. 367.

Grayston JT, Kuo CC, Coulson AS, et al: Chlamydia pneumoniae (TWAR) in atherosclerosis of the carotid artery. Circulation 92:3397-3400, 1995. 368.

Muhlestein JB, Hammond EH, Carlquist JF, et al: Increased incidence of Chlamydia species within the coronary arteries of patients with symptomatic atherosclerotic versus other forms of cardiovascular disease. J Am Coll Cardiol 27:1555-1561, 1996. 369.

Nieto FJ, Adam E, Sorlie P, et al: Cohort study of cytomegalovirus infection as a risk factor for carotid intimal-medial thickening, a measure of subclinical atherosclerosis. Circulation 94:922-927, 1996. 370.

Ridker PM: Inflammation, infection, and cardiovascular risk: How good is the clinical evidence? Circulation 97:1671-1674, 1998. 371.

Ridker PM, Hennekens CH, Buring JE, et al: Baseline IgG antibody titers to Chlamydia pneumoniae, Helicobacter pylori, herpes simplex virus, and cytomegalovirus and the risk for cardiovascular disease in women. Ann Intern Med 131:573-577, 1999. 372.

Ridker PM, Hennekens CH, Stampfer MJ, et al: Prospective study of herpes simplex virus, cytomegalovirus, and the risk of future myocardial infarction and stroke. Circulation 98:2796-2799, 1998. 373.

Wald NJ, Law MR, Morris JK, et al: Helicobacter pylori infection and mortality from ischaemic heart disease: Negative result from a large, prospective study. BMJ 315:1199-1201, 1997. 374.

Folsom AR, Nieto FJ, Sorlie P, et al: Helicobacter pylori seropositivity and coronary heart disease incidence. Atherosclerosis Risk In Communities (ARIC) Study Investigators. Circulation 98:845-850, 1998. 375.

Ridker PM, Kundsin RB, Stampfer MJ, et al: Prospective study of Chlamydia pneumoniae IgG seropositivity and risks of future myocardial infarction. Circulation 99:1161-1164, 1999. 376.

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Kalayoglu MV, Byrne GI: Induction of macrophage foam cell formation by Chlamydia pneumoniae. J Infect Dis 177:725-729, 1998. 377.

Fryer RH, Schwobe EP, Woods ML, et al: Chlamydia species infect human vascular endothelial cells and induce procoagulant activity. J Invest Med 45:168-174, 1997. 378.

Kol A, Sukhova GK, Lichtman AH, et al: Chlamydial heat shock protein 60 localizes in human atheroma and regulates macrophage TNF-alpha and matrix metalloproteinase expression. Circulation 98:300-307, 1998. 379.

Kol A, Bourcier T, Lichtman AH, et al: Chlamydial and human heat shock protein 60s activate human vascular endothelium, smooth muscle cells, and macrophages. J Clin Invest 103:571-577, 1999. 380.

Kol A, Lichtman AH, Finberg RW, et al: Heat shock protein (HSP) 60 activates the innate immune response: CD14 is an essential receptor for HSP60 activation of mononuclear cells. J Immunol 164:13-17, 2000. 381.

FUTURE DIRECTIONS IN CORONARY RISK ASSESSMENT Detrano RC, Wong ND, Doherty TM, et al: Coronary calcium does not accurately predict near-term future coronary events in high-risk adults. Circulation 99:2633-2638, 1999. 382.

Ridker PM, Stampfer MJ: Assessment of genetic markers for coronary thrombosis: Promise and precaution. Lancet 353:687-688, 1999. 383.




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Chapter 32 - Primary and Secondary Prevention of Coronary Heart Disease J. MICHAEL GAZIANO JOANN E. MANSON PAUL M RIDKER

The public health importance of both primary and secondary prevention of coronary heart disease (CHD) is indisputable. In view of the prevalence of CHD, preventing even a small proportion of cases would save thousands of lives, avoid inestimable suffering, and save billions of health care dollars. In addition, measures that prevent CHD may also mitigate other manifestations of atherosclerosis such as stroke and peripheral artery disease. Because cardiovascular diseases will become the number one killer worldwide early in the 21st century,[1] widespread deployment of affordable preventive strategies will be essential for both developed and developing countries.[2] While researchers have made great strides in identifying a large number of life style, biochemical, and genetic factors potentially associated with CHD, the process of disease prevention must push beyond understanding disease mechanisms and identifying risk factors toward establishing intervention strategies that definitively reduce risk. Weighing the benefits of given interventions against their risks and costs has led to

the establishment of guidelines for health providers and the general public. Implementing these guidelines, however, remains a difficult task. DEVELOPMENT OF PREVENTIVE INTERVENTIONS The multifactorial nature of atherogenesis makes the process of prevention complex. Potential risk factors for atherosclerotic disease include nonmodifiable factors such as age, sex, and race; behavioral characteristics such as smoking and physical activity; and biochemical variables such as the serum cholesterol level. Many factors are useful in assessing an individual's risk of development of a first or subsequent event. However, while predictive value is necessary to infer that modification of a risk factor will lead to reduced risk, it is not sufficient. Several additional steps are needed. First, the factor must be easy and inexpensive to measure--a major potential limitation for expensive techniques such as electron beam computed tomography. Second, the false-positive rate associated with screening must be low to avoid unnecessary and potentially hazardous consequences. Third, the benefit of intervention must clearly exceed any risks and be worth the cost. Finally, the intervention must be implemented in appropriate populations. Some factors, such as age, gender, and family history, are useful in assessing risk but are not modifiable. These factors will be considered only in the context of their ability to help us determine global risk. Assessing Causality of a Given Factor

A crucial step in developing preventive strategies is the establishment of cause and effect. Consistent data from several types of research are needed to establish a causal relationship between exposure and disease (Table 32-1) . Basic research is providing insight into the mechanisms underlying atherogenesis and can help elucidate potential interventions to modify these effects. It is in the area of drug development that basic research has been particularly successful. The role of epidemiology in the development of preventive strategies involves a number of complementary methods, including descriptive studies (cross-sectional surveys and cross-cultural analyses), analytical studies (case-control and prospective cohort studies), and intervention studies (randomized trials). DESCRIPTIVE STUDIES.

Descriptive studies include case reports, case series, cross-sectional surveys, cross-cultural TABLE 32-1 -- TYPES OF STUDIES USED IN ESTABLISHING PREVENTIVE STRATEGIES Basic research In vitro studies Animal studies Clinical investigation

Epidemiological studies Descriptive studies Case reports Cross-sectional surveys Cross-cultural comparison studies Temporal trend studies Analytical studies Observational Case-control studies Cohort studies Intervention (randomized trials) Cost efficacy studies Meta-analyses

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studies, and studies of population-based temporal trends. These studies are valuable primarily for their generation of hypotheses that can be tested in more analytical settings. The major contribution of descriptive studies, particularly cross-cultural studies and studies of temporal trends, has been the demonstration that environmental factors play an important role in the development of atherosclerotic disease. The higher rates of heart disease in northern Europe than southern Europe,[3] the differences in cardiovascular disease rates among industrialized and less developed nations,[1] and changing rates of heart disease over the past three decades in the United States (Fig. 32-1) and other industrialized nations all support critical environmental components in the pathogenesis of atherosclerosis. Migration studies, such as the Ni-Hon-San Study, which showed increasing heart disease rates as Japanese men migrated from Japan to Honolulu and San Francisco, indicated that behavioral and environmental factors could explain a large portion of the cross-cultural differences in heart disease rates. [4] However, preventive strategies cannot be based solely on descriptive studies because their design prevents adequate control for potential factors that may confound apparent associations. OBSERVATIONAL ANALYTICAL STUDIES.

In contrast to descriptive studies, observational analytical studies (case-control and prospective cohort studies) give researchers greater control over potential confounders. Observational studies suffer less from the biases of descriptive data since both outcome and exposure data are available for each individual in the study population, thus offering

the possibility of better control for many potential confounders. Case-Control Studies.

Case-control studies are designed to identify cases of a particular disease and appropriately matched controls and to compare the exposure status of potential risk factors typically ascertained at the time that disease status is established. Although case-control studies are more efficient and less costly than prospective cohort studies, recall bias may have an impact on risk estimates since exposure status is ascertained after the onset of disease. The selection process used to identify both cases and matched controls may also introduce bias since selected cases or controls may not adequately represent the intended source populations. Prospective Cohort Studies.

In these studies, researchers ascertain exposure status at the beginning of the study and monitor individuals for the development of subsequent events. Prospective cohort studies are thus less subject to the biases of case-control studies because exposure data are collected before the development of disease. Furthermore, selection bias is less of an issue because subjects are not initially chosen on the basis of their disease status. Case-control and prospective cohort studies are extremely useful in establishing risk attributable to a single factor, particularly when the effect of a given factor is large. Thus, as is the case for smoking and lung cancer, it is neither necessary nor ethical to conduct randomized trials to establish causality. On the other hand, when searching for small to moderate effects, the amount of uncontrolled confounding in observational studies may be as large as the probable risk reduction itself. In such cases, randomized trials are essential for confirming association. Even when causality is not in question, trials help quantify the magnitude of an intervention's effect. In addition, when the intervention is associated with competing risks and benefits, randomized trials are needed to determine the net clinical effect of the intervention. For example, observational studies indicate that estrogen replacement therapy may confer a protective effect in terms of coronary heart disease, but these benefits must be weighed against the potential increased risk of breast and uterine cancer. Assessment of Benefits and Risks of Intervention

Once a factor has been established as causally related to disease, interventions to modify the factor must be developed and tested. This critical element in prevention is necessary because the magnitude of associated risk is not necessarily related to the magnitude of benefit derived from the intervention. Such lack of correlation may be due to the inability of the intervention to achieve the necessary change, or a change in the parameter may not result in the necessary change in risk in a proportional manner. An example is the difference between the observed risk associated with a 1-mm Hg rise in blood pressure and the lower than anticipated benefit on CHD derived from reducing blood pressure by this amount.[5] [6] Similarly, while elevated levels of homocysteine have

been implicated as a risk factor for CHD and while folic acid reduces homocysteine levels, evidence from randomized trials indicating that reducing homocysteine levels with folic acid reduces vascular risk is not yet available. In addition to providing information on the causal nature of an association, randomized trials generally provide the best data on the magnitude of benefit and risk from a given intervention. This information is essential for assessing cost efficacy and developing preventive strategies.

Figure 32-1 Change in age-adjusted mortality from coronary heart disease (CHD), stroke, and all causes in the United States, 1950 to 1996. CVD=cardiovascular disease. (From 1998 Chartbook on Cardiovascular, Lung, and Blood Diseases. Bethesda, MD, National Institutes of Health, National Heart, Lung and Blood Institute, 1998, p 21.)

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Meta-Analysis

In some instances, data from individual randomized trials or observational studies fail to establish a clear risk or benefit, possibly because of small sample size. In these cases, it may be helpful to pool data from several studies in an overview, or meta-analysis. Pooling data is difficult if major differences exist in study design, interventional strategies, or definitions of exposure variables or outcome measures. Meta-analyses must be interpreted cautiously because the results may depend on the underlying assumptions dictating which studies were included or how data were summarized. Publication bias may also influence the results since it is often difficult to gain access to unpublished data for inclusion in the meta-analysis. Cost Efficacy of Preventive Interventions (see also Chap. 2)

Once reasonable estimates of benefit and risk have been established for a given factor, cost-effectiveness analyses can be helpful in establishing guidelines for intervention. The common currency used to compare interventions is the quality-adjusted life-year (QALY) or disability-adjusted life-year (DALY). As with estimates derived from meta-analyses, those from cost- and risk-benefit analyses are dependent on the underlying assumptions made in a given analysis. In particular, because prevention measures have a long time horizon (decades or more), the consequences of initial assumptions can be much more significant than those of interventions with a short time horizon. Nonetheless,

Figure 32-2 Coronary heart disease (CHD) score sheets for calculating 10-year CHD risk according to age, total cholesterol (TC) (or low-density lipoprotein cholesterol [LDL-C]), high-density lipoprotein cholesterol (HDL-C), blood pressure, diabetes, and smoking. A, Score sheet for men based on the Framingham experience in men 30 to 74 years old at baseline. Average risk estimates are based on typical Framingham subjects, and estimates of idealized risk are based on optimal blood pressure, TC of 160 to 199 mg/dl (or LDL of 100 to 129 mg/dl), HDL-C of 45 mg/dl, no diabetes, and no smoking. B, Score sheet for women based on the Framingham experience in women 30 to 74 years old at baseline. Aerage risk estimates are based on typical Framingham subjects, and estimates of idealized risk are based on optimal blood pressure, TC of 160 to 199 mg/dl (or LDL of 100 to 129 mg/dl), HDL-C of 55 mg/dl, no diabetes, and no smoking. Use of the LDL-C categories is appropriate when fasting LDL-C measurements are available. Pts=points. (From Wilson PW, D'Agostino RB, Levy D, et al: Prediction of coronary heart disease using risk factor categories. Circulation 97:1837-1847, 1998. By permission of the American Heart Association, Inc.)

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the cost-effectiveness of interventions to prevent heart disease is important because of both the prevalence of CHD and the high cost of treatment. Cost-effectiveness estimates are calculated as the ratio of net cost to the gain in life expectancy. Interventions with an incremental cost-effectiveness ratio of less than $40,000 per QALY are comparable to other chronic interventions such as hypertension management and hemodialysis. Those with a cost-effectiveness ratio under $20,000 per QALY are very favorable, while those exceeding $40,000 per QALY tend to be higher than generally accepted by most insurers. Assessing Absolute Risk

The cost efficacy of any intervention varies according to global risk in a given individual or population. Thus, a fundamental step in establishing a preventive strategy involves assessing an individual's risk of development of clinically relevant outcomes. To illustrate this concept, assume that an intervention reduces mortality by 25 percent in both primary and secondary prevention. Furthermore, assume that a high-risk individual with CHD has a 20 percent chance of death from cardiovascular disease over the next 10 years while a low-risk individual has a 1 percent chance of death over the same period. To save a life among those at high risk, one would have to treat only 20 patients (4 of whom are destined to die) for 10 years so that a 25 percent relative risk reduction would result in 1 life saved (3 deaths instead of 4). On the other hand, one would have to treat 400 low-risk patients (4 of whom are also destined to die) so that the same 25 percent relative risk reduction would yield 3 deaths instead of 4. Thus, the total cost per

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lives saved is considerably lower among individuals at higher absolute risk. Investigators with the Framingham Heart Study have developed a useful tool to assess

risk of a first cardiovascular event based on age, gender, total or low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, systolic and diastolic blood pressure, and history of diabetes and cigarette smoking[7] (Fig. 32-2) . Point-based weights are assigned to the presence and/or level of each risk factor. Once the points have been assigned and summed, the total score can be translated to an estimated absolute risk of a CHD event occurring within the next 10 years. The European Society of Cardiology has also assembled

Figure 32-3 Risk assessment tool using cholesterol levels, blood pressure, and smoking status devised by a European task force on coronary prevention. (From Wood D, De Backer G, Faergeman O, et al: Prevention of Coronary Heart Disease in Clinical Practice. Recommendations of the Second Joint Task Force of European and other Societies on Coronary Prevention. Eur Heart J 19:1434-1503, 1998.)

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recommendations for the prevention of heart disease that stratify preventive interventions according to whether a patient is at high, intermediate, or low risk.[8] Those with known CHD constitute the highest-risk category because most of these individuals have a greater than 20 percent chance of subsequent events over the next 10 years. Individuals without known CHD are assessed for risk with a modified Framingham assessment tool. This tool, presented in a series of easy-to-use charts, allows clinicians to assess risk over the next 10 years based on age, gender, smoking status, diabetes, level of cholesterol, and blood pressure (Fig. 32-3) . Those for whom the risk of a primary event exceeds 20 percent over the next 10 years are recommended for aggressive management. Those for whom risk is lower are prescribed a less intense and less costly approach. The major difference between the Framingham and the European Society of Cardiology scores is the absence of HDL cholesterol from the European formula, which was omitted because it is not routinely measured in general population screening in some countries. Risk assessment scales are also available from the Framingham investigators for the secondary prevention of myocardial infarction and stroke. However, since all patients with prior evidence of cardiovascular disease are at high risk for recurrent events and require aggressive preventive efforts, the utility of these tools is unclear. Primary Versus Secondary Prevention

A crude means of determining absolute risk is embedded in the concept of primary versus secondary prevention. While most factors that predict a first CHD event also predict subsequent events, the relative cost efficacy of an intervention for primary prevention versus secondary prevention varies. Preventive interventions tend to be more cost-effective in secondary prevention: Since absolute risk among those with known disease is higher, fewer higher-risk individuals require treatment to save one life in comparison to those at lower risk, even if relative risk reductions are identical in both

groups. Assessing an individual's absolute risk enables cost-effective targeting of interventions. Accordingly, the National Cholesterol Education Program (NCEP) and the Sixth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) use absolute risk to gauge the level of intensity of intervention. Guidelines from the NCEP Adult Treatment Panel II adjust treatment cut points and goals according to the level of underlying risk.[9] Individuals with clinical manifestations of CHD should receive the most aggressive lipid-lowering therapy (LDL goal of 160/>100)

Drug therapy

Drug therapy

Drug therapy

TOD/CCD=target organ disease/clinical cardiovascular disease (see Table 32-4) . From The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Bethesda, MD, National Institutes Of Health, National Heart, Lung, and Blood Institute, National High Blood Pressure Education Program, NIH Publication 98-4080, 1997. Life style modification should be adjunctive therapy for all patients recommended for pharmacological therapy. For those with heart failure, renal insufficiency, or diabetes. For patients with multiple risk factors, clinicians should consider drugs as initial therapy plus life style modifications.

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TABLE 32-7 -- CONSIDERATIONS FOR INDIVIDUALIZING ANTIHYPERTENSIVE DRUG THERAPY INDICATION SUGGESTED PHARMACOLOGICAL THERAPY Diabetes mellitus (type 1) with proteinuria

ACE inhibitors

Heart failure

ACE inhibitors, diuretics

Isolated systolic hypertension (older patients)

Diuretics (preferred), calcium antagonists (long-acting dihydropyridine)

Myocardial infarction

Beta blockers (nonintrinsic sympathomimetic activity) ACE inhibitors (with systolic dysfunction)

Angina

Beta blockers, calcium antagonists

Benign prostatic hyperplasia

Alpha blockers

ACE=angiotensin-converting enzyme. From The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Bethesda, MD, National Institutes Of Health, National Heart, Lung, and Blood Institute, National High Blood Pressure Education Program, NIH Publication 98-4080, 1997. age. In the United States, the proportion of hypertensives managed appropriately has recently decreased, thus reversing a two-decade trend.[10] In developing countries, hypertension rates are rising rapidly with urbanization and changes in life style habits. The attributable risk for hypertension tends to be greater in the developing world because the low rates of detection and treatment in such countries result in a proportionately higher rate of hypertensive heart disease and stroke.[57] Cardiac Protection with Aspirin, Beta Blockers, ACE Inhibitors

Several pharmacological interventions have proved highly effective in the secondary prevention of cardiovascular disease. Pharmacological reduction of risk during or immediately after the development of CHD has been demonstrated for thrombolytic agents, aspirin, beta blockers, and ACE inhibitors.[58] ASPIRIN IN SECONDARY PREVENTION (see also Chaps. 35 , 36 , and 62) .

Aspirin therapy in patients with existing cardiovascular disease reduces the risk of subsequent events by 25 percent.[59] Recent meta-analyses demonstrate clear reductions in mortality and nonfatal cardiovascular disease events among those with prior myocardial infarction,

Figure 32-7 Primary prevention guide to blood pressure management. BP=blood pressure; CHD=coronary heart disease; DBP=diastolic BP; SBP=systolic BP. (From Wood D, De Backer G, Faergeman O, et al: Prevention of Coronary Heart Disease in Clinical Practice. Recommendations of the Second Joint Task Force of European and other Societies on Coronary Prevention. Eur Heart J 19:1434-1503, 1998.)

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stroke, bypass surgery, angioplasty, peripheral vascular surgery, or angina. [59] [60] Unless contraindicated, aspirin should be used by most patients with known cardiovascular disease. Other antiplatelet agents with demonstrated efficacy such as ticlopidine and clopidogrel should be considered for patients with aspirin allergy or intolerance. However, the cost efficacy of these agents remains to be determined and will clearly be less favorable than the cost efficacy of aspirin. In primary prevention, aspirin is a class 2 intervention (see below). BETA BLOCKERS.

A number of trials have demonstrated the long-term efficacy of beta blockade after myocardial infarction in reducing mortality,[61] [62] and meta-analyses provide good estimates of the size of that benefit.[63] In longer-term secondary prevention, beta blockers lower the risk of a recurrent cardiovascular event by 18 percent.[64] Cross-trial comparisons suggest that the higher the level of beta blockade, as measured by heart rate reduction relative to the control group, the greater the benefit. Beta blockade after myocardial infarction is also extremely cost-effective.[65] ACE INHIBITORS.

The benefit of ACE inhibitors among individuals at high risk for CHD events is substantial. Following myocardial infarction, the use of ACE inhibitors is associated with a 7 percent reduction in mortality at 30 days,[66] [67] [68] while among individuals with a low ejection fraction after myocardial infarction, total mortality is reduced by 26 percent [58] (see also Chap. 35) . Higher doses may afford greater protection. [69] Currently, an ACE inhibitor should be used in any patient with depressed systolic left ventricular function of less than 40 percent (see also Chap. 18) . Findings from the Heart Outcomes Prevention Evaluation (HOPE) Study suggest that the benefits of ACE inhibitors extend to those with clinical CHD (see Chap. 37) and diabetes, even in the absence of left ventricular dysfunction.[70] RECOMMENDATIONS.

For secondary prevention, aspirin, beta blockers, and ACE inhibitors are cost-effective and should be considered standard therapy in appropriate patients--aspirin for any patient with cardiovascular disease, beta blockers after myocardial infarction, and ACE inhibitors in patients with a low ejection fraction, as well as in others with cardiovascular disease and diabetes. All three agents are recommended for secondary prevention by the American Heart Association, American College of Cardiology, and the European Society of Cardiology. CLASS 2 INTERVENTIONS

Class 2 interventions relate to risk factors that appear to have strong causal associations with CHD risk and for which intervention has the potential to reduce risk but for which intervention data are limited (see Table 32-4) . Factors in this category include diabetes, HDL and triglycerides, obesity, physical inactivity, postmenopausal hormones, alcohol intake, and aspirin in primary prevention. In general, cost efficacy data are not available because of a lack of adequate intervention data. Diabetes (see also Chap. 63) PREVALENCE.

In the United States, nearly 16 million people have diabetes mellitus (DM); approximately 90 percent of cases are type II DM.[71] Fully one-third of people with diabetes are not aware they have this disease. The prevalence of DM will increase with the adoption of new recommendations revising the definition of diabetes to include those with a fasting plasma blood glucose level of 126 mg/dl or higher.[72] In addition, the prevalence of diabetes appears to have increased over the last decade, which may be a reflection of increasing body mass index (BMI).[71] ASSOCIATED RISK.

Diabetes increases the risk of atherosclerotic disease, and CHD is a major complication of both type I and type II DM. By age 40, CHD is the leading cause of death in both diabetic males and females,[73] and a recent survey found that CHD was listed on 69 percent of death certificates in a representative national cohort of adults with diabetes.[74] Age-adjusted rates for CHD are two to three times higher among diabetic men and three to seven times higher among diabetic women than among their counterparts without diabetes.[75] The onset of clinically apparent CHD in those with type I DM occurs at an early age, with markedly increased risk by the third decade of life; risk is clearly related to the duration of disease.[76] [77] In the Danish Steno Hospital Study, mortality from myocardial infarction alone was 12.5 percent after 35 years of diabetes regardless of the age of onset.[78] Thus, individuals with diabetes must be considered at high risk for CHD, regardless of the presence or absence of other risk factors. BENEFIT OF TREATMENT.

Maintaining normoglycemia may reduce the risk of microvascular (renal and eye) disease. However, data demonstrating reduced risk of CHD with tight glycemic control are scant. In the Diabetes Complications and Control Trial (DCCT), an apparent reduction in CHD events among patients with type I DM assigned to intensive therapy did not achieve statistical significance, possibly because of the small number of events in this relatively young cohort.[79] While oral hypoglycemic agents and insulin can improve glycemic control, their role in the reduction of risk from macrovascular complications of type II DM remains unclear.[80] [81] Interestingly, the recent HOPE trial showed that ACE inhibitor therapy could reduce onset of diabetes.[70] [81A]

GUIDELINES/RECOMMENDATIONS.

Diet and exercise are integral components of the treatment strategy for patients with diabetes. In many patients with type II DM, glycemic control can be achieved by modest weight loss through diet and exercise.[82] While tight control with insulin in type I DM is appropriate, its role in the prevention of CHD among those with type II DM remains unclear. In contrast to patients with type I DM, those with type II DM are much more likely to have multiple coronary risk factors than is the case in the general population. Thus, aggressive modification of associated risk factors--including treatment of hypertension, aggressive reduction of serum cholesterol, reduction of weight, and increased physical activity--is of paramount importance in reducing the risk of CHD among people with diabetes. In addition, aspirin[83] and ACE inhibitors[70] have been demonstrated to have clear efficacy in reducing coronary events in this population. HDL and Triglycerides (see also Chaps. 31 and 33) PREVALENCE.

Low HDL and high triglyceride levels tend to coincide and often result from metabolic phenomena that are distinct from those leading to high levels of LDL cholesterol. Thus, low HDL and high triglyceride levels can occur alone or in combination with high LDL levels. ASSOCIATED RISK.

HDL cholesterol has emerged as an important independent predictor of CHD--every 1 mg/dl decrease in HDL cholesterol causes a 3 to 4 percent increase in coronary artery disease.[84] [85] [86] Furthermore, an emerging body of evidence indicates that the ratio of total or LDL cholesterol to HDL cholesterol may be a better predictor of CHD risk than LDL alone. Data from the Physicians' Health Study, for example, suggest that a one-unit

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decrease in this ratio (which is easily achievable with statin drugs) reduces the risk of myocardial infarction by 53 percent.[87] Imprecision in triglyceride measurements, within-individual variability, and complex interactions between triglycerides and other lipid parameters may obscure the impact of triglycerides in the development of CHD. However, fasting triglyceride levels represent a useful marker of the risk for CHD, particularly when HDL levels are considered.[88] Trial data testing interventional strategies specifically targeted at individuals with low HDL or

elevated triglycerides in the setting of normal LDL levels are limited. BENEFIT OF INTERVENTION.

Data from the Helsinki Heart Study demonstrate that gemfibrozil, an agent that increases HDL and lowers triglyceride levels, reduces risk among those with high total and LDL cholesterol.[89] In the more recent Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT), a 22 percent reduction in cardiovascular events was observed with gemfibrozil treatment in a population with low HDL ( 70 percent) ST segment resolution have the lowest 30-day mortality followed by patients with partial (30-70 percent) and no (< 30 percent) ST segment resolution. The gradient of mortality stratified by ST segment resolution is evident at both 90 minutes and 180 minutes after initiation of thrombolytic therapy. (Adapted from data in Schroder R, et al: Comparison of the predictive value of ST segment elevation resolution at 90 and 180 min after start of streptokinase in acute myocardial infarction: A substudy of the

Hirudin for Improvement of Thrombolysis [HIT]-4 study. Eur Heart J 20:1563-1571, 1999.

widespread clinical application.[253] [254] Defects in perfusion patterns seen with myocardial contrast echocardiography correlate with regional wall motion abnormalities[255] and lack of myocardial viability on dobutamine stress echocardiography.[256] A practical limitation to myocardial contrast echocardiography is the need for intracoronary injection of echo contrast medium, although this may be circumvented

Figure 35-23 Myocardial perfusion in AMI. A, 99m Tc-sestamibi SPECT before reperfusion; vertical long-axis slice; reduced tracer uptake of basal inferior left ventricular myocardium (arrows). B, 99m Tc-sestamibi SPECT 7 days after stenting of left circumflex coronary artery; nearly normal tracer uptake of basal inferior left ventricular myocardium. (From Horcher J, et al: Myocardial perfusion in acute coronary syndrome. Circulation 99:e15, 1999. Copyright 1999, American Heart Association.)

by the availability of new echo contrast agents that may be injected intravenously.[257] [257A] Doppler flow wire studies, MRI, and nuclear imaging with positron emission tomography (Fig. 35-23) have also been used to define abnormalities of myocardial perfusion.[245] [258] [259] [260] A new angiographic method for assessing myocardial perfusion has also been introduced by Gibson and colleagues--the TIMI myocardial perfusion grade (Fig. 35-24) . Abnormalities of increasing myocardial perfusion as assessed by the TIMI myocardial perfusion grade correlate with mortality risk even after adjusting for the presence of TIMI grade 3 flow or a normal TIMI frame count.[261] A variety of treatments have been tested for increasing myocardial perfusion. A generally consistent theme is that myocardial protective agents should be administered either before or concurrent with efforts at restoration of flow in the epicardial infarct-related artery to minimize damage that may occur as a consequence of reperfusion strategies. Administration of adenosine in the Acute Myocardial Infarction Study of Adenosine (AMISTAD) trial was associated with a reduction in infarct size in patients with an anterior wall MI.[262] Efforts to treat vasospasm with vasodilators such as nicorandil, papavarine, verapamil, and trimetazidine have been associated with improvement in myocardial perfusion in several small series.[216] The most promising intervention to date for treating obstruction of the microvasculature is the administration of an intravenous GPIIb/IIIa inhibitor either in conjunction with a reduced dose of thrombolytic or in association with a catheter-based reperfusion strategy.

Figure 35-24 Relationship between TIMI myocardial perfusion grade and mortality. TIMI myocardial perfusion (TMP) grade 0 or no perfusion of the myocardium is associated with the highest mortality. If the stain of the myocardium is present (grade 1), mortality is also high. A reduction in mortality is seen if the dye enters the microvasculature but is still persistent at the end of the washout phase (grade 2). The lowest mortality is observed in those patients with normal perfusion (grade 3) in whom the dye is minimally persistent at the end of the washout phase. (From Gibson CM, et al: Circulation 101:125-130,

2000. Copyright 2000, American Heart Association.)

1149

With the exception of intravenous GPIIb/IIIa inhibitors, no intervention can be recommended definitively for the specific purposes of improving myocardial perfusion, although this situation may change as more data become available. Effect on Mortality

There is no doubt that early intravenous therapy and thrombolytic drugs improve survival in patients with AMI[15] [52] (Fig. 35-25) . Mortality varies considerably depending on patients included for study and adjunctive therapies employed. The benefit of thrombolytic therapy appears to be greatest when agents are administered as early as possible, with the most dramatic results when the drug is given less than 1 to 2 hours after symptoms begin.[166] [263] [264] The Fibrinolytic Therapy Trialists' (FTT) collaborative group has performed a comprehensive overview of nine trials of thrombolytic therapy, each of which enrolled more than 1000 patients[15] (Fig. 35-26) . The data base for the FTT overview consisted of a total of 58,600 patients, including 6,177 (10.5 percent) who died, 564 (1.0 percent) who sustained a stroke, and 436 (0.7 percent) who sustained major noncerebral hemorrhages. The absolute mortality rates for the control and fibrinolytic groups stratified by presenting features are shown in Figure 35-26 . The overall results indicated an 18 percent reduction in short-term mortality, but as much as a 25 percent reduction in mortality for the subset of 45,000 patients with ST segment elevation or bundle branch block. Two trials, Late Assessment

Figure 35-25 Cumulative vascular mortality (deaths from cardiac, cerebral, hemorrhagic, or other known vascular disease, or unknown causes) in days 0 to 35 of the Second International Study of Infarct Survival (ISIS-2). The four curves describe mortality for patients allocated (i) active streptokinase only, (ii) active aspirin only, (iii) both active treatments, and (iv) neither. Note that individually aspirin and streptokinase have a favorable effect of similar magnitudes and together the benefits appear additive. (From ISIS-2 [Second International Study of Infarct Survival] Collaborative Group: Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 2:349, 1988.)

of Thrombolytic Efficacy (LATE) and Estudio Multicentrico Estreptquinasa Republicas de America del Sur (EMERAS), viewed together provide evidence that a mortality reduction may still be observed in patients treated with thrombolytics between 6 and 12 hours from the onset of ischemic symptoms.[265] [266] The data from LATE and EMERAS and the FTT overview form the basis for extending the "window" of treatment with thrombolytics up to 12 hours from the onset of symptoms. Boersma and colleagues pooled the trials in the FTT overview, 2 smaller studies with data on time to randomization, and 11 additional trials of more than 100 patients. Patients were divided into six time categories from symptom onset to randomization. A regression analysis revealed there was a nonlinear relationship of treatment benefit to time.

MORTALITY REDUCTIONS IN SUBGROUPS.

The mortality effect of thrombolytic therapy in elderly patients is of considerable interest and controversy.[23A] [23B] Whereas patients older than the age of 75 were initially excluded from randomized trials of thrombolytic therapy, they now constitute about 15 percent of the patients studied in recent megatrials of thrombolysis and are being analyzed in registries of AMI patients.[19] [267] [268] Barriers to initiation of therapy in older patients with AMI include a protracted period of delay in seeking medical care, a lower incidence of ischemic discomfort and greater incidence of atypical symptoms and concomitant illnesses, and an increased incidence of nondiagnostic ECGs.[158] Younger patients with AMI achieve a slightly greater relative reduction in mortality compared with elderly patients, but the higher absolute mortality in the elderly results in similar absolute mortality reductions. Thus, as seen in Figure 35-26 , there was a 26 percent decrease in mortality in patients who were younger than 55 years of age (11 lives saved per 1000 with thrombolytic therapy) and a 4 percent reduction in mortality in patients older than age 75 (10 lives saved per 1000 treated). Observational data from the Cooperative Cardiovascular Project (CCP) have raised concern about increased mortality in patients over age 75 years.[23A] However, such observations should not be considered definitive given the nonrandomized nature of the dataset. [23B] Nevertheless clinicians should consider the risks of thrombolysis, especially intracranial hemorrhage, when selecting a reperfusion strategy for elderly patients.[23B] Other important baseline characteristics that have an impact on the mortality effect of thrombolytic therapy include the vital signs at presentation and the presence of diabetes mellitus (see Fig. 35-26) . For example, there was an 18 percent decrease in mortality for patients presenting with a systolic pressure less than 100 mm Hg (62 lives saved per 1000 treated), compared with a 12 percent reduction in mortality for patients with a systolic pressure of 175 mm Hg or more (10 lives saved per 1000 treated). Patients with a history of diabetes mellitus experienced a mortality reduction of 21 percent (37 lives saved per 1000 treated), compared with a mortality reduction of 15 percent (15 lives saved per 1000 treated) in patients without a history of diabetes. A number of models have been developed to integrate the many clinical variables that affect a patient's mortality risk before administration of thrombolytic therapy. In the TIMI II trial, patients were classified as low risk if they lacked any of the following: age of 70 years or older, previous infarction, atrial fibrillation, anterior infarction, rales in more than one third of the lung fields, hypotension and sinus tachycardia, female gender, and diabetes mellitus (see Table 35-4) (Table Not Available) . A more comprehensive, convenient, bedside, simple risk-scoring system for predicting 30-day mortality at presentation for fibrinolytic-eligible patients with ST-elevation MI was developed by Morrow et al using the InTIME-2 trial database[268A] (Fig. 35-27) . However, modeling of mortality risk cannot cover all clinical scenarios and should not substitute for clinical judgment in individual cases. For

1150

Figure 35-26 Mortality differences during days 0 to 35 subdivided by presentation features in a collaborative overview of results from nine trials of thrombolytic therapy. The absolute mortality rates are shown for fibrinolytic and control groups in the center portion of the figure for each of the clinical features at presentation listed on the left side of the figure. The odds ratio for death in the fibrinolytic group to that in the control group is shown for each subdivision (colored square), along with its 99 percent confidence interval (horizontal line). The summary odds ratio at the bottom of the figure corresponds to an 18 percent proportional reduction in 35-day mortality and is highly statistically significant. This translates to a reduction of 18 deaths per 1000 patients treated with thrombolytic agents. (From Fibrinolytic Therapy Trialists' [FTT] Collaborative Group: Indications for fibrinolytic therapy in suspected acute myocardial infarction: Collaborative overview of mortality and major morbidity results from all randomized trials of more than 1000 patients. Lancet 343:311, 1994.)

example, patients with inferior MI who might otherwise be considered to have a low risk of mortality and for whom many physicians have questioned the benefits of thrombolytic therapy might be in a much higher mortality risk subgroup if their inferior infarction is associated with right ventricular infarction, precordial ST segment depression, or ST segment elevation in the lateral precordial leads. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) I investigators developed a regression model to illustrate the relative importance of clinical characteristics on 30-day mortality in contemporary thrombolytic-treated patients. [269] Much greater proportions of the risk of mortality are contributed by the systolic blood pressure and heart rate at presentation than precisely which thrombolytic agent is selected. CLINICAL BENEFIT.

As a result of greater patency of the infarct vessel in patients treated with thrombolytic agents, the clinical benefits that appear to accrue and contribute to the reduction in mortality include reductions in left ventricular failure, malignant arrhythmias,[270] and serious complications of AMI such as septal rupture and cardiogenic shock.[270] [271] [272] The short-term survival benefit enjoyed by patients who receive thrombolytic therapy is maintained over the 1- to 10-year follow-up that has been reported in a number of studies.[230] However, room for improvement remains, given reports of reocclusion rates of the infarctrelated artery as high as 10 percent in hospital and up to 30 percent by 3 months[273] and reinfarction rates as high as 5 percent in hospital and 7 percent within the first year in thrombolytic-treated patients. Comparison of Thrombolytic Agents (See also Chap. 62)

There has been considerable controversy regarding the efficacy of various thrombolytic agents[274] (Table 35-6) . In the GUSTO I trial, 41,021 patients were randomized into one of four treatment arms: streptokinase,

1151

Figure 35-27 TIMI Risk Score for STEMI for predicting 30-day mortality. STE=ST elevation; LBBB=left bundle branch block; h/o=history of; HTN=hypertension. (From Morrow DA, Antman EM, Charlesworth A, et al: The TIMI risk score for ST elevation myocardial infarction: A convenient, bedside, clinical score for risk assessment at presentation: An InTIME II substudy. Circulation, in press.)

1.5 MU over 60 minutes with immediate intravenous heparin to a target activated partial thromboplastin time of 60 to 85 seconds; accelerated t-PA with immediate intravenous heparin; a combination arm of intravenous t-PA (1 mg/kg over 60 minutes) and streptokinase (1.0 MU over 60 minutes); and streptokinase, 1.5 MU over 60 minutes with subcutaneous heparin. The 30-day mortality for the accelerated t-PA group was 6.3 percent; streptokinase plus subcutaneous heparin, 7.2 percent; streptokinase plus intravenous heparin, 7.4 percent; and streptokinase plus t-PA combination plus intravenous heparin, 7.0 percent. In the GUSTO angiographic substudy involving 2431 patients, those with TIMI grade 0 or 1 flow had a 30-day mortality of 9.8 percent that was reduced to 7.9 percent in patients with TIMI grade 2 flow and to 4.3 percent in those with TIMI grade 3 flow.[238] The 90-minute patency rates for the infarct-related artery in the four treatment arms were as follows: accelerated t-PA, 81 percent (54 percent grade 3 flow); combination t-PA plus streptokinase, 73 percent (38 percent grade 3 flow); streptokinase plus intravenous heparin, 60 percent (32 percent grade 3 flow); and streptokinase plus subcutaneous heparin, 54 percent (29 percent grade 3 flow). This early gradient in patency rates favoring t-PA was no longer apparent beyond 180 minutes, presumably because of a "catch-up" phenomenon whereby late patency rates with streptokinase approach those of front-loaded t-PA, albeit beyond a time when as much myocardial salvage is possible as with t-PA. A related observation on early arterial patency was made in the TIMI 4 trial that randomized patients with AMI presenting within 6 hours to receive front-loaded t-PA, anistreplase (APSAC, anisoylated plasminogen streptokinase activator complex), or a combination of a reduced dose of both t-PA and anistreplase.[275] The 90-minute patency rate for front-loaded t-PA was 84 percent (60 percent grade 3); anistreplase, 73 percent (43 percent grade 3); and the combination, 68 percent (45 percent grade 3). A mortality trend favoring t-PA compared with both of the other treatment regimens was seen at 1 year. [275] TISSUE PLASMINOGEN ACTIVATOR.

The t-PA molecule contains the following five domains: finger, epidermal growth factor, kringle 1 and kringle 2, and serum protease[276] (Fig. 35-28) . In the absence of fibrin, t-PA is a weak plasminogen activator; fibrin provides a scaffold on which t-PA and plasminogen are held in such a way that the catalytic efficiency for plasminogen activation of t-PA is increased manyfold. Plasma clearance of t-PA is mediated to a varying degree by residues in each of the domains except the serine protease domain, which is responsible for the enzymatic activity of t-PA. The accelerated dose regimen of

t-PA over 90 minutes produces more rapid thrombolysis than the standard 3-hour infusion of t-PA. A double-bolus regimen of t-PA was not shown to be equivalent to the accelerated dose regimen[277] [278] [279] and was associated with a slightly higher rate of intracranial hemorrhage; the double-bolus regimen has not been recommended for clinical use. Modifications of the basic t-PA structure have been made to yield a group of third-generation fibrinolytics (see Fig. 35-28 and Table 35-6) . A common feature among the third-generation fibrinolytics is prolonged plasma clearance, allowing them to be administered as a bolus rather than the TABLE 35-6 -- KEY PROPERTIES OF NEW FIBRINOLYTIC AGENTS AS COMPARED WITH t-PA AND STREPTOKINASE PROPERTY SK t-PA r-PA TNK-tPA SAK Molecular weight (daltons)

47,000

70,000

39,000

70,000

16,500

Plasma half-life (min)

23-29

4-8

15

±20

6

Fibrin specificity

--

++

+

+++

++++

Indirect

Direct

Direct

Direct

Indirect

1.5 MU/60 min

100 mg/90 min

2×10 MU bolus 30 min apart

0.5 mg/kg bolus

20-30 mg/30 min

Antigenic

+

-

-

-

+

Hypotension

+

-

-

-

-

Patency at 90 min

+

+++

++++

+++

+++(+?)

Hemorrhagic stroke

+

++

++

++

?

Mortality reduction

+

++

++

++

?

Cost

+

+++

+++

+++(?)

++(?)

Concomitant heparin

?

+

+

+

+

Bleeding (noncerebral)

+++

++

++

+

?

Plasminogen activation Dose*

Modified from White HD, van de Werf F: Thrombolysis for acute myocardial infarction. Circulation 97:1632-1646, 1998. Copyright 1998, American Heart Association. SK=streptokinase; t-PA=recombinant tissue-type plasminogen activator (alteplase); SAK=recombinant staphylokinase; TNK-tPA=TNK variant of tissue-type plasminogen activator; r-PA=reteplase. *Most frequently used/tested.

With the exception of SK and t-PA, the need for concomitant heparin has not been formally tested.

1152

Figure 35-28 Molecular structure of alteplase (t-PA), lanoteplase (n-PA), reteplase (r-PA), and tenecteplase. Streptokinase is the least fibrin-specific thrombolytic agent in clinical use; the progressive increase in relative fibrin specificity for the various thrombolytics is shown at the bottom. (Modified from Brener SJ, Topol EJ: Third-generation thrombolytic agents for acute myocardial infarction. In Topol EJ [ed]: Acute Coronary Syndromes. New &York, Marcel Dekker, Inc., 1998, p. 169.)

bolus and double infusion technique by which accelerated dose t-PA is administered.[276]

RETEPLASE (rPA).

This is a recombinant deletion mutant form of t-PA lacking the finger, epidermal growth factor, and kringle 1 domains as well as the carbohydrate side chains (see Fig. 35-28 and Table 35-6) . After a series of four phase II angiographic trials were performed (GRECO,[280] GRECO-DB,[281] Recombinant Plasminogen Activator Angiographic Phase II International Dose Finding Study [RAPID]-1,[282] RAPID-2[283] ), it was determined that the optimum dose and administration schedule for reteplase was 10 + 10 units delivered as two separate intravenous boluses separated by 30 minutes. The TIMI 3 flow rate with a 10 + 10-unit regimen of reteplase was 51.2 percent at 60 minutes and 59.5 percent at 90 minutes compared with 37.4 percent and 45.2 percent at 60 and 90 minutes, respectively, for 100 mg of accelerated dose t-PA. [283] The International Joint Efficacy Comparison of Thrombolytics (INJECT) trial was the first equivalence trial in the field of thrombolytic therapy for STEMI.[284] A total of 6010 patients were randomized to a double bolus 10 + 10-unit reteplase regimen given 30 minutes apart or 1.5 million units of streptokinase over 60 minutes. Mortality at 35 days was 9.02 percent in the reteplase group and 9.53 percent in the streptokinase group. The 95 percent confidence intervals of the differences in mortality range from -1.98 percent to 0.96 percent, satisfying the prespecified definition for equivalence between reteplase and streptokinase. The intracranial hemorrhage rate with reteplase was 0.77 percent compared with 0.37 percent for streptokinase. The GUSTO III trial compared the 10 + 10-unit regimen of reteplase with accelerated t-PA in 15,059 patients.[20] The 30-day mortality rate was 7.47 percent in the reteplase group and 7.24 percent in the t-PA group, corresponding to an absolute difference of 0.23 percent, with a 95 percent confidence interval of -0.66 percent to +1.1 percent (Fig. 35-29) . The results of GUSTO III did not demonstrate superiority of reteplase over t-PA;

using a 1 percent absolute difference as a boundary for equivalence, the mortality results also do not formally demonstrate equivalence. [278] [279] The intracranial hemorrhage rate was 0.91 percent with reteplase and 0.87 percent with t-PA. The secondary composite endpoint of net clinical benefit (death or disabling stroke) was 7.89 percent with reteplase and 7.91 percent with accelerated t-PA. Although GUSTO III did not fulfill formal criteria for equivalence of reteplase and t-PA, many clinicians consider the two agents to be therapeutically similar and consider the double bolus method of administration of reteplase to be an advantage over t-PA. LANOTEPLASE.

Lanoteplase (nPA, novel plasminogen activator) is a mutant of t-PA lacking the finger and epidermal growth factor domains and also containing an amino acid substitution in the kringle 1 domain, leading to deletion of a glycosylation site (see Fig. 35-28 and Table 35-6) . The phase II dose-ranging angiographic trial InTIME I suggested that lanoteplase at a dose of 120 kU/kg was superior to accelerated dose t-PA in that the TIMI 3 flow rate at 90 minutes was 57.1 percent with lanoteplase versus 46.4 percent with t-PA.[285] InTIME II was a phase III double-blind equivalence trial in 15,078 patients comparing 120 kU/kg of lanoteplase with 100 mg of accelerated dose t-PA. The 30-day mortality was 6.61 percent in the t-PA group and 6.75 percent in the lanoteplase group[21] (relative risk 1.02; p = 0.075 for equivalence) (Fig. 35-29) . The intracranial hemorrhage rate was 0.64 percent for t-PA and 1.12 percent for lanoteplase (p = 0.004). TENECTEPLASE.

Tenecteplase (TNK-t-PA) is a mutant of t-PA with specific amino acid substitutions in the kringle 1 domain and protease domain introduced to decrease plasma clearance, increase fibrin specificity, and reduce sensitivity to PAI-1[286] (see Fig. 35-28 and Table 35-6) . The phase II angiographic dose-ranging studies TIMI 10A and TIMI 10B defined the optimum dose of tenecteplase with respect to efficacy.[287] [288] A single bolus of 40 mg of tenecteplase over 5 to 10 seconds was associated with a 63 percent rate of TIMI 3 flow at 90 minutes; 50 mg of tenecteplase

Figure 35-29 Mortality rates in trials of bolus thrombolytics. A 30-day mortality rate was similar in patients receiving the bolus thrombolytics in the trials shown compared with patients receiving the accelerated dose regimen of tissue plasminogen activator. (Adapted from data in [1] The Global Use of Strategies to Open Occluded Coronary Arteries [GUSTO III] Investigators. N Engl J Med 337:1118-1123, 1997. [2] Neuhaus KL: InTIME-2 results. Presented at the Scientific Sessions of the American College of Cardiology, New Orleans, March 9, 1999; and [3] Assessment of the Safety and Efficacy of a New Thrombolytic [ASSENT-2] Investigators. Lancet 354:716-722, 1999.)

1153

produced a 66 percent TIMI 3 flow rate. An analysis comparing the weight-adjusted

dose of tenecteplase compared with TIMI 3 flow indicated that a dose of 0.53 mg/kg was optimal for achieving high rates of TIMI 3 flow. [288] The safety of tenecteplase was evaluated in both TIMI 10B and another large phase II clinical trial called ASSENT 1.[289] Initially, tenecteplase doses of 30, 40, and 50 mg were tested in ASSENT 1, but the 50-mg dose was discontinued and replaced by the 40-mg dose because of increased bleeding observed in the TIMI 10B study. An overall rate of intracranial hemorrhage of 0.77 percent was observed in the total ASSENT 1 study population. Observations made in the combined data set of TIMI 10B and ASSENT 1 suggested that a reduction in the dose of adjunctive unfractionated heparin was associated with a reduction in the risk of intracranial hemorrhage. ASSENT 2 was a randomized double-blind phase III equivalence trial comparing single-bolus tenecteplase with accelerated dose t-PA in 16,949 patients.[22] The 30-day mortality rate with tenecteplase was 6.179 percent and with t-PA 6.151 percent (p = 0.0059 for equivalence) (see Fig. 35-29) . The rate of intracranial hemorrhage was 0.93 percent with tenecteplase and 0.94 percent with t-PA. Major bleeding occurred in 4.66 percent of tenecteplase-treated patients compared with 5.94 percent of t-PA-treated patients (peak was 0.0002). There was no specific subgroup of patients in whom tenecteplase or t-PA was significantly better, with the exception of patients treated after 4 hours from the onset of symptoms in whom the mortality rate was 7.0 percent with tenecteplase and 9.2 percent with t-PA (p = 0.018). OTHER THROMBOLYTIC AGENTS.

SPB, a naturally occurring plasminogen activator, has been undergoing evaluation for treatment of AMI for at least three decades. Although it offers the potential advantage of less antigenicity than that with streptokinase, infarct artery patency rates are about the same as those achieved with streptokinase. Although it is prescribed in an intravenous regimen for AMI in some countries, given its high cost and lack of advantage over streptokinase, its use in the United States is almost exclusively for intracoronary infusion (6000 IU/min to an average cumulative dose of 500,000 IU) to lyse intracoronary thrombi that are believed to be responsible for an evolving AMI. Anistreplase, usually administered in a dose of 30 mg over 2 to 5 minutes intravenously, has a side effect profile similar to that of streptokinase, a patency profile similar to that of conventional-dose t-PA, and a mortality benefit similar to that of streptokinase or t-PA (double-chain form, duteplase). The lack of any compelling advantages (other than bolus administration) and costs higher than streptokinase have relegated anistreplase to an extremely infrequently prescribed drug for AMI in the United States. SPB (scuPA or prourokinase) has been produced both in nonglycosylated (e.g., saruplase) and glycosylated (e.g., Abbott-74187) forms. Angiographic studies of saruplase (PRIMI,[290] Saruplase and Urokinase in the Treatment of Acute Myocardial Infarction [SUTAMI][291] , Study in Europe with Saruplase and Alteplase in Myocardial Infarction [SESAMI][292] ) have shown it to have thrombolytic efficacy similar to streptokinase, urokinase, and a 3-hour infusion of t-PA; and the Practical Applications of Saruplase Study (PASS) suggested it could be administered safely (intracranial hemorrhage rate of 0.5 percent in 1698 patients).[276] [293] In the Comparison Trial of

Saruplase and Streptokinase (COMPASS), the 30-day mortality was 5.8 percent for saruplase versus 6.7 percent for streptokinase; intracranial hemorrhage occurred in 0.9 percent of saruplase patients and 0.3 percent of streptokinase patients. [294] In the Bolus versus Infusion in Rescuepase Development (BIRD) trial, single-bolus administration of saruplase, 80 mg, was found to be similar to a 1 hour infusion.[295] Staphylokinase.

This is a highly fibrin-specific plasminogen activator that requires priming on the surface of a clot.[296] (see Table 35-6) . Recombinant forms of staphylokinase have shown high degrees of thrombolytic efficiency (STAR trial[297] ), and dose-ranging studies are the ongoing Collaborative Angiographic Patency Trial of Recombinant Staphylokinase [CAPTORS].[298] Of concern is the fact that recombinant staphylokinase is highly antigenic, which may limit its use beyond a single administration unless pegilated variants with reduced immunogenicity prove to be clinically safe and effective. Effect on Left Ventricular Function

Although precise measurements of infarct size would be an ideal endpoint for clinical reperfusion studies, such measures have been found to be impractical. Attempts to use LV ejection fraction as a surrogate for infarct size have not been productive because little difference is seen in ejection fraction between treatment groups that show a significant difference in mortality. Alternative methods of assessing left ventricular function, such as end-systolic volume[299] or quantitative echocardiography,[300] are more revealign because patients with smaller volumes and better-preserved ventricular shape have an improved survival. As with survival, improvement in global LV function is related to the time of thrombolytic treatment, with greatest improvement occurring with earliest therapy. Greater improvement in left ventricular function has been reported with anterior than with inferior infarcts. Earlier trials failed to demonstrate any difference in global left ventricular function when streptokinase and t-PA were compared.[301] The angiographic substudy in GUSTO I reported detailed regional wall motion analyses stratified by thrombolytic regimen.[238] Patients who received the accelerated t-PA regimen had significantly less depression of regional wall motion in the ischemic zone, as evidenced by fewer abnormal chords when their ventricular silhouettes were subjected to segmental wall motion analysis. In addition, this patient group tended to have a slightly higher global ejection fraction and slightly reduced end-systolic volume index at 90 minutes after initiation of thrombolytic therapy. The totality of the data presented in the GUSTO angiographic substudy[238] is consistent with the hypothesis that more rapid and complete restoration of normal coronary blood flow in the infarct-related artery with t-PA was associated with an improvement in regional and global left ventricular function (presumably through greater myocardial salvage in the ischemic zone) and that this difference in function compared with that obtained with streptokinase may have contributed to the mortality differences observed at 30 days and beyond.

Complications of Thrombolytic Therapy

Recent (< 1 year) exposure to streptococci or streptokinase produces some degree of antibody-mediated resistance to streptokinase (and anistreplase) in most patients. Although this is of clinical consequence only rarely, it is recommended that patients not receive streptokinase for AMI if they have been treated with a streptokinase product within the past year. Bleeding complications are, of course, the most common and potentially the most serious. Most bleeding is relatively minor with all agents, with more serious episodes occurring in patients requiring invasive procedures.[302] [303] Overall, 70 percent of bleeding episodes occur at the site of vascular punctures.[302] [303] [304] Intracranial hemorrhage is the most serious complication of thrombolytic therapy [305] [306] ; its frequency varies with the clinical characteristics of the patient and the thrombolytic prescribed[306] [307] (Table 35-7) . Collaborators from the European Cooperative Society Group (ECSG) and GISSI, TAMI, TIMI, and ISAM groups pooled their respective data bases on thrombolytic-treated patients with AMI to develop a statistical model for individual risk assessment for intracranial hemorrhage using a case-control format.[307] The following four clinical variables known at hospital admission were shown to predict an increased risk of intracranial hemorrhage: age older than 65 years (odds ratio for intracranial hemorrhage = 2.2), weight less than 70 kg (2.1), hypertension on presentation (2.0), and use of t-PA as opposed to streptokinase (1.6). Assuming an overall incidence of intracranial hemorrhage of 0.75 percent, the expected incidence of intracranial hemorrhage stratified by the number of risk factors would be 0.26 percent for no risk factors, 0.96 percent for one risk factor, 1.32 percent for two risk factors, and 2.17 percent for three risk factors. The incremental incidence of intracranial hemorrhage with thrombolysis appears to be at least partially

1154

TABLE 35-7 -- INTRACRANIAL HEMORRHAGE IN RECENT THROMBOLYTIC TRIALS WITH TISSUE PLASMINOGEN ACTIVATORS PATIENT GUSTO-I GUSTO-II COBALT GUSTO-III ASSENT-2 IN CHARACTERISTICS TIME-II Number

41,021

3473

7169

15,059

62

62.5

62.4

63

>75 yr (%)

10.5

11.8

13.0

13.6

Female (%)

25.2

22.4

23.4

27.4

Average age (yr)

Intracranial hemorrhage rates

16,950

15,078

SK

0.51

0.37

Double bolus 1.12

t-PA

0.70

0.72

Accl infusion 0.81

t-PA TNK-tPA

0.87

0.94

0.64

0.91 0.70

nPA

0.72

0.94 1.13

Accl=accelerated; nPA=lanoteplase; rPA=reteplase; TNK-tPA=a genetically engineered variant of t-PA; t-PA=recombinant tissue-type plasminogen activator; SK=streptokinase. Modified from Ryan TJ, Antman EM, Brooks NH, et al: 1999 update: ACC/AHA Guidelines for the Management of Patients With Acute Myocardial Infarction: Executive Summary and Recommendations: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Circulation 100:1016-1030, 1999. Copyright 1999, American Heart Association. offset by a lower frequency of thrombotic strokes, so that the overall incidence of stroke is usually not much higher in patients receiving thrombolytic therapy than in control patients.[229] [305] [308] Gurwitz and colleagues analyzed 71,073 patients in the National Registry of Myocardial Infarction 2 who had received t-PA for AMI.[309] Multivariable analysis indicated the following patient characteristics were associated with an increased risk of intracranial hemorrhage: older age, female sex, black ethnicity, systolic blood pressure of 140 mm Hg or more, diastolic blood pressure of 100 mm Hg or more, history of stroke, t-PA dose more than 1.5 mg/kg, and a low body weight (Table 35-8) . There have been reports of an "early hazard" with thrombolytic therapy, that is, an excess of deaths in the first 24 hours in thrombolytic-treated patients compared with controls (especially in elderly patients treated >12 hours).[15] However, this excess early mortality is more than offset by the deaths prevented beyond the first day, culminating in an 18 percent (13 to 23 percent) reduction in mortality by 35 days.[15] The mechanisms responsible for this early hazard are not clear but probably are multiple, including an increased risk of myocardial rupture (particularly in the elderly), fatal intracranial hemorrhage,[305] inadequate myocardial reperfusion resulting in pump failure and cardiogenic shock,[310] and possible reperfusion injury of reperfused myocardium.[205] Reports of more unusual complications such as splenic rupture, aortic dissection, and cholesterol embolization have also appeared. Recommendations for Thrombolytic Therapy NET CLINICAL BENEFIT OF THROMBOLYSIS.

Perhaps one of the most important messages from all of the available evidence is that

thrombolytic therapy is underused in patients with AMI.[311] Hesitancy in prescribing a thrombolytic agent is often the result of uncertainty about the risk of bleeding, and analysis from GUSTO-1 shows that moderate to severe bleeding occurred more often in patients who were older, female, lighter, shorter, and of African ancestry and who underwent an invasive procedure.[312] The specific profile of patients at risk for intracranial hemorrhage was discussed previously. Patients with a higher baseline risk of mortality are more likely to benefit from thrombolytic therapy. Against the mortality benefit associated with thrombolytic therapy must be weighed the excess risk of stroke. By using the net clinical benefit composite endpoint of 30-day mortality or nonfatal stroke, a small but statistically significant benefit is seen for accelerated dose t-PA compared with streptokinase. Given the data from the GUSTO-3 and Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT)-2 trials, it appears that the net clinical benefit of accelerated dose t-PA is similar to that obtained with reteplase or tenecteplase.[20] [22] Of interest, the rate of noncerebral major bleeding was lower with tenecteplase than t-PA in the ASSENT-2 trial, possibly due to the greater fibrin specificity of tenecteplase.[22] CHOICE OF AGENT.

Analysis of the net clinical benefit and cost-effectiveness of t-PA versus streptokinase does not easily yield recommendations for treatment because clinicians must weigh the risk of mortality and risk of intracranial hemorrhage when confronting a thrombolytic-eligible patient with AMI; additional considerations may be the constraints placed on physicians' therapeutic decision-making TABLE 35-8 -- ADJUSTED ODDS RATIOS RELATING PATIENT CHARACTERISTICS TO INTRACRANIAL HEMORRHAGE CHARACTERISTIC ADJUSTED ODDS RATIO (95%CI) Age < 65 yr

1.00

65-74 yr

2.71 4.34

75 yr Sex Male

1.00

Female

1.59

Ethnicity White

1.00

Black

1.70

History of stroke No

1.00

Yes

1.90

Systolic blood pressure < 140 mm Hg

1.00

140-159 mm Hg

1.33 1.48

160 mm Hg Diastolic blood pressure < 80 mm Hg

1.00

80-99 mm Hg

1.09 (p=NS) 1.40

100 mm Hg Dose of tissue plasminogen activator < 1.5 mg/kg

1.00 1.49

1.5 mg/kg Modified from Gurwitz JF, Gore JM, Goldberg RJ, et al: Risk for intracranial hemorrhage after tissue plasminogen activator treatment for acute myocardial infarction. Participants in the National Registry of Myocardial Infarction 2. Ann Intern Med 129:597-604, 1998.

1155

by the health care system in which they are practicing.[313] We are in agreement with the general recommendations by Martin and Kennedy[193] and Simoons and Arnold[314] that categorize patients into those that are at high risk of death (advanced age, female gender, depressed left ventricular function, anterior MI, bundle branch block, total magnitude of ST segment elevation, diabetes, heart rate greater than 100 beats/min, systolic pressure less than 100 mm Hg, long delay since onset of ischemic discomfort),[193] [314] and high risk of intracranial hemorrhage. In the subgroup of patients presenting within 4 hours of symptom onset, the speed of reperfusion of the infarct vessel is of paramount importance, and a high-intensity thrombolytic regimen such as accelerated t-PA or tenecteplase is the preferred treatment, except in those individuals in whom the risk of death is low (e.g., a young patient with a small inferior MI) and the risk of intracranial hemorrhage is increased (e.g., acute hypertension), in whom streptokinase and accelerated t-PA are approximately equivalent choices. Of note, for those patients presenting between 4 and 12 hours from symptom onset with a low mortality risk but an increased risk of intracranial hemorrhage (e.g., elderly patients with inferior MI, blood pressure greater than 100 mm Hg, and heart rate less than 100 beats/min), streptokinase is probably preferable to t-PA because of cost considerations if thrombolytic therapy is prescribed at all in such a patient.

In those patients considered appropriate candidates for thrombolysis and in whom t-PA would have been selected as the agent of choice in the past, we believe clinicians should now consider using a bolus thrombolytic such as reteplase or tenecteplase. The rationale for this recommendation is that bolus thrombolysis has the advantage of ease of administration and a lower chance of medication errors (and the associated increase in mortality when such medication errors occur) and also offers the potential for prehospital thrombolysis. LATE THERAPY.

No mortality benefit was demonstrated in the LATE and EMERAS trials when thrombolytics were routinely administered to patients between 12 and 24 hours, [265] [266] although we believe it is still reasonable to consider thrombolytic therapy in appropriately selected patients with persistent symptoms and ST segment elevation on ECG beyond 12 hours (see Fig. 35-17) . Persistent chest pain late after the onset of symptoms correlates with a higher incidence of collateral or antegrade flow in the infarct zone and is therefore a marker for patients with viable myocardium that might be salvaged.[315] Because elderly patients treated with thrombolytics more than 12 hours after the onset of symptoms are at increased risk of cardiac rupture, it is our practice to restrict late thrombolytic administration to younger patients (12 hours) is probably better managed with direct (primary) PTCA (discussed subsequently) than with thrombolytic therapy. Before the institution of thrombolytic therapy, consideration should be given to the patient's need for intravascular catheterization, as would be required for the placement of an arterial pressure monitoring line, a pulmonary artery catheter for hemodynamic monitoring, or a temporary transvenous pacemaker. If any of these are required, ideally they should be placed as expeditiously as possible before infusion of the thrombolytic agent. If such procedures require an additional delay of more than 30 minutes, they should be deferred as long as possible after thrombolytic therapy is begun. In the early hours after institution of thrombolytic therapy, such catheterization should be performed only if crucial to survival, and then sites where excessive bleeding can be controlled should be chosen (e.g., subclavian vein catheterization should be avoided). As noted earlier, all patients with suspected AMI should receive aspirin (160 to 325 mg) regardless of the thrombolytic agent prescribed. Aspirin should be continued indefinitely. The issues surrounding antithrombin therapy as an adjunct to thrombolysis are complex and are discussed in detail in a subsequent section (see p. 1162 ). CATHETER-BASED REPERFUSION (See also Chap. 38) It is now established that reperfusion can be achieved by emergency percutaneous coronary intervention (PCI). By using a guidewire and balloon catheter, it is technically easier to cross a total occlusion consisting of a fresh thrombus than to cross a long-standing occlusion of a coronary artery. Thus, wire-guided balloon angioplasty can be useful to achieve reperfusion in two quite different circumstances: (1) in lieu of

thrombolytic therapy where it is referred to as direct or primary angioplasty[316] and (2) as adjunctive therapy with thrombolysis or as a management strategy in the subacute phase of AMI (days 2 to 7) in patients who do not receive thrombolysis. Several clinical scenarios have been described that represent different categories of use of PCI when it is not selected as the primary reperfusion strategy. When thrombolysis has failed to reperfuse the infarct vessel or a severe stenosis is present in the infarct vessel, a rescue PCI may be performed as soon as possible. Alternatively, strategies of empirical immediate (i.e., performed urgently within a few hours) or deferred (i.e., performed within the first week) PCI have been proposed for all patients with residual critical stenosis (> 70 percent of lumen diameter) who receive thrombolysis. Finally, a more conservative approach of elective PCI may be used to manage AMI patients only when spontaneous or exercise-provoked ischemia occurs whether or not they have received a previous course of thrombolytic therapy. Catheter-based strategies for reperfusion of the occluded infarct-related artery in patients with AMI is a rapidly evolving field. Coronary artery stenting, originally introduced for elective percutaneous procedures, was originally withheld in patients with AMI because of concerns over acute stent thrombosis. However, with advances in stent deployment (high pressure inflations, intravascular ultrasound guidance), improvements in antiplatelet therapy (GPIIb/IIIa inhibitors) and operator experience have fueled interest in primary coronary artery stenting as a new catheter-based strategy for reperfusion.[316] [317] Primary Angioplasty

ADVANTAGES.

An important advantage of primary PCI in AMI is the ability to achieve reperfusion of the infarct vessel without the risk of bleeding associated with thrombolytic therapy. In addition, primary PCI (performed predominantly in experienced centers) as compared with thrombolytic therapy has been shown in several randomized trials and registries to yield higher patency rates of the infarct vessel both at 90 minutes (85 to 90 percent for PCI vs. 65 percent for thrombolysis).[238] [273] [318] Systematic overviews of trials of primary PTCA versus thrombolysis collectively enrolling 2635 patients revealed lower 30-day and 6-month mortality rates for patients treated with primary PTCA versus thrombolysis[319] [320] (Fig. 35-30) . The rate of recurrent infarction was also lower for patients treated with primary PTCA[320] (see Fig. 35-30) . Primary PTCA was also associated with significant reductions in total stroke and hemorrhagic stroke. Thus, primary PCI appears to be superior to thrombolytic therapy when it is performed in experienced

1156

Figure 35-30 Comparison of mortality and reinfarction in AMI patients treated with thrombolysis vs. primary percutaneous transluminal coronary angioplasty (PTCA). Pooled data from 11 randomized trials

revealed significant reductions in the 30-day and 6-month rates of mortality and reinfarction in patients treated with primary PTCA. (Adapted from Grines CL, Ellis SG, Jones M, et al: Primary coronary angioplasty vs. thrombolytic therapy for acute myocardial infarction (MI): Long term follow-up of ten randomized trials. Circulation [Suppl] I-499, 1999.)

centers with a well-staffed invasive angiography team. It is also associated with a shorter length of hospital stay and reduced costs because of fewer patients with recurrent ischemia and recurrent MI when treated with primary PCI. [321] [322] Primary PCI appears to have a particular advantage over thrombolysis for the management of high-risk AMI patients such as diabetics and the elderly.[323] [324] In an analysis of Medicare patients in the Cooperative Cardiovascular Project data base, primary PCI was associated with improved 30-day survival (hazard ratio 0.74, 95 percent confidence interval 0.63-0.88) and also 1-year survival (hazard radio 0.88, 95 percent confidence intervals 0.73-0.94).[325] The benefits of primary PCI in the elderly persisted after stratification by the volume of AMI patients cared for at individual hospitals and the presence of on-site angiography. Why have these dramatic differences favoring primary PCI over thrombolytic therapy been observed? In addition to the high level of technical expertise in the dedicated centers that have reported promising results with primary PCI, differences in the adequacy of reperfusion and responses of ischemic myocardium to restoration of flow by thrombolysis and mechanical means should be considered. Early patency of the infarct-related artery is higher with direct PCI, full reperfusion (TIMI grade 3 flow) is higher, the degree of residual stenosis is less, reocclusion rates are lower,[273] and collateral flow to non-infarct-related myocardial zones is probably increased--all features that promote better healign in the infarct zone, less left ventricular dilatation, and reduced morbidity and mortality.[326] [327] [328] Mechanical recanalization of the infarct vessel does not produce the interstitial edema, contraction band necrosis, and microvascular hemorrhage seen with thrombolytic therapy (see Figs. 35-8 and 35-9) . OBSTACLES TO IMPLEMENTATION.

The clinical trial results and intriguing experimental observations cited earlier must be placed in perspective when one considers implementing primary PCI as a treatment strategy for the majority of patients with AMI. Because PCI is performed only in patients with suitable angiographic anatomy, a bias may have been introduced in the available data bases excluding patients at higher risk of events from being treated by PCI. [329] The MITRA Registry of 54 university and community hospitals in Germany found that in clinical practice patients treated with primary PTCA are more often given beta blockers and ACE inhibitors than patients treated with thrombolytics, drug treatment practices that could contribute to a reduction in mortality that is not a direct result of PTCA.[330] Although reports from individual community hospitals replicating the results in randomized trials can be found in the literature, fewer than 20 percent of hospitals in the United States and less than 10 percent of hospitals in Europe can perform primary PCI, and an even smaller proportion are capable of performing it on an emergency basis 24 hours a day, 7 days a week.[331]

It remains to be determined whether lower-volume PCI centers with less-experienced investigators can replicate the encouraging results reported to date. In addition, it is unclear whether on-site cardiac surgical backup is a necessary component of a primary PCI strategy for AMI. [332] The problem of lack of on-site surgical backup is being evaluated in studies such as Air PAMI in which patients who present to a community hospital that does not perform primary PCI and who are thrombolytically eligible with at least one high-risk criterion are randomized to either immediate intravenous thrombolysis or emergency transfer for PCI.[333] The randomized population in Air PAMI will be compared with a separate registry of Air PAMI-eligible patients who have PCI performed in hospitals with catheterization laboratories but no on-site surgery (No S.O.S. Registry).[333] Preliminary results from the No S.O.S. Registry are encouraging in that the in-hospital death rate was 2.7 percent and the stroke rate was 2.7 percent in 500 patients.[332] The PRAGUE study compared the incidence of death/MI/stroke at 30 days in a randomized trial of aspirin plus streptokinase with management in a community hospital (Group A); aspirin plus streptokinase with transfer to a nearby interventional center (Group B); and aspirin plus heparin (10,000 U) with transfer to a nearby interventional center (Group C). All patients received fraxiparine for 3 days and ticlopidine for 1 month.[334] There were no deaths during or within 30 minutes of transport. The primary composite endpoint occurred in 23 percent of group A, 15 percent of group B, and 8 percent of group C patients, respectively (p < 0.02), indicating that interhospital transport for primary PCI is feasible and safe and may be associated with a lower event rate after AMI. The potential cost implications of offering primary PCI to all eligible patients with AMI are staggering and have been the subject of considerable ongoing debate in several countries.[316] Primary Stenting

Although it has been agreed that primary PTCA has an advantage over thrombolysis in AMI patients with a prior CABG, observations from the National Registry of Myocardial Infarction (NRMI)-2 suggest the outcome is similar to the two reperfusion strategies.[335] Interventionalists have begun to embrace new strategies such as stenting and intravenous GPIIb/IIIa inhibitors (see Chap. 38) to improve on results with PTCA in AMI. Experience gained with elective coronary stenting (see Chap. 38) led to a series of reports of implantation of coronary stents in AMI patients. [336] A high procedural success rate was reported and the subacute thrombosis rate was low (< 3 percent), largely due to aggressive use of antiplatelet therapy with aspirin and ticlopidine. Table 35-9 summarizes major randomized trials of primary stenting versus primary PTCA in AMI. In general, the procedural success rate was high with both stenting and PTCA. Of interest, in the largest of the trials, PAMI-STENT, a slightly lower rate of TIMI grade 3 flow was seen with stenting compared with PTCA, raising the possibility of embolization of platelet aggregates at the time of stent deployment.[337] Mortality rates were generally low, with

1157

TABLE 35-9 -- RANDOMIZED TRIALS OF PRIMARY STENT PLACEMENT VS. PRIMARY PERCUTANEOUS TRANSLUMINAL CORONARY ANGIOPLASTY (PTCA) IN ACUTE MYOCARDIAL INFARCTION ESCOBAR FRESCO GRAMI PASTA PRISAM PAMI-STENT No. of patients Stent

112

75

52

67

39

452

PTCA

115

75

52

69

49

448

6 hr after symptoms onset; 6-24 hr of persistent symptoms

6 hr after symptoms onset; 6-24 hr of persistent symptoms; ST segment elevation

12 hr after symptom onset

24 hr 12 hr after after symptom symptom onset onset

Lesion suitable for stenting



6 mo

30 d

Enrollment criteria

< 30 min after symptoms onset; ST segment elevation; 24 hr after symptoms onset; 75 years old

Randomization criteria

Lesion Optimal suitable for PTCA stenting result


Length of follow-up

6 mo

1 yr

6 mo

1 yr

Crossover 15 (13) (bailout), No. (%)

0 (0)

13 (25)

68 (15.1)

100

98 p 90 to 100 seconds), and the performance of invasive procedures.[302] [303] [312] [363] Frequent monitoring of the activated partial thromboplastin time (facilitated by use of a bedside testing device) reduces the risk of major hemorrhagic complications in patients treated with heparin. However, during the first 12 hours after thrombolytic therapy, the activated partial thromboplastin time may be elevated from the thrombolytic agent alone (particularly if streptokinase is administered), making it difficult to accurately interpret the effects of a heparin infusion on the patient's coagulation status. The optimal dose of unfractionated heparin as an adjunct to thrombolysis and its potential causative role in intracranial hemorrhage is unclear. Giugliano and associates examined the data from four sets of trials: (1) TIMI trials studying accelerated t-PA and intravenous heparin, (2) studies with t-PA and intravenous unfractionated heparin in which the heparin regimen was changed during the course of the trial, (3) phase III trials with accelerated dose t-PA and intravenous unfractionated heparin, and (4) trials of new single-bolus thrombolytics.[364] The intracranial hemorrhage rate in the angiographic TIMI trials was nearly double that in the nonangiographic TIMI trials (1.42 percent vs. 0.76 percent). Lower rates of intracranial hemorrhage were observed among studies of t-PA that reduced the dose of unfractionated heparin midtrial (TIMI 9A-9B, 1.87 percent-1.07 percent; GUSTO IIA-IIb, 0.92 percent-0.7 percent; TIMI 10B, 2.80 percent-1.16 percent). The rates of intracranial hemorrhage with accelerated-dose t-PA gradually increased from GUSTO I (0.72 percent) conducted in 1990-1993 to ASSENT 2 (0.94 percent) conducted in 1997-1998. Potential explanations for the increase in intracranial hemorrhage rates over time include enrollment of higher-risk patients and greater ascertainment of intracranial hemorrhage due to increased availability of imaging modalities such as CT and MRI. This trend in intracranial hemorrhage with t-PA was reversed in the InTIME-II trial, which used the lowest dose of heparin and most aggressive activated partial thromboplastin time monitoring and observed an intracranial hemorrhage rate of 0.64 percent. Observations regarding the benefit of a reduction in the dose of intravenous unfractionated heparin with t-PA also were extended to tenecteplase and laneteplase. NEW ANTITHROMBOTIC AGENTS

Potential disadvantages of unfractionated heparin include dependency on antithrombin III for inhibition of thrombin activity, sensitivity to platelet factor 4, inability to inhibit clot-bound thrombin, marked interpatient variability in therapeutic response, and the need for frequent activated partial thromboplastin time monitoring. [365] In an effort to circumvent these disadvantages of unfractionated heparin, there has been interest in

the development of novel antithrombotic compounds. HIRUDIN.

The prototypical direct antithrombin hirudin was compared with heparin in several phase III trials: TIMI 9A, GUSTO IIA, and r-Hirudin for Improvement of Thrombolysis (HIT) III.[302] [303] [366] A feature common to all three trials was that they were stopped prematurely because of unacceptable rates of serious bleeding, particularly intracranial hemorrhage. This excessive rate of bleeding appeared to be attributable to high levels of anticoagulation in both the heparin and hirudin groups. Possible explanations for the unexpectedly high rates of bleeding were low estimates of the hemorrhagic risk of the doses of hirudin infused owing to the relatively small number of patients previously evaluated in phase II studies and attempts to push the heparin dose to achieve activated partial thromboplastin time levels in an effort to prevent reocclusion of successfully reperfused vessels.[302] After downward modification of the dose of antithrombins, the TIMI 9B and GUSTO IIb trials were initiated.[354] [367] The results of a prospectively planned meta-analysis of the TIMI 9B and GUSTO IIB data are shown in Table 35-11 . [368] Mortality rates were similar at 30 days in both trials. A generally consistent reduction in the rate of reinfarction was seen in the two trials, but this was of borderline statistical significance in the pooled data set: no statistically significant reduction

1161

TABLE 35-11 -- GUSTO-TIMI METAANALYSIS: EVENTS WITHIN 30 DAYS GROUP NO. MORTALITY Heparin (%)

Hirudin (%)

OR (95% CI)

TIMI 9

3002

5.1

6.1

1.21 (0.88-1.65)

GUSTO II Lytic

3052

6.5

6.0

0.91 (0.68-1.23)

Combined

6054

GROUP

1.04 (0.84-1.29)

NO.

REINFARCTION Heparin (%)

Hirudin (%)

OR (95% CI)

TIMI 9

3002

5.2

4.5

0.85 (0.61-1.18)

GUSTO II Lytic

3052

6.8

5.3

0.77 (0.58-1.04)

Combined

6054

GROUP TIMI 9

0.81 (0.65-1.00)

NO. 3002

DEATH+ REINFARCTION Heparin (%)

Hirudin (%)

OR (95% CI)

9.5

9.7

1.02 (0.80-1.31)

GUSTO II Lytic

3052

Combined

6054

12.1

10.2

0.84 (0.66-1.03) 0.91 (0.77-1.08)

Modified from Antman EM, Bittl JA: Direct thrombin inhibitors. In Hennekens CH [ed]: Clinical Trials in Cardiovascular Disease: A Companion to Braunwald's Heart Disease. Philadelphia, WB Saunders, 1999, p 155. was seen in the composite endpoint of death and nonfatal reinfarction. By inhibiting the coagulation cascade upstream from thrombin, heparin has an advantage over the direct antithrombins because of its additional ability to decrease thrombin generation along with its ability to inhibit thrombin activity. Hirudin has a greater ability than heparin to decrease thrombin activity, but once the thrombin inhibitory capacity is exceeded (by virtue of the local concentration of hirudin), free thrombin may be generated in an explosive fashion. The net result of this balance of actions is that use of heparin or the direct antithrombins in a dose that is safe results in an equivalent decrement in thrombus formation in the infarct-related artery. EFEGATRAN.

Efegatran, another direct antithrombin, was compared with unfractionated heparin as an adjunct to streptokinase in the ESCALAT study.[369] Efegatran was not superior to heparin in achieving coronary patency and was associated with high rates of bleeding. HIRULOG.

It has been argued by the Hirulog Early Reperfusion/Occlusion (HERO) trial investigators that in order to truly expose the benefits of a direct antithrombin, it must be administered before a thrombolytic.[370] The ongoing HERO II trial is comparing hirulog with unfractionated heparin for reduction in mortality in patients receiving streptokinase.[371] LOW-MOLECULAR-WEIGHT HEPARINS.

These are formed by controlled enzymatic or chemical depolymerization producing chains of glycosaminoglycans of varying length but with a mean molecular weight of approximately 5000 daltons.[365] Advantages of low-molecular-weight heparins include a stable, reliable anticoagulant effect, high bioavailability permitting administration by means of the subcutaneous route, and a high anti-factor Xa:anti-factor IIa ratio producing blockade of the coagulation cascade in an upstream location resulting in a marked decrement in thrombin generation. Preliminary observations suggest that low-molecular-weight heparins facilitate thrombolysis and prevent recurrent ischemic events.[372] [373] [374] Low-molecular-weight heparin preparations are now being examined in AMI patients both in the presence (AMISK, HART-2, ENTIRE-TIMI 23) and absence (TETAMI) of thrombolytic therapy.

Recommendations for Antithrombin Therapy

Given the pivotal role played by thrombin in the pathogenesis of AMI, antithrombotic therapy remains an important therapeutic intervention. All patients with an acute coronary syndrome should receive antiplatelet therapy (aspirin remains the recommended agent at this time). For patients who do not receive thrombolytic therapy, overviews of the available data indicate that heparin reduces mortality and morbidity from serious complications such as reinfarction and thromboembolism.[52] Therefore, in the absence of contraindications to anticoagulation we routinely use antithrombin therapy in all AMI patients presenting with ST segment elevation who are not candidates for thrombolysis and also prescribe it for AMI patients presenting without ST segment elevation. Although intravenous unfractionated heparin for 48 to 72 hours is an acceptable choice, given the greater ease of use we prefer subcutaneous injections of a low-molecular-weight heparin instead of either subcutaneous or intravenous unfractionated heparin for such patients.[375] In view of its superiority over unfractionated heparin[376] in patients with an acute coronary syndrome presenting without ST segment elevation, we prefer to prescribe enoxaparin, 1 mg/kg twice daily, for the duration of the hospitalization.[376] In patients at high risk for systemic emboli (large or anterior MI, atrial fibrillation, previous embolus, known left ventricular thrombus), intravenous unfractionated heparin is the preferred form of anticoagulation because of insufficient data to formulate recommendations for treatment with a low-molecular-weight heparin.

1162

For patients receiving thrombolytic therapy with either streptokinase or anistreplase, there is no apparent mortality benefit of immediate intravenous heparin, and we do not recommend its use if those thrombolytics are prescribed. The only exception to this are patients who have another compelling indication for anticoagulation, such as a large anterior MI with a significant wall motion abnormality[360] or atrial fibrillation; in this case we generally use intravenous heparin administered to a target activated partial thromboplastin time of 50 to 70 seconds. The relative benefits of routine use of delayed (4 to 12 hours), high-dose (12,500 IU twice daily) subcutaneous heparin in patients receiving streptokinase remain unresolved.[377] On the basis of the principle that t-PA is a more fibrin-specific lytic agent and the evidence that infarct-related artery patency rates are higher in patients receiving intravenous heparin adjunctively with t-PA, it is commonly recommended that with t-PA, intravenous heparin should be administered.[360] A similar line of reasoning can be applied to reteplase and tenecteplase. Nevertheless, the dose of heparin in thrombolytic-treated patients remains controversial. Lessons learned from clinical trials over the past 5 to 10 years suggest that the target activated partial thromboplastin time values should be lower than was previous practice; the current recommendation is an activated partial thromboplastin time of 50 to 70 seconds. [312] In addition, unfractionated heparin should be administered using a weight-based regimen with lower total maximum doses than was previous practice. An initial 60-unit/kg bolus (maximum 4000 units) should be followed by a maintenance infusion of 12 units/kg/hr (maximum 1000

units/hr).[52] It is important to emphasize that it is difficult to provide a heparin adjustment nomogram that is universally applicable because of varying responsiveness of the thromboplastin reagent used in local laboratories for measuring the activated partial thromboplastin time. The appropriate therapeutic range must be established for each local laboratory reagent, with nomograms developed corresponding to the defined therapeutic range. Whereas for patients with venous thrombosis or pulmonary embolism, the target activated partial thromboplastin time should be equivalent to a heparin level of 0.3 to 0.7 unit/ml by anti-factor Xa heparin levels, the therapeutic range should be lower in patients receiving thrombolytics and/or GPIIb/IIIa inhibitors. Although no large-scale studies are available, we are in agreement with the recommendation of Hochman and coworkers, who proposed a therapeutic range corresponding to anti-factor Xa levels of 0.14 to 0.34 unit/ml. [378] Because of concern about the possibility of a rebound increase in thrombin generation and recurrent ischemia after cessation of heparin therapy, some clinicians have suggested a tapering of heparin infusions rather than abrupt discontinuation together with continued aspirin.[379] Antiplatelet Therapy

As discussed earlier (see p. 1116), platelets play a major role in the thrombotic response to rupture of a coronary artery plaque[380] (see Fig. 35-3) . Platelets are activated in response to thrombolysis and platelet-rich thrombi are also more resistant to thrombolysis than are fibrin and erythrocyte-rich thrombi[381] (Fig. 35-31) . Thus, there is a sound scientific basis for inhibiting platelet aggregation in all AMI patients, regardless of whether a thrombolytic agent is prescribed. Comprehensive overviews of randomized trials of antiplatelet therapy have summarized the overwhelming evidence of the benefit of antiplatelet therapy for a wide range of vascular disorders. [14] [382] [383] [384] In patients at risk for AMI, patients with a documented prior AMI, and patients in the acute phase of an AMI, dramatic reductions (between 25 to 50 percent in relative risk) in mortality, nonfatal reduction of recurrent infarction, and nonfatal stroke are achieved by antiplatelet therapy[14] (Fig. 35-32) . Not unexpectedly, the absolute benefits are greatest in those patients at highest baseline risk.[14] Although several antiplatelet regimens have been evaluated, the agent most extensively tested has been aspirin, and this also is the drug for which the most compelling evidence of benefit exists.[274] The ISIS-2 study was the largest trial of aspirin in AMI and provides the single strongest piece of evidence that aspirin reduces mortality in AMI[308] (see Fig. 35-25) . Of interest, in contrast to the observations of a time-dependent mortality effect of thrombolytic therapy, the mortality reduction with aspirin was similar in patients treated within 4 hours (25 percent reduction in mortality), between 5 and 12 hours (21 percent reduction), and between 13 and 24 hours (21 percent reduction). There was an overall 23 percent reduction in mortality from aspirin in ISIS-2 that was largely additive to the 25 percent reduction in mortality from streptokinase, so that patients receiving both therapies experienced a 42 percent reduction in mortality.[308] The mortality reduction was as high as 53 percent in those patients who received both aspirin and streptokinase within 6 hours of symptoms. Of particular interest was the finding that the combination of streptokinase and aspirin reduced mortality from 23.8 to 15.8 percent (34 percent

reduction) without increasing the risk of stroke or hemorrhage. Fibrinogen bound to the GPIIb/IIIa receptor on platelets interacts with leukocytes by means of the CD116/CD18 (Mac-1) receptor, providing a link between platelet activation and inflammatory processes in AMI.[385] [386] Obstructive arterial thrombi that are platelet rich are resistant to thrombolysis and have an increased tendency to produce reocclusion after initial successful reperfusion in patients with ST segment elevation AMI.[47] [51A] [387] Despite the inhibition of cyclooxygenase by aspirin, platelet activation continues to occur through thromboxane A2-independent pathways, leading to platelet aggregation and increased thrombin formation. Activation of platelets by a variety of agonists results in the expression of functional receptors for fibrinogen and other ligands on the platelet surface--the GPIIb/IIIa receptor. [388] GPIIb/IIIa inhibition accelerates thrombolysis and prevents reocclusion in several animal species with experimentally induced platelet-rich coronary thromboses.[237] [389] Potential mechanistic explanations for the beneficial effects of GPIIb/IIIa inhibition when combined with thrombolytics center around important interactions between thrombolytics and platelets (see Fig. 35-31) . Platelets can be stimulated by thrombolytics (e.g., by the exposure of clot-bound thrombin). A narrowed lumen and a highly stenosed infarct-related artery generate high shear forces, a potent stimulus to platelet activation. Activated platelets may inhibit thrombolysis through the release of substances such as PAI-1, alpha2 -plasminogen inhibitor, and factor XIII, which stabilize the clot and also enhance clot retraction, all features that make the clot more resistant to thrombolysis. Observations such as those just noted served as the foundation for testing the hypothesis that GPIIb/IIIa inhibition is a potent and safe addition to thrombolytic regimens and introduced the concept of combination reperfusion for STEMI.[390] GPIIb/IIIa INHIBITION.

Reperfusion in AMI represents a potent stimulus for platelet activation and aggregation as well as activation of the coagulation cascade. Thus, GPIIb/IIIa inhibition has also been used to support PCI and stenting in AMI patients with the hopes of decreasing the risk of acute thrombotic occlusion of the infarct artery and also reducing the risk of death and cardiac ischemic events.[390] Aspirin only partially inhibits platelet aggregation by inhibiting the thromboxane A2 pathway. Thienopyridines such as ticlopidine and clopidogrel inhibit binding to the adenosine diphosphate receptor and also block adenosine diphosphate-dependent pathways for platelet activation. Platelet inhibition by aspirin and the thienopyridines blocks only a limited number of the pathways of platelet activation. Irrespective of the stimulus for platelet activation, the final common pathway is expression of the GPIIb/IIIa receptor on the platelet surface.[47] Therefore, direct inhibition of the GPIIb/IIIa receptor with intravenous agents such as abciximab, tirofiban, and eptifibatide has been studied in patients with AMI[391] (see Fig. 35-31) .

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Figure 35-31 Pharmacological dissolution of thrombus in infarct-related artery. The three panels shown in this figure are schematic views of a longitudinal section of an infarct-related artery at the level of the obstructive thrombus. A, After rupture of a vulnerable plaque (bottom center), the coagulation cascade is activated, ultimately leading to the deposition of fibrin strands (black curvilinear arcs); platelets are activated and begin to aggregate (transition from flat discs representing inactive platelets to spiked ball elements representing activated and aggregating platelets). The mesh of fibrin strands and platelet aggregates obstructs flow (normally moving from left to right) in the infarct-related artery; this would correspond to TIMI grade 0 on angiography. Pharmacological reperfusion is a multipronged approach consisting of thrombolytics that digest fibrin, antithrombins that prevent the formation of thrombin and inhibit the activity of thrombin that is formed, and antiplatelet therapy. B, Full-dose thrombolysis results in incomplete reperfusion in about 50 percent of patients because of persistent platelet aggregates and fibrin strands. On angiography, this would correspond to TIMI flow grade 2. C, Combination reperfusion therapy with an intravenous glycoprotein IIb/IIIa inhibitor and reduced dose thrombolytic facilitates the rate and extent of thrombolysis. Prevention of platelet aggregates allows deeper penetration of the thrombolytic into the weakened clot structure, and full reperfusion (TIMI flow grade 3) is achieved. (Courtesy of Luke Welles, The Exeter Group.)

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Figure 35-32 Antiplatelet therapy in myocardial infarction. Pooled data from randomized control trials (RCTs) of acute myocardial infarction indicate reductions in the rate of reinfarction, stroke (cerebrovascular accident [CVA]), and death in patients receiving antiplatelet therapy compared with control. Similarly, reductions in reinfarction, CVA, and death are seen in the pooled data from trials of secondary prevention with antiplatelet therapy after AMI. Based on the absolute event rates and the treatment effect for each endpoint, the benefit per 1000 patients treated with an antiplatelet agent can be calculated. (Adapted from data in Antiplatelet Trialists' Collaboration: Collaborative overview of randomised trials of antiplatelet therapy: I. Prevention of death by myocardial infarction and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 308:81-106, 1994.) Pharmacological Reperfusion with Thrombolytic and GPIIb/IIIa Inhibition

Several clinical studies evaluated the combination of GPIIb/IIIa inhibitors and thrombolytics. The first series of trials combined full doses of thrombolytic agents with GPIIb/IIIa inhibitors. TAMI-8 was a dose-ranging study that demonstrated that 80 percent or more inhibition of platelet aggregation with the murine Fab fragments of a monoclonal antibody against the GPIIb/IIIa receptor (m7E3) could be accomplished safely.[392] TIMI grade 2 or 3 flow was seen in the infarct-related artery at follow-up angiography at day 5 in 56 percent of 9 control patients and 92 percent of 37 patients receiving m7E3 (p = 0.02). The IMPACT AMI trial demonstrated that patients receiving doses of eptifibatide achieving 50 to 60 percent of platelet aggregation in combination with full-dose t-PA showed an increased rate of TIMI grade 3 flow at 90 minutes (66 percent compared with 39 percent in the placebo group).[393] The streptokinase-eptifibatide trial combined full-dose streptokinase with ascending doses of

eptifibatide. Although increased rates of TIMI grade 3 flow were observed in the combination arms, unacceptably high rates of major hemorrhage were also observed, leaving the investigators to conclude that eptifibatide could not be safely combined with full doses of streptokinase.[394] The Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction (PARADIGM) investigators compared different doses of lamifiban with either t-PA or streptokinase at standard doses.[395] Lamifiban was associated with improved ST segment resolution on continuous ECG monitoring, suggesting improved myocardial perfusion. The combination of a reduced dose thrombolytic agent and GPIIb/IIIa inhibitor was tested in a subsequent series of trials. The TIMI 14 trial demonstrated that abciximab facilitated the rate and extent of thrombolysis, producing early, marked increases in TIMI 3 flow when combined with half the usual dose of t-PA (50 mg) (Fig. 35-33) (Figure Not Available) . [237] The improvement in epicardial reperfusion with reduced-dose t-PA occurred without an increase in major bleeding. Although modest improvements in TIMI 3 flow were seen when abciximab was combined with reduced doses of streptokinase, there was an increased risk of bleeding suggesting that even reduced doses of streptokinase could not be safely combined with a GPIIb/IIIa inhibitor. [237] In multivariate logistic regression analyses, after adjusting for infarct location and time from symptom onset to administration of the reperfusion regimen when compared with a full-dose thrombolytic, use of abciximab with a reduced-dose thrombolytic was associated with a significant increase Figure 35-33 (Figure Not Available) Abciximab (Abx) facilitates the rate and extent of thrombolysis. Compared with patients receiving full-dose t-PA (100 mg), patients receiving abciximab and reduced-dose t-PA (50 mg) had a significantly higher rate of TIMI grade 3 flow at 60 minutes after initiation of reperfusion therapy. A significantly greater proportion of patients treated with the combination reperfusion regimen had lower frame counts (i.e., faster flow).

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Figure 35-34 Improved myocardial perfusion with combination therapy. Abciximab in combination with reduced-dose thrombolytics increased the proportion of patients achieving complete ST segment resolution at 90 minutes and TIMI myocardial perfusion grade 2 or 3 at 90 minutes. TMPG = TIMI myocardial perfusion grade. (Modified from data in de Lemos JA, Antman EM, Gibson CM, et al: Circulation. 2000;101:239-43 and Antman EM, Gibson CM, de Lemos JA, et al: Combination reperfusion therapy with abciximab and reduced dose reteplase: Results from TIMI 14. Eur Heart J, 2000, in press.)

in the probability of achieving TIMI 3 flow and complete ST segment resolution at 90 minutes.[396] Improvement in ST segment resolution and TIMI myocardial perfusion grade was observed even among patients with normal epicardial flow, indicating that abciximab improves not only epicardial flow but also myocardial perfusion (Fig. 35-34) . [396A] Combination reperfusion therapy for STEMI is being studied in GUSTO IV, a large phase III trial that will provide data on the impact of abciximab with reduced doses of reteplase on clinical outcome.

The Strategies for Patency Enhancement in the Emergency Department (SPEED) and INTRO-AMI trials evaluated abciximab with low-dose reteplase and eptifibatide with low-dose t-PA, respectively.[397] [398] Both studies showed that combination therapy with intravenous GPIIb/IIIa inhibitors and reduced doses of lytics increased the proportion of patients achieving TIMI 3 flow by 60 to 90 minutes and also facilitated rescue PTCA procedures. GPIIb/IIIa Inhibition to Support Catheter-Based Reperfusion

Interest in the use of intravenous GPIIb/IIIa inhibitors to support primary PTCA for AMI began with a small series of patients studied by Gold and colleagues and a subset of patients in the EPIC trial.[399] [400] Promising observations included improvements in TIMI 3 flow and a reduction in the primary composite endpoint of death, MI, or urgent revascularization in patients treated with abciximab and primary PTCA. Neumann and colleagues reported that improvement in papaverine-induced peak flow velocities and wall motion indices was seen in patients undergoing stenting for AMI when the procedure was supported by abciximab[260] (Fig. 35-35) . Schomig and associates reported that in patients with AMI, coronary stenting plus abciximab led to a greater degree of myocardial salvage and a better clinical outcome than did fibrinolysis with t-PA.[260A] Abciximab given in the emergency department in patients awaiting primary angioplasty increases the probability of achieving TIMI grade 3 flow before the procedure. Compared with an 8 percent incidence of TIMI 3 flow in the GUSTO IIB trial in patients receiving heparin and aspirin, a time-dependent increase in the proportion of patients with TIMI 3 flow was seen with 18 percent in the Glycoprotein Receptor Antagonist Patency Evaluation (GRAPE) trial (45 minutes), 23 percent in the SPEED trial (60 minutes), and 32 percent in TIMI 14 (90 minutes).[401] The ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT) was a double-blind comparison of abciximab versus placebo.[402] The composite endpoint of death, MI, or urgent target vessel revascularization was reduced from 17.8 percent in the placebo group to 11.6 percent in the abciximab group, the benefit being driven almost entirely by a 64 percent reduction in the odds of requiring urgent target vessel revascularization when abciximab was used. Major bleeding occurred significantly more frequently in the abciximab group (16.6 percent vs. 9.5 percent, p = 0.02) mostly at the arterial access site. The Abciximab before Direct angioplasty and stenting in Myocardial Infarction Regarding Acute and Long-term follow-up (ADMIRAL) investigators randomized AMI patients with 12 hours of symptoms to either abciximab or placebo, which was administered in the ambulance, emergency department, or catheterization

Figure 35-35 Effect of abciximab on myocardial flow and contractile function. A, Plot of differences between 14-day follow-up and initial postinterventional study in basal flow velocity and papaverine-induced flow velocity in patients treated with primary percutaneous intervention for acute MI. The columns represent mean differences. B, Plot of differences between 14-day follow-up and initial postinterventional study in wall motion index and in number of cords with an infarct region. (From Neumann FJ, Blasini R, Schmitt C, et al: Effect of glycoprotein IIb/IIIa receptor blockade on recovery of

coronary flow and left ventricular function after the placement of coronary-artery stents in acute myocardial infarction. Circulation 98:2695-2701, 1998. Copyright 1998, American Heart Association.)

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Figure 35-36 Glycoprotein IIb/IIIa receptor antagonists for failed rescue angioplasty. A, Before balloon angioplasty there is acute inferior MI with hampered flow and cardiogenic shock. A thrombus is seen in the middle of the right coronary artery (arrow). B, After balloon angioplasty, there is no reflow. Although proximal coronary artery is patent, smaller distal vessels are occluded (arrow). C, Approximately 10 minutes after abciximab administration (0.25-mg/kg bolus and a 10-mug/min infusion), coronary artery flow is restored to TIMI 3 flow. (Reproduced from Ronner E, et al: IIb/IIIa receptor antagonists for failed rescue angioplasty. Circulation 101:214-215, 2000. Copyright 2000, American Heart Association.)

laboratory as soon as AMI was diagnosed and before sheath insertion. The incidence of death/recurrent MI/urgent target vessel revascularization at 30 days was reduced by 46.5 percent with abciximab from 20.0 percent in the placebo group to 10.7 percent in the abciximab group (p < 0.03). [403] As was observed in the RAPPORT trial, the major benefit of abciximab was in reducing urgent target vessel revascularization. The CADILLAC trial was designed to compare in a 2 × 2 factorial fashion the effects of balloon angioplasty (with or without abciximab) and stenting (with or without abciximab) in AMI patients presenting within 12 hours of symptoms. TIMI 3 flow was obtained after PTCA in about 95 percent of patients both with and without abciximab treatment. There was a slight reduction in the rate of TIMI 3 flow to 92.1 percent in the stent group without abciximab, which rose to 96.7 percent in patients receiving a stent in combination with abciximab. Use of abciximab was associated with reductions in target vessel revascularization and recurrent ischemia both in patients undergoing primary PTCA without stenting and those patients undergoing primary stenting.[404] Recommendations for Antiplatelet Therapy

Some uncertainty about the optimal dose of aspirin for acute treatment of AMI remains. In general, high doses of aspirin are not more effective than lower doses but are more likely to provoke gastrointestinal side effects. However, adequate cyclooxygenase inhibition (and reduction in thromboxane A2 production) takes several days to accomplish with less than 75 mg of aspirin, and loading doses of 160 to 325 mg (preferably chewed) are therefore recommended for all AMI patients without a history of aspirin allergy whether they present with ST segment elevation or not and whether they undergo reperfusion with thrombolytics or PTCA or are treated with a more conservative medical regimen (see Fig. 35-17) . Active peptic ulcer disease is a relative contraindication to antiplatelet therapy. For patients with severe nausea and vomiting, aspirin suppositories (325 mg) can be used. Aspirin should be continued indefinitely in patients with AMI. In patients with AMI who cannot tolerate aspirin, clopidogrel, 75 mg orally, is an

acceptable alternative. Administration of intravenous GPIIb/IIIa inhibitors cannot be recommended as a routine measure after full-dose thrombolytic therapy has been given. However, as reviewed earlier they are useful to support primary PCI (Fig. 35-36) .[405] [406] [407]




Hospital Management CORONARY CARE UNITS Deaths from primary ventricular fibrillation in AMI have been prevented because the CCU allows continuous monitoring of cardiac rhythm by highly trained nurses with the authority to initiate immediate treatment of arrhythmias in the absence of physicians and because of the specialized equipment (defibrillators, pacemakers) and drugs available. Although all of these benefits can be achieved for patients scattered throughout the hospital, the clustering of patients with AMI in the CCU has greatly improved the efficient use of the trained personnel, facilities, and equipment. In recent years, with increasing emphasis on hemodynamic monitoring and treatment of the serious complications of AMI with such modalities as thrombolytic therapy, afterload reduction, and intraaortic balloon counterpulsation, the CCU has assumed even greater importance.[185] Improvements in the 30-day survival of elderly patients with AMI can be traced to advances in therapy delivered in CCUs.[408] As interventional strategies including thrombolytic therapy and acute coronary angioplasty are used more routinely in AMI patients, facilities in which patients may undergo diagnostic and therapeutic angiographic procedures are being integrated into the CCU structure. At the same time, the value of CCUs for patients with uncomplicated AMI has been questioned and restudied.[185] With increasing attention directed to the limitation of resources and to the economic impact of intensive care, there have been efforts to select patients for whom hospitalization in a CCU would likely be of benefit. The ECG, on presentation, particularly in conjunction with previous tracings[409] and an immediate general clinical assessment, can be useful both for predicting which patients will have the diagnosis of AMI confirmed and identifying low-risk patients who may require less intensive care.[55] Among patients with a history of typical chest pain but with a normal ECG in the emergency department, less than 20 percent ultimately have an AMI on that

admission, and less than 1 percent develop any significant complication. Thus, a patient with a normal ECG may not require admission to a full-fledged CCU. Careful analysis of the quality of pain may help identify such low-risk patients as well. Patients without a history of angina pectoris or MI presenting with pain that is sharp or stabbing and pleuritic, positional, or reproduced by palpation of the chest wall are extremely unlikely to have an AMI. Computer-guided decision protocols are being developed to aid clinicians in identifying those AMI patients who require admission to the CCU as opposed to a less intensive hospital ward.[174] Contemporary CCUs typically have equipment available

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for noninvasive monitoring of single or multiple ECG leads, cardiac rhythm, ST segment deviation, arterial pressure, and arterial oxygen saturation. Computer algorithms for detection and analysis of arrhythmias are superior to visual surveillance by skilled CCU staff. However, even the most sophisticated ECG monitoring systems are susceptible to artifacts due to patient movement or noise on the signal from poor skin preparation when monitoring electrodes are applied.[185] Noninvasive monitoring of arterial blood pressure using a sphygmomanometric cuff that undergoes cycles of inflation and deflation at programmed intervals is suitable for the majority of patients admitted to a CCU. Invasive arterial monitoring is preferred in patients with a low output syndrome under circumstances in which inotropic therapy is initiated for severe left ventricular failure.[185] The CCU remains the appropriate hospital unit for patients with complicated infarctions (e.g., hemodynamic instability, recurrent arrhythmias) and those patients requiring intensive nursing care for devices such as an intraaortic balloon pump.[44] For patients with a low risk of mortality from AMI (Fig. 35-27) , the clinician should consider admission to an intermediate care facility (see later) equipped with simple ECG monitoring and resuscitation equipment.[52] This strategy has been shown to be cost-effective and may reduce CCU utilization by one third, shorten hospital stays, and have no deleterious effect on patients' recovery. Intermediate-care units for low-risk AMI patients may also be appealign to patients who stand to gain little benefit from the high staffing, intense activity, and elaborate technology available in current CCUs (with their attendant high costs) and who may be disturbed by that activity and equipment.[410] [411] RECOMMENDATIONS FOR ADMISSION TO THE CCU.

The following should be considered: 1. Patients with clear-cut AMI, presenting within 12 to 24 hours of symptoms, should, in general, be admitted to a CCU. A possible exception are patients who are taken directly from the emergency department to the catheterization laboratory where they undergo a successful and uncomplicated revascularization procedure. Such patients may be considered for admission to an intermediate-care unit rather than

2.

3. 4.

5.

the CCU. Patients with severe unstable angina should also be admitted to the CCU, particularly if episodes of chest pain occur at rest, high doses of intravenous nitroglycerin (e.g., 300 mg/min) are required to relieve chest pain, or frequent adjustments of intravenous nitroglycerin infusions are required because of fluctuating symptoms and hemodynamic status (see Chap. 36) . Once an AMI is ruled out (ideally by 12 hours) and symptoms are controlled with oral or topical pharmacological agents, discharge from the CCU should be considered. AMI patients with an uncomplicated status, such as those without a history of previous infarction, persistent ischemic-type discomfort, congestive heart failure, hypotension, heart block, or hemodynamically compromising ventricular arrhythmias, may be safely transferred out of the CCU within 24 to 36 hours. In patients with a complicated AMI, the duration of the CCU stay should be dictated by the need for "intensive" care, that is, hemodynamic monitoring, close nursing supervision, intravenous vasoactive drugs, and frequent changes in the medical regimen.

General Measures for Management of AMI

The CCU staff must be sensitive to patient concerns about mortality, prognosis, and future productivity. A calm, quiet atmosphere and the "laying on of hands" with a gentle but confident touch help allay anxiety and reduce sympathetic tone, ultimately leading to a reduction in hypertension, tachycardia, and arrhythmias.[185] To reduce the risk of nausea and vomiting early after infarction and to reduce the risk of aspiration, during the first 4 to 12 hours after admission patients should receive either nothing by mouth or a clear liquid diet (Table 35-12) (Table Not Available) . Subsequently, a diet with 50 to 55 percent of calories from complex carbohydrates and up to 30 percent from mono- and unsaturated fats should be given. The diet should be enriched in foods that are high in potassium, magnesium, and fiber but low in sodium (see Table 35-12) (Table Not Available) . The results of laboratory tests obtained in the CCU should be scrutinized for any derangements potentially contributing to arrhythmias, such as hypoxemia, hypovolemia, disturbances of acid-based balance or of electrolytes, and drug toxicity. Oxazepam, 15 to 30 mg orally four times a day, is useful to allay the anxiety that is common in the first 24 to 48 hours (see Table 35-12) (Table Not Available) . Delirium may be provoked by medications frequently used in the CCU, including antiarrhythmic drugs, histamine-2 blockers, narcotics, and beta blockers. Potentially offending agents should be discontinued in patients with an abnormal mental status. Haloperidol, a butyrophenone, may be used safely in patients with AMI beginning with a dose of 2 mg intravenously for mildly agitated patients and 5 to 10 mg for progressively more agitated patients. Hypnotics, such as temazepam, 15 to 30 mg, or an equivalent, should be provided as needed for sleep. Dioctyl sodium sulfosuccinate, 200 mg daily, or another stool softener should be used to prevent constipation and straining (see Table 35-12) (Table Not Available) .

"Coronary precautions" that do not appear to be supported by evidence from clinical research include the avoidance of iced fluids,[412] hot beverages, caffeinated beverages, rectal examinations, back rubs, and assistance with eating.[185] PHYSICAL ACTIVITY.

In the absence of complications, patients with AMI need not be confined to bed for more than 12 hours and, unless they are hemodynamically compromised, they may use a bedside commode shortly after admission (see Table 35-12) (Table Not Available) . Progression of activity should be individualized depending on the patient's clinical status, age, and physical capacity. In patients without hemodynamic compromise, early ambulation (including dangling feet on the side of the bed, TABLE 35-12 -- SAMPLE ADMITTING ORDERS (Not Available) From 1999 Updated ACC/AHA AMI Guidelines (Web version), p 54. Severe chronic obstructive pulmonary disease

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sitting in a chair, standing, and walking around the bed) does not cause important changes in heart rate, blood pressure, or pulmonary wedge pressure. Although heart rate increases slightly (usually by less than 10 percent), pulmonary wedge pressures fall slightly as the patient assumes the upright posture for activities. Early ambulatory activities are rarely associated with any symptoms; when symptoms do occur, they generally are related to hypotension. Thus, when Levine and Lown proposed the "armchair" treatment of AMI in 1952, they were undoubtedly correct that stress to the myocardium is less in the upright position.[413] As long as blood pressure and heart rate are monitored carefully, early ambulation offers considerable psychological and physical benefit without any clear medical risk. The Intermediate Coronary Care Unit

AMI patients are at risk for late in-hospital mortality from recurrent ischemia or infarction, hemodynamically significant ventricular arrhythmias, and severe congestive heart failure after discharge from the CCU. Therefore, continued surveillance in intermediate CCUs (also called step-down units) is justifiable. Risk factors for mortality in the hospital after discharge from the CCU include significant congestive heart failure, evidenced by persistent sinus tachycardia for more than 2 days and rales greater than one third of the lung fields; recurrent VT and ventricular fibrillation; atrial fibrillation or flutter while in the CCU; intraventricular conduction delays or heart block; anterior location of infarction;

and recurrent episodes of angina with marked ST segment abnormalities at low activity levels. Although it has not been shown rigorously, it is likely that a reduction in late hospital mortality can be achieved with the use of intermediate CCUs, which permits prolonged continuous monitoring of the ECG and prompt, effective treatment of ventricular fibrillation and other serious arrhythmias. The availability of intermediate care units may also be helpful in identifying those patients who remain free of complications and are suitable candidates for early discharge from the hospital. Aggressive reperfusion protocols with angioplasty or thrombolytics can reduce length of hospital stay.[322] In patients who are believed to have undergone successful reperfusion, the absence of early sustained ventricular tachyarrhythmias, hypotension, or heart failure, coupled with a well-preserved LV ejection fraction, predicts a low risk of late in-hospital complications.[414] Such patients are suitable candidates for discharge from the hospital in less than 5 days from the onset of symptoms,[410] although decisions regarding the length of stay must also factor in the need to optimize medication dosages and the patient's psychological state and support systems at home. [411] After AMI, patients are often eager for information, in need of reassurance, confused by misinformation and prior impressions, capable of counterproductive denial, and simply frightened.[185] Intermediate care facilities provide ideal settings and ample opportunities to begin the rehabilitation process.[52] 414b The capacity for the early detection of problems after AMI and the social and educational benefits of grouping such patients together strongly argue for continued utilization of intermediate CCUs. Furthermore, the economic advantage of grouping such patients together for sharing of skilled personnel and resources outweighs any questions raised by the lack of a clear consensus regarding reduced mortality. An additional potential advantage is the facilitation of patient education in a group setting with lectures and audiovisual programs. PHARMACOLOGICAL THERAPY The rationale and recommendations for initiation of several pharmacological measures to treat AMI in the emergency department have been reviewed previously (see p. 1139 ; see Fig. 35-18) . The early use of beta blockers, ACE inhibitors, calcium antagonists, nitrates, and other therapies such as magnesium and glucose-insulin-potassium is discussed in this section. Secondary prevention with some of these agents is discussed subsequently (see p. 1203 ). Beta Blockers

The effects of beta blockers on AMI can be divided into those that are immediate, when the drug is given very early in the course of infarction, and long term (secondary prevention), when the drug is initiated sometime after infarction. The intravenous administration of beta-adrenoceptor blockers reduces cardiac index, heart rate, and blood pressure.[186] The net effect is a reduction in myocardial oxygen consumption per minute and per beat. Favorable effects of acute intravenous administration of beta-adrenoceptor blockers on the balance of myocardial oxygen supply and demand are reflected in reductions in chest pain, in the proportion of patients with threatened

infarction who actually evolve AMI, and in the development of ventricular arrhythmias.[415] Because beta-adrenoceptor blockade diminishes circulating levels of free fatty acids by antagonizing the lipolytic effects of catecholamines and because elevated levels of fatty acids augment myocardial oxygen consumption and probably increase the incidence of arrhythmias, these metabolic actions of beta-blocking agents may also be beneficial to the ischemic heart. Objective evidence of beneficial effects of beta blockers in AMI has been reported using the precordial ST segment mapping technique. Acute beta blockade probably reduces infarct size in AMI. Reduction in release of cardiac enzymes with beta blockade[416] is suggestive of a smaller infarct, as is the preservation of R waves and reduction in the development of Q waves. At least 29 randomized beta blocker trials involving more than 28,970 patients have been undertaken. Intravenous, followed by oral, beta-blocker therapy is associated with about a 13 percent relative reduction in the risk of mortality [417] (Fig. 35-37) . Although antagonism of sympathetic stimulation to the heart might be expected to exacerbate pulmonary edema in patients with occult heart failure, usually only small changes in pulmonary capillary wedge pressure occur when the drug is used in patients with AMI. Thus, in appropriately selected patients (Table 35-13) (Table Not Available) the

Figure 35-37 Effect of beta blockers on mortality in myocardial infarction. The relative risk of mortality is reduced with beta blockers both during the acute phase of treatment and when prescribed as secondary prevention after acute myocardial infarction. (Adapted from data in Chae CU, Hennekens CH: Beta blockers. In Hennekens CH [ed]: Clinical Trials in Cardiovascular Disease: A Companion to Braunwald's Heart Disease. Philadelphia, WB Saunders, 1999, p 84.)

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TABLE 35-13 -- CONTRAINDICATIONS TO BETA-ADRENOCEPTOR BLOCKER THERAPY IN ACUTE MYOCARDIAL INFARCTION (Not Available) From 1999 Updated ACC/AHA AMI Guidelines (Web version), p 109. benefits just noted occur at a cost of about a 3 percent incidence of provocation of congestive heart failure or complete heart block and a 2 percent incidence of the development of cardiogenic shock. Because reduction of infarct size in AMI patients treated with beta blockers is likely to occur only with early treatment (4 hours from the onset of pain), investigators have sought other explanations for the reduction in the mortality in the acute phase that has been observed. Intriguing observations from the ISIS-1 trial raise the possibility that a reduction in the development of cardiac rupture or electromechanical dissociation during

the first day is achieved with early beta blockade.[418] In the TIMI-II trial the addition of a beta blocker (metoprolol) to thrombolytic therapy was studied.[349] Although recurrent ischemia and reinfarction were reduced by immediate intravenous versus delayed use of metoprolol, mortality was not reduced nor was ventricular function improved. Thus, immediate intravenous beta blockade, although clinically beneficial, may not enhance salvage of myocardium in the setting of early reperfusion but may confer clinical benefit by means of its antiischemic effect.[213] Substantial proportions of elderly patients who are hospitalized with AMI and are ideal candidates for early beta blocker therapy do not receive this treatment.[419] Compared with elderly patients who receive early beta blockade in AMI, those who do not receive beta blockade are older, more likely to be women, and less likely to be white. Elderly patients who receive early beta-blocker therapy have significantly lower in-hospital mortality rates than those who do not receive beta blockers (5.1 percent compared with 8.1 percent; p 0.001). RECOMMENDATIONS.

Given the overwhelming evidence of benefits of early blockade in AMI, patients without a contraindication who can be treated within 12 hours of the onset of infarction, irrespective of administration of concomitant thrombolytic therapy or performance of primary angioplasty, should receive beta blockers. We do not draw a distinction between AMI patients presenting with ST segment elevation and those presenting without ST segment elevation and therefore consider early beta blockade applicable across the entire spectrum of acute coronary syndromes. For patients presenting within 12 hours of the onset of symptoms or for those presenting with overactivity of the sympathetic nervous system, we prefer to begin beta-blocker therapy intravenously. For patients presenting after 12 hours, especially if there is little sympathetic overactivity, it is our practice to begin beta-blocker therapy orally. Beta blockers are especially helpful in patients in whom infarction is complicated by persistent or recurrent ischemic pain, by progressive or repetitive serum enzyme elevations suggestive of infarct extension, or by tachyarrhythmias early after the onset of infarction. If adverse effects of beta blockers develop or if patients present with complications of infarction that are contraindications to beta blockade such as heart failure or heart block, the beta blocker should be withheld. Unless there are contraindications (see p. 1243 ), beta blockade probably should be continued in patients who develop AMI. Selection of Beta Blocker.

Favorable effects have been reported with atenolol, timolol, and alprenolol; these benefits probably occur with propranolol and with esmolol, an ultra-short-acting agent, as well. In the absence of any favorable evidence supporting the benefit of agents with intrinsic sympathomimetic activity, such as pindolol and oxprenolol, and with some unfavorable evidence for these agents in secondary prevention,[420] beta blockers with intrinsic sympathomimetic activity probably should not be chosen for treatment of AMI. Occasionally, the clinician may wish to proceed with beta-blocker therapy even in the

presence of relative contraindications, such as a history of mild asthma, mild bradycardia, mild heart failure, or first-degree heart block. In this situation, a trial of esmolol may help determine whether the patient can tolerate beta blockade.[188] [420] Because the hemodynamic effects of this drug, with a half-life of 9 minutes, disappear in less than 30 minutes, it offers considerable advantage over longer-acting agents when the risk of a beta blocker complication is relatively high. ACE Inhibitors

In 1992, with the publication of the Survival and Ventricular Enlargement (SAVE) trial,[421] ACE inhibitors were established as an important addition to the list of treatments for AMI. The rationale for their use includes experimental and clinical evidence of a favorable impact on ventricular remodeling, improvement in hemodynamics, and reductions in congestive heart failure.[78] [191] There is now unequivocal evidence from randomized, placebo-controlled mortality trials that ACE inhibitors reduce death from AMI.[199B] These trials may be grouped into two categories. The first selected AMI patients for randomization, based on features indicative of increased mortality such as left ventricular ejection fraction less than 40 percent,[421] clinical signs and symptoms of congestive heart failure,[422] anterior location of infarction,[423] and abnormal wall motion score index[424] (Fig. 35-38) . The second group were unselective trials that randomized all patients with AMI provided they had a minimum systolic pressure of approximately 100 mm Hg (ISIS-4,[425] GISSI-3,[426] Cooperative North Scandinavian Enalapril Survival Study [CONSENSUS] II,[427] and Chinese Captopril Study[428] ) (Fig. 35-39) . With the exception of the Survival

Figure 35-38 Effect of angiotensin-converting enzyme inhibitors on mortality after myocardial infarction: Results from the long-term trials. (From Flather MD, Pfeffer MA: Angiotensin-converting enzyme inhibitors. In Hennekens CH [ed]: Clinical Trials in Cardiovascular Disease: A Companion to Braunwald's Heart Disease. Philadelphia, WB Saunders, 1999, p 97.)

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Figure 35-39 Effects of angiotensin-converting enzyme inhibitors on mortality after myocardial infarction: results from the short-term trials. (From Flather MD, Pfeffer MA: Angiotensin-converting enzyme inhibitors. In Hennekens CH [ed]: Clinical Trials in Cardiovascular Disease: A Companion to Braunwald's Heart Disease. Philadelphia, WB Saunders, 1999, p 101.)

of Myocardial Infarction Long-term Evaluation (SMILE) trial,[423] all of the selective trials initiated ACE inhibitor therapy between 3 and 16 days after AMI and maintained it for 1 to 4 years, whereas the unselective trials all initiated treatment within the first 24 to 36 hours and maintained it for only 4 to 6 weeks. A consistent survival benefit was observed in all of the trials already noted, except for

CONSENSUS II, the only study that used an intravenous preparation early in the course of AMI.[427] Estimates of the mortality benefit of ACE inhibitors in the unselective, short duration of therapy trials was 5 per 1000 patients treated. [429] [430] Analysis of these unselective short-term trials indicates that approximately one third of the lives saved occurred within the first 1 to 2 days. Certain subgroups such as those with anterior infarction showed proportionately greater benefit from early administration (11 lives saved/1000) of ACE inhibitors. Not unexpectedly, greater survival benefits of 42 to 76 lives saved per 1000 patients treated were obtained in the selective, long duration of therapy trials. Of note, there was generally a 20 percent reduction in the risk of death attributable to ACE inhibitor treatment in the selective trials. The mortality reduction with ACE inhibitors is accompanied by significant reductions in the development of congestive heart failure, supporting the underlying pathophysiological rationale for administering this class of drugs in AMI.[421] [422] [424] [426] In addition, some data suggest that ischemic events, including recurrent infarction and the need for coronary revascularization, can also be reduced by chronic administration of ACE inhibitors after an AMI.[431] The mortality benefits of ACE inhibitors are additive to those achieved with aspirin and beta blockers.[421] [426] Thus, ACE inhibitors should not be considered a substitute for these other therapies with proven benefit in AMI patients.[199B] The benefits of ACE inhibition appear to be a class effect because mortality and morbidity have been reduced by several agents. However, to replicate these benefits in clinical practice, physicians should select a specific agent and prescribe the drug according to the protocols used in the successful clinical trials reported to date. The major contraindications to the use of ACE inhibitors in AMI include hypotension in the setting of adequate preload, known hypersensitivity, and pregnancy. Adverse reactions include hypotension, especially after the first dose, and intolerable cough with chronic dosing; much less commonly angioedema can occur (see Chap. 18) . The benefits of an alternative method of pharmacological inhibition of the renin-angiotensin system by angiotensin-II receptor antagonists is being evaluated in the VALIANT[431A] and Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan, (OPTIMAAL) trials.[432] RECOMMENDATIONS.

After administration of aspirin and initiating reperfusion strategies and, where appropriate, beta blockade, all AMI patients should be considered for ACE inhibition therapy. Although there is little disagreement that high-risk AMI patients (elderly, anterior infarction, prior infarction, Killip class II or greater, and asymptomatic patients with evidence of depressed global ventricular function on an imaging study) should receive life-long treatment with ACE inhibitors,[191] [433] therapy to a broader group of patients has also been proposed based on the pooled results of the unselective mortality trials.[425] Considering all the available data, we favor a strategy of an initial trial of oral ACE inhibitors in all AMI patients with congestive heart failure as well as in hemodynamically stable patients with ST segment elevation or left bundle branch block, commencing within the first 24 hours.[430] [434] Recommendations for chronic use of ACE

inhibitors are discussed on p. 1203 . Nitrates

Sublingual nitroglycerin very rarely opens occluded coronary arteries. However, in patients with AMI the potential for reductions in ventricular filling pressures, wall tension, and cardiac work coupled with improvement in coronary blood flow, especially in ischemic zones, and antiplatelet effects make nitrates a logical and attractive pharmacological intervention in AMI.[435] [436] In patients with AMI, the administration of nitrates reduces pulmonary capillary wedge pressure and systemic arterial pressure, left ventricular chamber volume, infarct size, and the incidence of mechanical complications. As with other interventions to spare ischemic myocardium in AMI, intravenous nitroglycerin appears to be of greatest benefit in patients treated earliest after the onset of symptoms. CLINICAL TRIAL RESULTS.

In the prethrombolytic era, 10 randomized trials of acute administration of intravenous nitroglycerin (or nitroprusside, another nitric oxide donor) collectively enrolled 2042 patients. A meta-analysis of these trial results showed a reduction in mortality of 35 percent associated with nitrate therapy. In the thrombolytic era two megatrials of nitrate therapy have been conducted--GISSI-3[426] and ISIS-4.[425] In GISSI-3, there was no independent effect of nitrates on short-term mortality.[426] Similarly, in ISIS-4, no effect of a mononitrate on 35-day mortality was observed. A pooled analysis of over 80,000 patients treated with nitrate-like preparations intravenously or orally in 22 trials revealed a mortality rate of 7.7 percent in the control group, which was reduced to 7.4 percent in the nitrate group. These data are consistent with a small treatment effect of nitrates on mortality such that three to four fewer deaths would occur for every 1000 patients treated. [425]

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NITRATE PREPARATIONS AND MODE OF ADMINISTRATION.

Intravenous nitroglycerin can be administered safely to patients with evolving MI as long as the dose is titrated carefully to avoid induction of reflex tachycardia or systemic arterial hypotension. Patients with inferior wall infarction are particularly sensitive to an excessive fall in preload, particularly if concurrent right ventricular infarction is present.[52] In such cases nitrate-induced venodilatation could impair cardiac output and reduce coronary block flow, thus worsening myocardial oxygenation rather than improving it. A useful regimen employs an initial infusion rate of 5 to 10 mug/min with increases of 5

to 20 mug/min until the mean arterial blood pressure is reduced by 10 percent of its baseline level in normotensive patients and by 30 percent for hypertensive patients, but in no case below a systolic pressure of 90 mm Hg. Alternatively, nitroglycerin may be administered as a sustained-release oral preparation (30 to 60 mg/d) or as an ointment (1 to 3 inches every 6 to 8 hours for patients with a systolic pressure greater than 120 mm Hg). Nitroglycerin can also be given sublingually at doses of 0.3 to 0.6 mg. This route may be more hazardous because the rate of absorption is difficult to control and arterial pressure may decline precipitously. ADVERSE EFFECTS.

Clinically significant methemoglobinemia has been reported to occur during administration of intravenous nitroglycerin. Although uncommon, this problem is seen when unusually large doses of nitrates are administered. It is important not only for its potential to cause symptoms of lethargy and headache but also because elevated methemoglobin levels can impair the oxygencarrying capacity of blood, potentially exacerbating ischemia. Dilatation of the pulmonary vasculature supplying poorly ventilated lung segments may produce a ventilation-perfusion mismatch. Tolerance to intravenous nitroglycerin (as manifested by increasing nitrate requirements) develops in many patients, often as soon as 12 hours after the infusion is started. Despite the theoretical and demonstrated benefit of sulfhydryl agents in diminishing tolerance, their use has not become widespread. RECOMMENDATIONS.

Nitroglycerin is indicated for the relief of persistent pain and as a vasodilator in patients with infarction associated with left ventricular failure. In the absence of recurrent angina or congestive heart failure, we do not routinely prescribe them in AMI patients. Higher-risk patients such as those with large transmural infarctions, especially of the anterior wall, have the most to gain from nitrates in terms of reduction of ventricular remodeling, and we therefore routinely use intravenous nitrates for 24 to 48 hours in such patients. There is no clear benefit to empirical long-term cutaneous or oral nitrates in the asymptomatic patient, and we therefore do not prescribe nitrates beyond the first 48 hours unless angina or ventricular failure is present. Calcium Antagonists

Despite sound experimental and clinical evidence of an antiischemic effect, calcium antagonists have not been found to be helpful in the acute phase of AMI; concern has been raised in several systematic overviews about an increased risk of mortality when they are prescribed on a routine basis to AMI patients. [186] [437] [438] Perhaps in response to the lack of compelling data showing a beneficial effect and concerns about the risk of excess mortality coupled with more convincing evidence of benefit from aspirin and beta blockers, many clinicians have decreased their use of calcium antagonists in the setting of AMI.[26] [439] A distinction should be made between the dihydropyridine type of calcium antagonists (e.g., nifedipine) and the nondihydropyridine calcium antagonists (e.g.,

verapamil and diltiazem).[437] NIFEDIPINE.

In multiple trials involving a total of over 5000 patients, the immediate-release preparation of nifedipine has not shown any reduction in infarct size, prevention of progression to infarction, control of recurrent ischemia, or lowering of mortality. When trials of the immediate-release form of nifedipine are pooled in a meta-analysis, evidence suggests a dose-related increased risk of in-hospital mortality (especially above 80 mg of nifedipine),[438] [440] although post-hospital mortality does not appear to be increased in nifedipine-treated patients.[441] Nifedipine does not appear to be helpful in conjunction with either thrombolytic therapy or beta blockade.[442] A potential mechanism by which the immediate-release form of nifedipine may be harmful in AMI is coronary hypoperfusion due to an abrupt fall in systolic pressure from peripheral vasodilatation. The abrupt fall in arterial pressure may also provoke a reflex action of the renin-angiotensin system and sympathetic discharge that produces tachycardia. Thus, we do not recommend use of immediate-release nifedipine early in the treatment of AMI. No trials of the sustained-release preparations of nifedipine in AMI have been reported to date. VERAPAMIL AND DILTIAZEM.

When administered during the acute phase of AMI, these drugs have not had any demonstrated favorable effect on infarct size or other important endpoints in patients with AMI, with the exception of control of supraventricular arrhythmias.[443] Although the possibility has been raised that verapamil and diltiazem in the first few days after AMI may be helpful in preventing reinfarction in patients with non-Q-wave infarction,[443] [444] [445] the data supporting this contention are not statistically robust and require further evaluation in future studies. Subgroup analyses of the Multicenter Diltiazem Postinfarction Trial (MDPIT) and the Danish Verapamil Infarction Trial (DAVIT)-II with both diltiazem and verapamil have suggested that mortality is reduced in patients free of heart failure in the CCU.[446] [447] These subgroup analyses must be interpreted with caution because in the MDPIT study about 50 percent of patients in the placebo and diltiazem groups were also receiving beta blockers that may have contributed to the observed mortality reduction[446] ; in the DAVIT-II study patients with an indication for beta blockers were excluded from the trial.[447] Furthermore, both the MDPIT and DAVIT-II studies were conducted in an era when aspirin, ACE inhibitors, and early use of coronary angiography for recurrent ischemia were not as common as they are now. The Incomplete Infarction Trial of European Research Collaborators Evaluating Prognosis Post-Thrombolysis (INTERCEPT) trial is testing the hypothesis that sustained-release diltiazem will decrease death and cardiac ischemic events in patients receiving thrombolytic therapy for a first AMI. [448] RECOMMENDATIONS.

Based on the available data, we do not recommend the routine use of either verapamil or diltiazem in AMI regardless of whether it is believed that the patient is suffering from a Q-wave or non-Q-wave infarction.[449] Verapamil and diltiazem may be given for relief of

ongoing ischemia or slowing of a rapid ventricular response in atrial fibrillation in patients for whom beta blockers are ineffective or contraindicated. [52] Their use should be avoided in patients with Killip class II or greater hemodynamic findings. MAGNESIUM

Patients with AMI may have a total body deficit of magnesium because of a low dietary intake, advanced age, or prior diuretic use. They may also acquire a functional deficit of available magnesium due to trapping of free magnesium in adipocytes, because soaps are formed when free fatty acids are released by catecholamine-induced lipolysis with the onset of infarction. Myocardial and urinary losses of magnesium that occur during AMI may increase a patient's magnesium

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requirement. The magnesium cation serves as a critical cofactor in over 300 intracellular enzymatic processes, including several that are integrally involved in mitochondrial function, energy production, maintenance of trans-sarcolemmal ionic gradients, cell volume control, and resting membrane potential.[450] Experimental models of AMI in at least four different animal species have shown that supplemental administration of magnesium before coronary occlusion, during occlusion, coincident with reperfusion, or for a short time interval (15 to 45 minutes) after reperfusion reduces infarct size and prevents myocardial stunning due to reperfusion injury.[208] However, delayed administration of magnesium beyond a very short interval (15 to 60 minutes) after reperfusion is no longer effective in reducing myocardial damage.[208] Since 1984, several trials of routine supplemental administration of intravenous magnesium in patients with suspected AMI have been conducted. Synthesis of all the trials published before ISIS-4 suggests that the treatment effect of magnesium is greatest in patients at highest risk of mortality and decreases progressively as the mortality risk in the control population decreases.[208] Despite its large sample size, the negative results for magnesium in ISIS-4 do not conclusively exclude benefits of magnesium in AMI. The control group mortality was 7.2 percent in ISIS-4 compared with 7.6 percent in the magnesium group.[425] Given the low control group mortality rate in ISIS-4, the lack of a beneficial effect of magnesium was not unexpected. In addition, ISIS-4 required that acute phase treatment for MI, including lytic therapy, be administered before randomization and that study drugs such as magnesium be administered beyond the "early" lytic phase (e.g., first hour). Because the time for randomization to actual administration of magnesium was not recorded in ISIS-4, the actual relationship between reperfusion and timing of administration of magnesium cannot be determined with certainty but the available information suggests that magnesium was administered relatively late in ISIS-4--a second feature that may have biased ISIS-4 toward a null effect of magnesium. In contrast, Shechter and associates reported a reduction in mortality with magnesium in a high-risk population of patients who were considered unsuitable for thrombolysis.[451] Because of the trivial cost of magnesium, its ease of administration, widespread availability, and the fact that it has the potential to reduce mortality in high-risk AMI patients, another large-scale

randomized multicenter trial (Magnesium in Coronaries [MAGIC]) is underway to define more explicitly the role of magnesium in AMI.[452] RECOMMENDATIONS.

Because of the risk of cardiac arrhythmias when electrolyte deficits are present in the early phase of infarction, all patients with AMI should have a serum magnesium measurement on admission. We advocate repleting magnesium deficits to maintain a serum magnesium level of 2.0 mEq/liter or more. In the presence of hypokalemia ( < 4.0 mEq/liter) during the course of treatment of AMI, the serum magnesium level should be rechecked and repleted if necessary because it is often difficult to correct a potassium deficit in the presence of a concurrent magnesium deficit. Episodes of torsades de pointes should be treated with 1 to 2 gm of magnesium delivered as a bolus over about 5 minutes. Although routine early (ideally < 6 hours from the onset of chest pain) supplemental magnesium administration may be helpful in certain high-risk patients such as the elderly or those for whom reperfusion therapy is contraindicated,[52] additional data are needed before definite recommendations regarding patient selection and dosing can be made. There does not appear to be any benefit to routine late (> 6 hours) administration of magnesium to patients with uncomplicated AMI who do not have electrolyte deficits. Because it may cause vasodilation and hypotension, magnesium infusions should not be administered in patients with a systolic pressure less than 80 to 90 mm Hg. Patients with renal failure may not excrete magnesium normally and should not be considered candidates for supplemental magnesium infusions. Other Approaches GLUCOSE-INSULIN-POTASSIUM.

Administration of a solution of glucose-insulin-potassium (300 gm of glucose, 50 units of insulin, and 80 mEq of KCl in 1000 ml of water administered at a rate of 1.5 ml/kg/hr) lowers the concentration of plasma free fatty acids and improves ventricular performance, as reflected in systolic arterial pressure, cardiac output, and stroke work at any level of left ventricular filling pressure; also the frequency of VPBs decreases.[453] Fath-Ordoubadi and Beatt reported in a meta-analysis of nine studies conducted between 1965 and 1987 enrolling a cumulative total of 1932 patients that the mortality rate was reduced from 21 percent in the placebo group to 16.1 percent in the glucose-insulin-potassium group (OR 0.72, 95 percent CI 0.57-0.90; p = 0.004).[454] Subsequently, the Estudios Cardiologicos Latinoamerica (ECLA) group performed a randomized trial of AMI patients treated within 24 hours of onset of symptoms.[455] Mortality was reduced from 15.2 percent in the control group to 5.2 percent in the glucose-insulin-potassium group for the subset of patients who received thrombolysis (OR 0.34; 95 percent CI 0.15-0.77; p = 0.01). The findings from the ECLA study raise the possibility that therapeutic metabolic manipulation in AMI patients may be a fruitful avenue of investigation, particularly in specific patient subgroups such as those with left ventricular hypertrophy and those for whom there is a delay until the performance of a

primary catheter-based reperfusion procedure. [456] [457] The Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study reported a significant 30 percent relative decrease in mortality at 1 year in diabetics with AMI who received a strict regimen of an insulin-glucose infusion for 24 hours, followed by 3 months of subcutaneous injections of insulin four times daily as compared with standard therapy[458] (Fig. 35-40) . Thus, "infusions of glucose-insulin-potassium (GIK) may provide necessary metabolic support for the ischemic myocardium; this may be particularly important in patients with large anterior infarcts and cardiogenic shock."[84] INTRAAORTIC BALLOON COUNTERPULSATION. (See also Chap. 19.)

From a theoretical standpoint, intraaortic balloon counterpulsation might be expected to limit infarct size for several reasons. In experimental animals, intraaortic balloon counterpulsation decreases preload, increases coronary blood flow, and improves cardiac performance. No definitive information is available, indicating that intraaortic balloon counterpulsation alters the prognosis in patients with relatively uncomplicated infarction. The Second Primary Angioplasty in Myocardial Infarction (PAMI-II) investigators randomized high-risk patients undergoing primary PTCA to 36 to 48 hours of intraaortic balloon counterpulsation treatment versus traditional care. There was no significant difference in the predefined composite endpoint of death, reinfarction, infarct-related artery reocclusion, stroke, or new-onset heart failure/hypotension in patients treated with an intraaortic balloon counterpulsation versus those treated conservatively.[350] Intraaortic balloon counterpulsation also did not result in enhanced myocardial recovery after PTCA. Given the relatively frequent rate of complications after intraaortic balloon insertion and the absence of convincing data for infarct size reduction, intraaortic balloon pumping should be reserved for hemodynamically compromised patients and for those with refractory ischemia. Although noninvasive external forms of counterpulsation have been developed, these approaches have not been rigorously studied in patients with AMI. OTHER AGENTS.

Oxygen-derived free radicals are abundant in ischemic tissue and may contribute to myocardial injury, particularly after

Figure 35-40 Actuarial mortality curves in patients receiving insulin-glucose infusion and in control subjects of the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study during 1 year of follow-up. Numbers below graph indicate the number of patients at different times of observation. Active = patients receiving infusion. (From Malmberg K, Ryden L, Efendic S, et al: Randomized trial of insulin glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI Study): Effects on mortality at 1 year. J Am Coll Cardiol 26:57, 1995.)

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reperfusion (see Chap. 34) . Although evidence from studies in animals suggested that the extent of myocardial necrosis and postischemic dysfunction can be affected favorably by treatment with oxygen free radical scavengers such as superoxide dismutase,[195] initial results in patients have not been encouraging. Given the important role that nitric oxide (NO) plays in regulating platelet activation, interest has arisen in developing techniques for increasing NO production or providing exogenous NO donors in the setting of AMI other than the nitrates discussed earlier. Adenosine, a widely used pharmacological stress agent for detection of coronary artery disease, has been shown in animal models of reperfusion injury to decrease infarct size. The AMISTAD trial tested the hypothesis that a 3-hour infusion of adenosine as an adjunct to thrombolysis would reduce myocardial infarct size.[262] Although there was a reduction in infarct size as determined by single-photon emission computed tomographic cardiac imaging, this observation was restricted to patients with an anterior infarction. Despite the reduction in left ventricular infarct size in the adenosine group, in-hospital clinical outcomes were similar between the two treatment groups. Previous studies suggested that poloxamer 188 (RheothRx) reduces infarct size and improves left ventricular function. However, the Collaborative Organization for RheothRx Evaluation (CORE) trial showed no effect on the composite endpoint of mortality, reinfarction, or cardiogenic shock but did increase the risk of renal failure in patients with AMI.[459] The HALT-AMI trial tested whether a humanized IgG4 monoclonal antibody that binds to CD11b/CD18 receptors on leukocytes, would reduce MI size in patients treated with primary angioplasty.[460] Although the study drug was well tolerated when given just before angioplasty, no significant reduction in infarct size or major cardiac adverse events was seen.




Hemodynamic Disturbances HEMODYNAMIC ASSESSMENT In patients with clinically uncomplicated AMI, invasive hemodynamic monitoring is not necessary because the status of the circulation can be assessed by careful clinical evaluation. This ordinarily consists of monitoring of heart rate and rhythm, repeated measurement of systemic arterial pressure by cuff, obtaining chest roentgenograms to detect heart failure, careful and repeated auscultation of the lung fields for pulmonary congestion, measurement of urine flow, examination of the skin and mucous membranes for evidence of the adequacy of perfusion, and arterial sampling for P O2 , PCO2 , and pH when hypoxemia or metabolic acidosis is suspected. In contrast, in patients with AMI whose ventricular contractile performance is not normal, it is important to assess the degree of hemodynamic compromise to initiate therapy with drugs such as vasodilators and diuretics. In the past, central venous or right atrial pressure was used to gauge the degree of left ventricular failure in patients with AMI. However, this technique is fraught with error because central venous pressure actually reflects right rather than left ventricular function. Right ventricular function and therefore systemic venous pressure may be normal or nearly so in patients with significant left ventricular failure. Conversely, patients with right ventricular failure due to right ventricular infarction or pulmonary embolism may exhibit elevated right atrial and central venous pressures despite normal left ventricular function. Low values for right atrial and central venous pressures imply hypovolemia, whereas elevated right atrial pressures usually result from right ventricular failure secondary to left ventricular failure, pulmonary hypertension, or right ventricular infarction or less commonly from tricuspid regurgitation or pericardial tamponade.

Major advances in the management of AMI have resulted from the hemodynamic monitoring that has become widespread in CCUs[461] [462] (Table 35-14) (Table Not Available) . This often consists of both an intraarterial catheter and a pulmonary artery catheter for measurement of pulmonary artery, pulmonary artery occlusive (equivalent to pulmonary wedge) and right atrial pressures, and cardiac output by thermodilution. In patients with hypotension, a Foley catheter provides accurate and continuous measurement of urine output. NEED FOR INVASIVE MONITORING.

The use of invasive hemodynamic monitoring is based on the following principal factors: 1. Difficulty of interpreting clinical and radiographic findings of pulmonary congestion because of phase lags, such as those occurring after diuretic therapy. Severe depression of cardiac index and/or elevation of left ventricular filling pressure may be unsuspected in as many as 15 percent of patients when estimates are based exclusively on clinical criteria. 2. Need for identifying noncardiac causes of arterial hypotension, particularly hypovolemia. 3. Possible contribution of reduced ventricular compliance to impaired hemodynamics, requiring judicious adjustment of intravascular volume to optimize left ventricular filling pressure. 4. Difficulty in assessing the severity and sometimes even determining the presence of lesions such as mitral regurgitation and ventricular septal defect when the cardiac output or the systemic pressures are depressed. 5. Establishing a baseline of hemodynamic measurements and guiding therapy in patients with clinically apparent pulmonary edema or cardiogenic shock. 6. Underestimation of systemic arterial pressure by the cuff method in patients with intense vasoconstriction. The prognosis and the clinical status are related to both the cardiac output and the pulmonary artery wedge pressure. Patients with normal cardiac output after AMI have an extremely low expected mortality; prognosis worsens as cardiac output declines. Patients with intraventricular conduction defects, AV block, or both after anterior infarction have lower cardiac indices and higher pulmonary capillary wedge pressures than do patients without these conduction disturbances. On the other hand, patients with these conduction defects and inferior MI usually do not demonstrate such hemodynamic abnormalities. PULMONARY ARTERY PRESSURE MONITORING.

Patients most likely to benefit from pulmonary artery catheter monitoring TABLE 35-14 -- INDICATIONS FOR HEMODYNAMIC MONITORING OF ACUTE MYOCARDIAL INFARCTION (Not Available)

From Gore JM, Zwernet PL: Hemodynamic monitoring of acute myocardial infarction. In Francis GS, Alpert JS (eds): Modern Coronary Care. Boston, Little, Brown & Co, 1990, p 138.

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include those whose AMI is complicated by (1) hypotension that is not easily corrected by fluid administration; (2) hypotension in the presence of congestive heart failure; (3) hemodynamic compromise severe enough to require intravenous vasopressors or vasodilators or intraaortic balloon counterpulsation; (4) mechanical lesions (or suspected ones) such as cardiac tamponade, severe mitral regurgitation, and a ruptured ventricular septum; and (5) right ventricular infarction. [63] Other indications for hemodynamic monitoring include assessment of the effects of mechanical ventilation, differentiating pulmonary disease from left ventricular failure as the cause of hypoxemia, and management of septic shock[185] (see Table 35-14) (Table Not Available) . Before inserting a pulmonary artery catheter into a patient with an AMI, the physician must decide that the potential benefit of the information to be obtained outweighs any potential risks. Major complications from pulmonary artery catheters are relatively rare (3 to 5 percent of cases), but severe problems can occur, including sepsis, pulmonary infarction, and pulmonary artery rupture. By minimizing the duration of catheterization and by strict adherence to aseptic techniques, risk can be diminished.[462A] Catheter-related bloodstream infections can also be reduced by using antiseptic-impregnated catheters.[463] Accurate determination of hemodynamics by clinical assessment is difficult in critically ill patients. The use of a pulmonary artery catheter often leads to important changes in therapy that would not have occurred if the hemodynamic information had not been available. Of note, reports exist that complications and mortality may be higher in patients who undergo pulmonary artery catheterization, although such patients are often at higher risk initially. These observations emphasize the importance of patient selection, meticulous technique, and correct interpretation of the data obtained. Hemodynamic Abnormalities

In 1976, Swan, Forrester, and their associates measured the cardiac output and wedge pressure simultaneously in a large series of patients with AMI and identified four major hemodynamic subsets of patients (Table 35-15) : (1) patients with normal perfusion and without pulmonary congestion (normal cardiac output and normal wedge pressure), (2) patients with normal perfusion and pulmonary congestion (normal cardiac output and elevated wedge pressure), (3) patients with decreased perfusion but without pulmonary congestion (reduced cardiac output and normal wedge pressure), and (4) patients with decreased perfusion and pulmonary congestion (reduced cardiac output and elevated wedge pressure). This classification, which overlaps with a crude clinical classification proposed earlier by Killip and Kimball (see Table 35-15) , has proved to be quite useful, but it should be noted that patients frequently pass from one category to another with

therapy and sometimes apparently even spontaneously. HEMODYNAMIC SUBSETS.

These are usually reflected in the patient's clinical status. Hypoperfusion usually becomes evident clinically when the cardiac index falls below approximately 2.2 liters/min/m2 , whereas pulmonary congestion is noted when the wedge pressure exceeds approximately 20 mm Hg. However, approximately 25 percent of patients with cardiac indices less than 2.2 liters/min/m2 and 15 percent of patients with elevated pulmonary capillary wedge pressures are not recognized clinically. Discrepancies in hemodynamic and clinical classification of patients with AMI arise for a variety of reasons. Patients may exhibit "phase lags" as clinical pulmonary congestion develops or resolves, symptoms secondary to chronic obstructive pulmonary disease may be confused with those resulting from pulmonary congestion, or longstanding left ventricular dysfunction may mask signs of hypoperfusion secondary to compensatory vasoconstriction.[69] The hemodynamic findings shown in Tables 35-15 and 35-16 allow for rational approaches to therapy. The goals of hemodynamic therapy are to maintain ventricular performance, support blood pressure, and protect jeopardized myocardium. Because these goals occasionally may be at cross-purposes, recognition of the hemodynamic profile, as assessed clinically or as available from hemodynamic monitoring, is required before optimal therapeutic interventions can be designed along the lines discussed here. Hypotension in the Prehospital Phase

During the prehospital phase of AMI, invasive hemodynamic monitoring is not feasible; during this period, therapy should be guided by frequent clinical assessment and measurement of arterial pressure by cuff, with the recognition that intense vasoconstriction can provide a falsely low pressure measured by this method. Hypotension associated with bradycardia often reflects excessive vagotonia. Relative or absolute hypovolemia is often present when hypotension occurs with a normal or rapid heart rate, particularly among patients receiving diuretics just before the occurrence of infarction. Marked diaphoresis, reduction of fluid intake, or vomiting during the period preceding and accompanying the onset of AMI may all contribute to the development of hypovolemia. Even if the effective vascular volume is normal, relative hypovolemia may be present because ventricular compliance is reduced in AMI and a left ventricular filling pressure as high as 20 mm Hg may be needed to provide an optimal preload. MANAGEMENT.

In the absence of rales involving more than one third of the lung fields, the patient should be put in the reverse Trendelenburg position, and in those with TABLE 35-15 -- HEMODYNAMIC CLASSIFICATIONS OF PATIENTS WITH ACUTE MYOCARDIAL INFARCTION

B. BASED ON INVASIVE MONITORINGb

A. BASED ON CLINICAL EXAMINATIONa Class I

Definition

Subset

Rales and S3 absent

I

Definition Normal hemodynamics PCWP < 18, CI > 2.2

II

Rales over < 50% of lung

II

Pulmonary congestion PCWP > 18, CI < 2.2

III

Rales over > 50% of lung fields (pulmonary edema)

III

Peripheral hypoperfusion PCWP < 18, CI > 2.2

IV

Shock

IV

Pulmonary congestion and peripheral hypoperfusion PCWP > 18, CI < 2.2

PCWP=pulmonary capillary wedge pressure; CI=cardiac index. Modified from Killip T, Kimball J: Treatment of myocardial infarction in a coronary care unit: A two year experience with 250 patients. Am J Cardiol 20:457, 1967; and Forrester J, Diamond G, Chatterjee K, et al: Medical therapy of acute myocardial infarction by the application of hemodynamic subsets. N Engl J Med 295:1356, 1976. CARDIAC CONDITION 12-20 50-60/12-20 30-40/18-25 12-16 2.5

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TABLE 35-16 -- HEMODYNAMIC PATTERNS FOR COMMON CLINICAL CONDITIONS CARDIAC CONDITION CHAMBER PRESSURE (mm Hg) RA Normal

0-6

RV 25/0-6

PA

PCW

25/0-12

6-12

CI 2.5

AMI without LVF

0-6

25/0-6

30/12-18 18

2.5

AMI with LVF

0-6

30-40/0-6

30-40/18-25 > 18

> 2.0

Biventricular failure

>6

50-60/>6

50-60/25

> 2.0

RVMI

12-20 30/12-20

18-25

30/12

< 2.0 12

Cardiac tamponade

12-16 25/12-16

25/12-16

12-16

< 2.0

Pulmonary embolism

12-20 50-60/12-20 50-60/12

< 12

< 2.0

AMI=acute myocardial infarction; CI=cardiac index; LVF=left ventricular failure; PA=pulmonary artery; PCW=pulmonary capillary wedge; RA=right atrium; RV=right ventricle; RVMI=right ventricular myocardial infarction. From Gore JM, Zwerner PL: Hemodynamic monitoring of acute myocardial infarction. In Francis GS, Alpert JS (eds): Modern Coronary Care, pp 139-164, 1990. sinus bradycardia and hypotension, atropine should be administered (0.3 to 0.6 mg intravenously repeated at 3- to 10-minute intervals up to 2.0 mg). If these measures do not correct the hypotension, normal saline should be administered intravenously, beginning with a bolus of 100 ml followed by 50-ml increments every 5 minutes. The patient should be carefully observed and the infusion stopped when the systolic pressure returns to approximately 100 mm Hg, if the patient becomes dyspneic, or if pulmonary rales develop or increase. Because of the poor correlation between LV filling pressure and mean right atrial pressure, assessment of systemic (even central) venous pressure is of limited value as a guide to fluid therapy. Administration of cardiotonic agents is indicated during the prehospital phase if systemic hypotension persists despite correction of hypovolemia and excessive vagotonia. In the absence of invasive hemodynamic monitoring, assessment of peripheral vascular resistance must be based on clinical observations. If cutaneous vasoconstriction is present, therapy with dobutamine, which stimulates cardiac contractility without unduly accelerating heart rate and which does not increase the impedance to ventricular outflow, may be helpful (see Chap. 18) . In hypotensive patients with AMI with clinical evidence of vasodilatation, an uncommon circumstance, phenylephrine hydrochloride, is preferable, although this agent, which increases coronary as well as peripheral vascular tone, should be used with caution. Hypovolemic Hypotension

Recognition of hypovolemia is of particular importance in hypotensive patients with AMI because of the hazard it poses and because of the improvement in circulatory dynamics that can be achieved so readily and safely by augmentation of vascular volume. Because hypovolemia is often occult, it is frequently overlooked in the absence of invasive hemodynamic monitoring. Hypovolemia may be absolute, with low LV filling pressure (8 mm Hg), or relative, with normal (8 to 12 mm Hg) or even modestly increased (13 to 18 mm Hg) left ventricular filling pressures. Because of the reduction of left ventricular compliance that occurs with acute ischemia and infarction (see Chap. 34) , LV filling pressures between 13 and 18 mm Hg, although above the upper limits of normal, may actually be suboptimal. Exclusion of hypovolemia as the cause of hypotension requires the documentation of a reduced cardiac output despite left ventricular filling pressure exceeding 18 mm Hg. If, in a hypotensive patient, the pulmonary capillary wedge pressure (ordinarily measured as the pulmonary artery occlusive pressure) is below this level, fluid challenge should be carried out as described previously. If hypovolemia is documented or suspected, the fluid replaced should resemble the fluid lost. Thus, when a low hematocrit complicates

AMI, infusion of packed red blood cells or whole blood is the treatment of choice. On the other hand, crystalloid or colloid solutions should be administered when the hematocrit is normal or elevated. Hypotension caused by right ventricular infarction may be confused with that caused by hypovolemia because both are associated with a low, normal, or minimally elevated LV filling pressure. The findings and management of right ventricular infarction are discussed on page 1180 . The Hyperdynamic State

When infarction is not complicated by hemodynamic impairment, no therapy other than general supportive measures and treatment of arrhythmias is necessary. However, if the hemodynamic profile is of the hyperdynamic state (i.e., elevation of sinus rate, arterial pressure, and cardiac index, occurring singly or together in the presence of a normal or low LV filling pressure) and if other causes of tachycardia such as fever, infection, and pericarditis can be excluded, treatment with beta-adrenoceptor blockers is indicated. Presumably, the increased heart rate and blood pressure are the result of inappropriate activation of the sympathetic nervous system, possibly secondary to augmented release of catecholamines, pain and anxiety, or some combination of these. LEFT VENTRICULAR FAILURE Even in the thrombolytic era, left ventricular dysfunction remains the single most important predictor of mortality after AMI (Fig. 35-41) .[20] [22] In patients with AMI, heart failure is characterized either by systolic dysfunction alone or by both systolic and diastolic dysfunction. Left ventricular diastolic dysfunction leads to pulmonary venous hypertension and pulmonary congestion, whereas systolic dysfunction is principally responsible for a depression of cardiac output and of the ejection fraction. Clinical manifestations of left ventricular failure become more common as the extent of the injury to the left ventricle increases. In addition to infarct size, other important predictors of the development of symptomatic left ventricular dysfunction include advanced age and diabetes.[464] Mortality increases in association with the severity of the hemodynamic deficit.[69] THERAPEUTIC IMPLICATIONS.

Classification of patients with AMI by hemodynamic subsets has therapeutic relevance. As already noted, patients with normal wedge pressures and hypoperfusion often benefit from infusion of fluids, because the peak value of stroke volume is usually not attained until LV filling pressure reaches 18 to 24 mm Hg. However, a low level of left ventricular filling pressure

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Figure 35-41 Impact of left ventricular function on survival after myocardial infarction. The curvilinear relationship between left ventricular ejection fraction (LVEF) for patients treated in the thrombolytic era is shown. Among patients with an LVEF below 40 percent, mortality is markedly increased at 6 months. Thus, interventions such as thrombolysis, aspirin, and angiotensin-converting enzyme (ACE) inhibitors should be of considerable benefit in patients with acute myocardial infarction to minimize the amount of left ventricular damage and interrupt the neurohumoral activation seen with congestive heart failure. (Adapted from Volpi A, De VC, Franzosi MG, et al: Determinants of 6-month mortality in survivors of myocardial infarction after thrombolysis: Results of the GISSI-2 data base. The Ad Hoc Working Group of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-2 Data Base. Circulation 88:416-429, 1993. Copyright 1993, American Heart Association.)

does not imply that left ventricular damage is necessarily slight. Such patients may be relatively hypovolemic and/or may have suffered a right ventricular infarct with or without severe left ventricular damage. The relation between ventricular filling pressure and cardiac index when preload is increased by an infusion of saline or dextran can provide valuable hemodynamic information, in addition to that obtained from baseline measurements. For example, the ventricular function curve rises steeply (marked increase in cardiac index, small increase in filling pressure) in patients with normal left ventricular function and hypovolemia, whereas the curve rises gradually or remains flat in those patients with a combination of hypovolemia and depressed cardiac function. Invasive hemodynamic monitoring is essential to guide therapy for patients with severe left ventricular failure (pulmonary capillary wedge pressure > 18 mm Hg and cardiac index < 2.5 liters/min/m2 ). AVOIDANCE OF HYPOXEMIA.

Patients whose AMI is complicated by congestive heart failure characteristically develop hypoxemia due to a combination of pulmonary vascular engorgement (and in some cases pulmonary interstitial edema), diminished vital capacity, and respiratory depression from narcotic analgesics. Hypoxemia can impair the function of ischemic tissue at the margin of the infarct and thereby contribute to establishing or perpetuating the vicious circle (see Fig. 35-11) . The ventilation-perfusion mismatch that results in hypoxemia requires careful attention to ventilatory support. Increasing fractions of inspired oxygen (FIO2 ) via face mask should be used initially, but if the oxygen saturation of the patient's blood cannot be maintained above 85 to 90 percent on 100 percent FIO2 , strong consideration should be given to endotracheal intubation with positive-pressure ventilation. The improvement of arterial oxygenation and hence myocardial oxygen supply may help to restore ventricular performance. Positive end-expiratory pressure (PEEP) may diminish systemic venous return and reduce effective left ventricular filling pressure. This may require reduction in the amount of PEEP, normal saline infusions to maintain LV filling pressure, adjustment of the rate of infusion of vasodilators such as nitroglycerin, or some combination. Because myocardial ischemia frequently occurs during the return to unsupported spontaneous breathing, the

weaning process should be accompanied by observation for signs of ischemia and is potentially facilitated by a period of intermittent mandatory ventilation or pressure support ventilation before extubation. Continuous ST segment monitoring has been recommended for these patients. When wheezing complicates pulmonary congestion, bronchodilators that act primarily on beta2 -adrenoceptors, such as metaproterenol, given as an aerosol, or terbutaline, are more desirable than conventional bronchodilators such as isoproterenol or epinephrine. The latter act primarily on beta1 -receptors, which, by increasing myocardial oxygen consumption, can increase ischemia. Racemic beta2 agonists are composed of a 50:50 mixture of R and S isomers. The R isomers exhibit virtually all the bronchodilation, whereas the S isomers enhance bronchial reactivity to methacholine, eosinophil activation, and histamine-induced influx of fluid, proteins, and neutrophils into the airspaces. As suggested by Handley, use of pure R isomers of beta2 -adrenoceptor agonists may permit bronchodilation with few beta-adrenoceptor-mediated side effects.[465] Although positive inotropic agents may be useful, they do not represent the initial therapy of choice in patients with AMI. Instead, heart failure is managed most effectively first by reduction of ventricular preload and then, if possible, by lowering afterload. Arrhythmias may contribute to hemodynamic compromise and should be treated promptly in patients with left ventricular failure. DIURETICS. (See also Chap. 18.)

Mild heart failure in patients with AMI frequently responds well to diuretics such as furosemide, administered intravenously in doses of 10 to 40 mg, repeated at 3- to 4-hour intervals if necessary. The resultant reduction of pulmonary capillary pressure reduces dyspnea, and the lowering of LV wall tension that accompanies the reduction of LV diastolic volume diminishes myocardial oxygen requirements and may lead to improvement of contractility and augmentation of the ejection fraction, stroke volume, and cardiac output. The reduction of elevated LV filling pressure may also enhance myocardial oxygen delivery by diminishing the impedance to coronary perfusion attributable to elevated ventricular wall tension. It may also improve arterial oxygenation by reducing pulmonary vascular congestion. The intravenous administration of furosemide reduces pulmonary vascular congestion and pulmonary venous pressure within 15 minutes, before renal excretion of sodium and water has occurred; presumably this action results from a direct dilating effect of this drug on the systemic arterial bed. It is important not to reduce left ventricular filling pressure much below 18 mm Hg, the lower range associated with optimal left ventricular performance in AMI, because this may reduce cardiac output further and cause arterial hypotension. Excessive diuresis may also result in hypokalemia, with its attendant risk of digitalis intoxication. AFTERLOAD REDUCTION. (See also Chap. 18.)

Myocardial oxygen requirements depend on LV wall stress, which in turn is proportional to the product of peak developed left ventricular pressure, volume, and wall thickness. Vasodilator therapy is recommended in patients with AMI complicated by (1) heart failure unresponsive to treatment with diuretics, (2) hypertension, (3) mitral regurgitation, or (4) ventricular septal defect. In these patients, treatment with vasodilator agents increases stroke volume and may reduce myocardial oxygen requirements and thereby lessen ischemia. Hemodynamic monitoring of systemic arterial and, in many cases, pulmonary capillary wedge (or at least pulmonary artery) pressure and cardiac output in patients treated with these agents is important. Improvement of cardiac performance

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and energetics requires three simultaneous effects: (1) reduction of LV afterload, (2) avoidance of excessive systemic arterial hypotension in order to maintain effective coronary perfusion pressure, and (3) avoidance of excessive reduction of ventricular filling pressure with consequent diminution of cardiac output. In general, pulmonary capillary wedge pressure should be maintained at approximately 20 mm Hg and arterial pressure above 90/60 mm Hg in patients who were normotensive before developing the AMI. Vasodilator therapy is particularly useful when AMI is complicated by mitral regurgitation or rupture of the ventricular septum. In such patients, vasodilators alone or in combination with intraaortic balloon counterpulsation can sometimes serve as a "holding maneuver" and provide hemodynamic stabilization to permit definitive catheterization and angiographic studies to be carried out and to prepare the patient for early surgical intervention. Because of the precarious state of patients with complicated infarction and the need for meticulous adjustment of dosage, therapy is best initiated with agents that can be administered intravenously and that have a short duration of action, such as nitroprusside, nitroglycerin, or isosorbide dinitrate. After initial stabilization, the medication of choice is generally an ACE inhibitor, but long-acting nitrates given by mouth, sublingually, or by ointment may also be useful. Nitroglycerin. (See also Chap. 36.)

This drug has been shown in animal experiments to be less likely than nitroprusside to produce a "coronary steal" (i.e., to divert blood flow from the ischemic to the nonischemic zone). Therefore, apart from consideration of its routine use in AMI patients discussed earlier (see p. 1170 ), it may be a particularly useful vasodilator in patients with AMI complicated by left ventricular failure. Ten to 15 mug/min is infused, and the dose is increased by 10 mug/min every 5 minutes until (1) the desired effect (improvement of hemodynamics or relief of ischemic chest pain) is achieved or (2) a decline in systolic arterial pressure to 90 mm Hg, or by more than 15 mm Hg, has occurred. Although both nitroglycerin and nitroprusside lower systemic arterial pressure, systemic vascular resistance, and the heart rate/systolic blood pressure product, the reduction of LV filling pressure is more prominent with nitroglycerin because of its

relatively greater effect than nitroprusside on venous capacitance vessels. Nevertheless, in patients with severe left ventricular failure, cardiac output often increases despite the reduction in LV filling pressure produced by nitroglycerin. Oral Vasodilators.

The use of oral vasodilators in the treatment of chronic congestive heart failure is discussed in Chapter 21 . In patients with AMI and persistent heart failure, long-term treatment with a converting enzyme inhibitor should be carried out. This reduced ventricular load decreases the remodeling of the left ventricle that occurs commonly in the period after MI and thereby reduces the development of heart failure and risk of death.[72] DIGITALIS. (See also Chap. 18.)

Although digitalis increases the contractility and the oxygen consumption of normal hearts, when heart failure is present the diminution of heart size and wall tension frequently results in a net reduction of myocardial oxygen requirements. In animal experiments it fails to improve ventricular performance immediately after experimental coronary occlusion, but salutary effects are elicited when it is administered several days later. The absence of early beneficial effects may be due to the inability of ischemic tissue to respond to digitalis or the already maximal stimulation of contractility of the normal heart by circulating and neuronally released catecholamines. Although the issue is still controversial, arrhythmias may be increased by digitalis glycosides when they are given to patients in the first few hours after the onset of MI, particularly in the absence of hypokalemia. Also, undesirable peripheral systemic and coronary vasoconstriction may result from the rapid intravenous administration of rapidly acting glycosides such as ouabain. Administration of digitalis to patients with AMI in the hospital phase should generally be reserved for the management of supraventricular tachyarrhythmias such as atrial flutter and fibrillation and of heart failure that persists despite treatment with diuretics, vasodilators, and beta-adrenoceptor agonists. There is no indication for its use as an inotropic agent in patients without clinical evidence of left ventricular dysfunction, and it is too weak an inotropic agent to be relied on as the principal cardiac stimulant in patients with overt pulmonary edema or cardiogenic shock. It may, however, be useful as a supplement to vasodilator agents and in the maintenance phase of treatment for persistent or recurrent left ventricular failure.[466] Cardiac glycosides appear to become progressively more effective in the treatment of heart failure as the interval from onset of infarction lengthens; that is, they are more effective in the treatment of chronic than of acute heart failure secondary to ischemic heart disease. Of note, in a direct comparison of captopril versus digoxin for prevention of left ventricular remodeling and dysfunction after AMI, patients in whom captopril therapy was initiated 7 to 10 days after onset of infarction had less left ventricular remodeling and better preserved global left ventricular function than patients receiving

digitalis. In addition, the possibility that continued administration of digitalis might contribute to late mortality in the 2 years after AMI has been raised [467] [468] [469] and debated.[470] [471] Although it is clear that mortality is greater in patients treated with digoxin after AMI, it is not clear that this increase in mortality is due to digoxin itself or to confounding variables that correlate with use of digoxin.[471] At this time, digoxin appears to be indicated in AMI patients only if they exhibit supraventricular tachyarrhythmias or overt heart failure that is not adequately controlled by ACE inhibitors and diuretics. BETA-ADRENOCEPTOR AGONISTS.

When left ventricular failure is severe, as manifested by marked reduction of cardiac index ( < 2 liters/min/m2 ), and pulmonary capillary wedge pressure is at optimal (18 to 24 mm Hg) or excessive (> 24 mm Hg) levels despite therapy with diuretics, beta-adrenoceptor agonists are indicated. Although isoproterenol is a potent cardiac stimulant and improves ventricular performance, it should be avoided in AMI patients. It also causes tachycardia and augments myocardial oxygen consumption and lactate production; in addition, it reduces coronary perfusion pressure by causing systemic vasodilation and in animal experiments it increases the extent of experimentally induced infarction. Norepinephrine also increases myocardial oxygen consumption because of its peripheral vasoconstrictor as well as positive inotropic actions. Dopamine and dobutamine (see Chap. 18) may be particularly useful in patients with AMI and reduced cardiac output, increased left ventricular filling pressure, pulmonary vascular congestion, and hypotension. Fortunately, the potentially deleterious alpha-adrenergic vasoconstrictor effects exerted by dopamine occur only at higher doses than those required to increase contractility. Its vasodilating actions on renal and splanchnic vessels and its positive inotropic effects generally improve hemodynamics and renal function. In patients with AMI and severe left ventricular failure, this drug should be administered at a dose of 3 mug/kg/min while monitoring pulmonary capillary wedge and systemic arterial pressures as well as cardiac output. The dose may be increased stepwise to 20 mug/kg/min, to reduce pulmonary capillary wedge pressure to approximately 20 mm Hg and elevate cardiac index to exceed 2 liters/min/m2 . However, it must be recognized that doses exceeding 5 mug/kg/min activate peripheral alpha receptors and cause vasoconstriction.

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Dobutamine has a positive inotropic action comparable to that of dopamine but a slightly less positive chronotropic effect and less vasoconstrictor activity. In patients with AMI, dobutamine improves left ventricular performance without augmenting enzymatically estimated infarct size.[472] It may be administered in a starting dose of 2.5 mug/kg/min and increased stepwise to a maximum of 30 mug/kg/min. Both dopamine and dobutamine must be given carefully and with constant monitoring of the ECG, systemic arterial pressure, and pulmonary artery or pulmonary artery occlusive pressure and, if possible, with frequent measurements of cardiac output. The dose must be reduced if the heart rate exceeds 100 to 110 beats/min, if supraventricular or ventricular

tachyarrhythmias are precipitated, or if ST segment changes increase. OTHER POSITIVE INOTROPIC AGENTS.

Milrinone is a noncatecholamine, nonglycoside, phosphodiesterase inhibitor with inotropic and vasodilating action (see Chap. 18) . It is useful in selected patients whose heart failure persists despite treatment with diuretics, who are not hypotensive, and who are likely to benefit from both an enhancement in contractility and afterload reduction. Milrinone should be given as a loading dose of 50 mug/kg over 10 minutes, followed by a maintenance infusion of 0.375 to 0.75 mug/kg/min. CARDIOGENIC SHOCK This severest clinical expression of left ventricular failure is associated with extensive damage to the left ventricular myocardium (about 40 percent) in more than 80 percent of AMI patients in whom it occurs; the remainder have a mechanical defect such as ventricular septal or papillary muscle rupture or predominant right ventricular infarction.[473] [473A] In the past, cardiogenic shock has been reported to occur in up to 20 percent of patients with AMI, [474] but estimates from recent large randomized trials of thrombolytic therapy and observational data bases report an incidence rate in the range of 7 percent.[192] [475] About 10 percent of patients with cardiogenic shock present with this condition at the time of admission, whereas 90 percent develop it during hospitalization. This low-output state is characterized by elevated ventricular filling pressures, low cardiac output, systemic hypotension, and evidence of vital organ hypoperfusion (e.g., clouded sensorium, cool extremities, oliguria, acidosis).[190] Patients with cardiogenic shock due to AMI are more likely to be older, to have a history of a prior MI or congestive heart failure, and to have sustained an anterior infarction at the time of development of shock.[190] [475A] Of note, although the incidence of cardiogenic shock in AMI has been relatively stable since the mid 1970s, the short-term mortality decreased from 70 to 80 percent in the 1970s to 50 to 60 percent in the 1990s. [475] Cardiogenic shock is the cause of mortality in about 60 percent of patients dying after thrombolysis for AMI.[476] PATHOLOGICAL FINDINGS.

At autopsy, more than two thirds of patients with cardiogenic shock demonstrate stenosis of 75 percent or more of the luminal diameter of all three major coronary vessels, usually including the left anterior descending coronary artery. Almost all patients with cardiogenic shock are found to have thrombotic occlusion of the artery supplying the major region of recent infarction with loss of about 40 percent of the left ventricular mass.[473] Other causes of cardiogenic shock in AMI include mechanical defects such as rupture of the ventricular septum, a papillary muscle, or a free wall with tamponade; right ventricular infarction[473] ; or marked reduction of preload due to conditions such as hypovolemia.[477] Patients who die as a consequence of cardiogenic shock often have "piecemeal" necrosis, that is, progressive myocardial necrosis from marginal extension of their

infarct into an ischemic zone bordering on the infarction. This is generally associated with persistent elevation of CK-MB. Early deterioration in left ventricular function secondary to apparent extension of infarction may, in some cases, result from expansion of the necrotic zone of myocardium without actual extension of the necrotic process (Fig. 35-42) . Shear forces that develop during ventricular systole can disrupt necrotic myocardial muscle bundles, with resultant expansion and thinning of the akinetic zone of myocardium, which in turn results in deterioration of overall left ventricular function. At autopsy, patients with cardiogenic shock consistently demonstrate marginal extension of recent areas of infarction. Additionally, focal areas of necrosis are frequently found in regions of the left and right ventricles that are not adjacent to the major area of recent infarction. Such extensions and focal lesions are probably in part the result of the shock state itself, because they can also be found in the hearts of patients dying of noncardiogenic shock. Infarction of the ischemic periinfarction zone can be precipitated by a number of factors that adversely affect the supply of oxygen or the metabolic demand in this zone of myocardium. These include a reduction of coronary perfusion pressure that causes impaired myocardial perfusion in the presence of atherosclerotic obstructions of the nonculprit artery. An augmentation of myocardial oxygen demand resulting from the local release of catecholamines from ischemic adrenergic nerve endings in the heart as well as from circulating

Figure 35-42 Infarct expansion after transmural anterior myocardial infarction. (From Tice FD, Kisslo J: Echocardiographic assessment and monitoring of the patient with AMI: Prospects for the thrombolytic era. In Califf RM, Mark DB, Wagner GS (eds): Acute Coronary Care. St. Louis, Mosby-Year Book, 1995, p 496.)

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endogenous or infused catecholamines may also play a role. Patients with shock due to a mechanical defect often have smaller infarcts than do those with cardiogenic shock secondary to ventricular failure without a mechanical lesion. The prognosis is better in such patients because the smaller infarct allows their left ventricle to support the circulation if the mechanical defect has been corrected surgically. PATHOPHYSIOLOGY.

The shock state in patients with AMI appears to be the result of a vicious circle, demonstrated in Figure 35-11 (see p. 1124).[190] According to this formulation, coronary obstruction leads to myocardial ischemia, which impairs myocardial contractility and ventricular performance. This, in turn, reduces arterial pressure and therefore coronary perfusion pressure, leading to further ischemia and extension of necrosis until the left ventricle has insufficient contracting myocardium to sustain life. The progressive nature of the myocardial insult in this syndrome is reflected in the stuttering and progressive evolution of elevations in the plasma enzyme-time activity curves of markers specific for

myocardial injury. Consideration of the vicious circle also points to the hazard of hypovolemic hypotension in patients with AMI but without cardiogenic shock. Hypotension, whatever its cause, reduces coronary perfusion, especially of myocardium in the territory of obstructive arteries, and thereby may enhance necrosis. DIAGNOSIS.

Cardiogenic shock is characterized by marked and persistent (>30 min) hypotension with systolic arterial pressure less than 80 mm Hg and a marked reduction of cardiac index (generally18 mm Hg). Spurious estimates of LV filling pressure based on measurements of the pulmonary artery wedge pressure can occur in the presence of marked mitral regurgitation, in which the tall v wave in the left atrial (and pulmonary artery wedge) pressure tracing elevates the mean pressure above LV end-diastolic pressure. Accordingly, mitral regurgitation and other mechanical lesions, such as ventricular septal defect, ventricular aneurysm, and pseudoaneurysm, must be excluded before the diagnosis of cardiogenic shock due to impairment of left ventricular function can be established. Mechanical complications should be suspected in any patient with AMI in whom circulatory collapse occurs.[190] Immediate hemodynamic, angiographic, and echocardiographic evaluations are necessary in patients with cardiogenic shock. It is important to exclude mechanical complications because primary therapy of such lesions usually requires immediate operative treatment with intervening support of the circulation by intraaortic balloon counterpulsation. Medical Management

When the aforementioned mechanical complications are not present, cardiogenic shock is due to impairment of left ventricular function. Although dopamine or dobutamine usually improves the hemodynamics in these patients, unfortunately neither appears to improve hospital survival significantly. Similarly, vasodilators have been used in an effort to elevate cardiac output and to reduce left ventricular filling pressure. However, by lowering the already markedly reduced coronary perfusion pressure, myocardial perfusion can be compromised further, accelerating the vicious circle illustrated in Figure 35-11 . Vasodilators may nonetheless be used in conjunction with intraaortic balloon counterpulsation and inotropic agents in an effort to increase cardiac output while sustaining or elevating coronary perfusion pressure.[190] The systemic vascular resistance is usually elevated in patients with cardiogenic shock, but occasionally resistance is normal and in a few cases vasodilation actually predominates. When systemic vascular resistance is not elevated (i.e., 48 hours) after presentation with AMI, entails a poor prognosis, with an in-hospital mortality rate of 40 to 60 percent.[521] [526] With the availability of amiodarone and new antitachycardia devices, the prognosis of late ventricular fibrillation is improving and is probably driven more by residual ventricular function and recurrent ischemia than the arrhythmic risk per se. [510] PROPHYLAXIS.

In the early years of MI care in CCUs, concern about the risk of primary ventricular fibrillation led to aggressive monitoring for "warning" ventricular arrhythmias and the initiation of antiarrhythmic therapy when they appeared. Later, when it was shown that warning arrhythmias could not be relied on to predict the risk of ventricular fibrillation, arrhythmia prophylaxis became routine.[527] [528] Lidocaine has been studied most extensively in this regard and has been shown to reduce the incidence of ventricular fibrillation,[529] leading to its widespread routine use in CCUs in patients with known or suspected AMI. However, we no longer endorse that CCU practice for the following reasons: 1. As already noted, the incidence of ventricular fibrillation in patients hospitalized for AMI is decreasing so that the risk for the arrhythmia is now much lower than it was several decades ago (probably under 5 percent). The reasons for this reduction in ventricular fibrillation are not clear but probably include general improvements in the care of AMI patients, greater use of beta blockers, aggressive repletion of electrolytes, prompt treatment of ischemia and congestive heart failure, and reduction in infarct size from reperfusion strategies.[511] 2. There is no evidence that prophylaxis with lidocaine actually reduces mortality in hospitalized patients with AMI because they can almost always be promptly defibrillated.[515] Furthermore, there appear to be trends to excess mortality risk when lidocaine is used on a routine prophylactic basis.[512] [513] [514] [529] 3. Beta-adrenoceptor blockers, which should be administered promptly to the majority of patients with AMI (see p. 1168 ), have been shown to reduce not only ventricular fibrillation[517] but also mortality from AMI. [510] [530] 4. There is an association between hypokalemia and the risk of ventricular fibrillation in the CCU.[531] [532] (see Fig. 35-50) Although it has not been conclusively shown that correction of hypokalemia to a level of 4.5 mEq/liter actually reduces the incidence of ventricular fibrillation, our experience suggests that this probably is protective and of little risk. The data on magnesium and the risk of ventricular fibrillation are incomplete at present. Despite the fact that no consistent relationship between hypomagnesemia and ventricular fibrillation has been observed,[532] magnesium deficits may still be involved in the risk of ventricular fibrillation

because intracellular magnesium levels are reduced in AMI and are not adequately reflected by serum measurements. For these reasons, plus the fact that it is often difficult to repair a potassium deficit without administering supplemental magnesium, we routinely replete magnesium to a level of 2 mEq/liter. The only situation in which we might consider prophylactic lidocaine (bolus of 1.5 mg/kg followed by 20 to 50 mug/kg/min) would be the unusual circumstance in which a patient within the first 12 hours of an AMI must be managed in a facility where cardiac monitoring is not available and equipment for prompt defibrillation is not readily accessible. MANAGEMENT. (See also Chap. 25.)

The likelihood of successful restoration of an effective cardiac rhythm declines rapidly with time after the onset of uncorrected ventricular fibrillation. Irreversible brain damage may occur within 1 to 2 minutes, particularly in elderly patients. The treatment of ventricular fibrillation is an unsynchronized electrical countershock with at least 200 to 300 J, implemented as rapidly as possible.[52] This interrupts fibrillation and restores an effective cardiac rhythm in patients under direct medical observation in the CCU. When ventricular fibrillation occurs outside an intensive care unit, resuscitative efforts are much less likely to be successful, primarily because the time interval between the onset of the episode and the institution of definitive therapy tends to be prolonged. Because closed-chest cardiopulmonary resuscitation with external cardiac compression provides only a marginal cardiac output even under optimal circumstances, countershock could be implemented as soon as possible after the detection of ventricular fibrillation rather than deferred under the mistaken impression that adequate circulatory and respiratory support can be maintained in the interim. Failure of electrical countershock to restore an effective cardiac rhythm is due almost always to rapidly recurrent VT or ventricular fibrillation, to electromechanical dissociation, or, very rarely, to electrical asystole. Ventricular fibrillation often recurs rapidly and repeatedly when the metabolic milieu of the heart has been compromised by severe or prolonged hypoxemia, acidosis, electrolyte abnormalities, or digitalis intoxication. Under these conditions, continued cardiopulmonary resuscitation, prompt implementation of pharmacological and ventilatory maneuvers designed to correct these abnormalities, and rapidly repeated attempts with electrical countershock may be effective. Even though repeated shocks with excessive energy may damage the myocardium and elicit arrhythmias, speed is essential and prompt efforts with high-intensity shocks (generally 300 to 400 watt-seconds) are justified. When ventricular fibrillation persists without documented interruption by electrical countershock, administration of epinephrine either by the intracardiac route (up to 10 ml of a 1:10,000 concentration) or intravenous route (1 mg initially) may facilitate a subsequent defibrillation attempt. Successful interruption of ventricular fibrillation or prevention of refractory recurrent episodes may also be facilitated by administration of bretylium tosylate, 5 mg/kg intravenously, repeated 5 to 20 minutes later if necessary, or amiodarone (75 to 150 mg bolus). When synchronous cardiac electrical activity is restored by countershock but contraction is ineffective (i.e., during electromechanical dissociation), the usual

underlying cause is very extensive myocardial ischemia or necrosis or rupture of the ventricular free wall or septum. If rupture has not occurred, intracardiac administration of calcium gluconate or epinephrine may promote restoration of an effective heartbeat. We do not usually administer bicarbonate injections to correct acidosis because of the high osmotic load they impose and the fact that hyperventilation of the patient is probably a more suitable means of clearing the acidosis. BRADYARRHYTHMIAS Sinus Bradycardia

Sinus bradycardia is a common arrhythmia occurring during the early phases of AMI, and it is particularly frequent in patients with inferior and posterior infarction. [52] Observations in mobile CCUs indicate that 25 to 40 percent of patients with AMI have ECG evidence of sinus bradycardia within the first hour after the onset of symptoms; however, 4 hours after infarction commences the incidence of sinus bradycardia has declined to 15 to 20 percent.[500] Stimulation of cardiac vagal afferent receptors (which are more common in the inferoposterior than the anterior or lateral portions of the left ventricle), with resulting efferent cholinergic stimulation of the heart, produces vagotonia with resultant bradycardia and hypotension. This is a manifestation of the

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Bezold-Jarisch reflex[533] that is mediated by the vagus nerves and occurs during reperfusion, particularly of the right coronary artery.[277] [308] [534] Often sinus bradycardia is a component of vasovagal or vasodepressor response, which may be intensified by severe pain as well as by morphine, and may be related to vasovagal syncope (see Chap. 27) . [535] On the basis of data obtained in experimental infarction and from some clinical observations, it appears that the increased vagal tone that produces sinus bradycardia during the early phase of AMI may actually be protective, perhaps because it reduces myocardial oxygen demands.[536] Thus, the acute mortality rate appears to be as low in patients with sinus bradycardia as in patients without this arrhythmia. MANAGEMENT.

Isolated sinus bradycardia, unaccompanied by hypotension or ventricular ectopy, should be observed rather than treated initially. In the first 4 to 6 hours after infarction, if the sinus rate is extremely slow (under 40 to 50 beats/min), administration of intravenous atropine in aliquots of 0.3 to 0.6 mg every 3 to 10 minutes (with a total dose not exceeding 2 mg) to bring heart rate up to approximately 60 beats/min often abolishes the VPBs commonly associated with this degree of sinus bradycardia.[537] Atropine often contributes to restoration of arterial pressure and hence coronary perfusion and should be employed if hypotension accompanying any degree of sinus bradycardia is present. The favorable effects of atropine may be accompanied by regression of ST segment

elevation. Elevation of the lower extremities also often elevates arterial pressure by redistributing blood from the systemic venous bed to the thorax, thereby augmenting ventricular preload, cardiac output, and arterial pressure. Sinus bradycardia occurring more than 6 hours after the onset of the AMI is often transitory, is caused by sinus node dysfunction or atrial ischemia rather than vagal hyperactivity, is usually not accompanied by hypotension, and does not usually predispose to ventricular arrhythmias. Treatment is not required unless ventricular performance is compromised or the administration of a beta-adrenoceptor blocker or high doses of antiarrhythmic drugs (which may slow the sinus rate further) is planned. When atropine is ineffective and the patient is symptomatic and/or hypotensive, electrical pacing is indicated.[52] In patients with depressed ventricular performance, who require the atrial contribution to ventricular filling, atrial pacing or atrioventricular sequential pacing is superior to simple ventricular pacing. Atrioventricular and Intraventricular Block

Ischemic injury can produce conduction block at any level of the AV or intraventricular conduction system. Such blocks may occur in the AV node and the bundle of His, producing various grades of AV block; in either main bundle branch, producing right or left bundle branch block; and in the anterior and posterior divisions of the left bundle branch, producing left anterior or left posterior (fascicular) divisional blocks.[538] Disturbances of conduction can, of course, occur in various combinations. The mechanisms and recognition of intraventricular and AV conduction disturbances are discussed in Chapter 22 . First-Degree AV Block

First-degree AV block occurs in less than 15 percent of patients with AMI admitted to CCUs. His bundle ECG studies have shown that almost all patients with first-degree AV block have disturbances in conduction above the bundle of His (i.e., intranodal). The localization of the site of block is important because development of complete heart block and ventricular asystole is restricted almost exclusively to those patients with first-degree block in whom the conduction disturbance is below the bundle of His; this occurs more commonly in patients with anterior infarction and those with associated bifascicular block. First-degree AV block generally does not require specific treatment. However, if digitalis intoxication is suspected as the cause, this drug should be discontinued. Beta blockers and calcium antagonists (other than nifedipine) prolong AV conduction and may be responsible for first-degree AV block as well. However, discontinuation of these drugs in the setting of AMI has the potential to increase ischemia and ischemic injury. Therefore, it is our practice not to decrease the dosage of these drugs unless the PR interval is greater than 0.24 second. Only if higher-degree block or hemodynamic impairment occurs should these agents be stopped. If the block is a manifestation of excessive vagotonia and is associated with sinus bradycardia and hypotension, administration of atropine, as already outlined, may be helpful. Continued ECG monitoring is important in

such patients in view of the possibility of progression to higher degrees of block. Second-Degree AV Block MOBITZ TYPE I OR WENCKEBACH AV BLOCK.

Mobitz type I block occurs in up to 10 percent of patients with AMI admitted to CCUs and accounts for about 90 percent of all patients with AMI and second-degree AV block. This type of block (1) generally occurs within the AV node, (2) is usually associated with narrow QRS complexes, (3) is presumably secondary to ischemic injury, (4) occurs more commonly in patients with inferior than anterior MI, (5) is usually transient and does not persist for more than 72 hours after infarction, (6) may be intermittent, and (7) rarely progresses to complete AV block (Table 35-21) . First-degree and type I second-degree AV blocks do not appear to affect survival, are most commonly associated with occlusion of the right coronary artery, and are caused by ischemia of the AV node. Specific therapy is not required in patients with second-degree AV block of the Mobitz type I variety when the ventricular rate exceeds 50 beats/min and ventricular irritability, heart failure, and bundle branch block are absent. However, if these complications develop or if the heart rate falls below approximately 50 beats/min and the patient is symptomatic, immediate treatment with atropine (0.3 to 0.6 mg) is indicated; temporary pacing systems are almost never needed in the management of this arrhythmia. MOBITZ TYPE II AV BLOCK.

This is a rare conduction defect after AMI, occurring in only 10 percent of all cases of second-degree block. Thus, the overall incidence of Mobitz type II block after infarction is less than 1 percent. In contrast to Mobitz type I block, type II second-degree block (1) usually originates from a lesion in the conduction system below the bundle of His, (2) is associated with a wide QRS complex, (3) often but not invariably reflects trifascicular block with impaired conduction distal to the bundle of His, (4) often progresses suddenly to complete AV block, and (5) is almost always associated with anterior rather than inferior infarction (see Table 35-21) . Because of its potential for progression to complete heart block, Mobitz type II second-degree AV block should be treated with a temporary external or transvenous demand pacemaker with the rate set at approximately 60 beats/min.[52] Complete (Third-Degree) AV Block

The AV conduction system has a dual blood supply: the AV branch of the right coronary artery and the septal perforating branch from the left anterior descending coronary artery. Therefore, complete AV block can occur in patients

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TABLE 35-21 -- ATRIOVENTRICULAR (AV) CONDUCTION DISTURBANCES IN ACUTE MYOCARDIAL INFARCTION LOCATION OF AV CONDUCTION DISTURBANCE Proximal

Distal

Site of block

Intranodal

Infranodal

Site of infarction

Inferoposterior

Anteroseptal

Compromised arterial supply

RCA (90%), LCX (10%)

Septal perforators of LAD

Pathogenesis

Ischemia, necrosis, hydropic cell swelling, excess parasympathetic activity

Ischemia, necrosis, hydropic cell swelling

Predominant type of AV nodal block

First-degree (PR>200 msec)

Mobitz type II second-degree

Mobitz type I second-degree

Third-degree

(a) First-second-degree AV block

(a) Intraventricular conduction block

(b) Mobitz I pattern

(b) Mobitz II pattern

Common premonitory features of third-degree AV block Features of escape rhythm following third-degree block (a) Location

(a) Proximal conduction system (a) Distal conduction system (His bundle) (bundle branches)

(b) QRS width

(b) < 0.12/sec-*

(b) > 0.12/sec

(c) Rate

(c) 45-60/min but may be as low as 30/min

(c) Often < 30/min

(d) Stability of escape rhythm

(d) Rate usually stable; asystole (d) Rate often unstable with uncommon moderate to high risk of ventricular asystole

Duration of high-grade AV block

Usually transient (2-3 days)

Usually transient but some form of AV conduction disturbance and/or intraventricular defect may persist

Associated mortality rate

Low unless associated with hypotension and/or congestive heart failure

High because of extensive infarction associated with power failure or ventricular arrhythmias

(a) Temporary

(a) Rarely required; may be considered for bradycardia associated with left ventricular power failure, syncope, or angina

(a) Should be considered in patients with anteroseptal infarction and acute bifascicular block

(b) Permanent

(b) Almost never indicated because conduction defect is usually transient

(b) Indicated for patients with high-grade AV block with block in His-Purkinje system and those with transient advanced AV block and associated bundle branch block

Pacemaker therapy

RCA=right coronary artery; LCX=left circumflex coronary artery; LAD= left anterior descending coronary artery. Modified from Antman EM, Rutherford JD: Coronary Care Medicine: A Practical Approach. Boston, Martinus Nijhoff, 1986; Dreifus LS, et al: Guidelines for implantation of cardiac pacemakers and antiarrhythmia devices. J Am Coll Cardiol 18:1, 1991. Reprinted with permission from the American College of Cardiology. *Some studies suggest that a wide QRS escape rhythm (>0.12 sec) following high-grade AV block in inferior infarction is associated with a worse prognosis.

with either anterior or inferior infarction. Complete AV block occurs in about 5 percent of patients in the thrombolytic era, although the incidence may be higher in patients with right ventricular infarction.[63] [539] [540] As with other forms of AV block, the prognosis depends on the anatomical location of the block in the conduction system and the size of the infarction.[541] Complete heart block in patients with inferior infarction usually results from an intranodal or supranodal lesion[542] and develops gradually, often progressing from first-degree or type I second-degree block (see Table 35-21) . The escape rhythm is usually stable without asystole and often junctional, with a rate exceeding 40 beats/min and a narrow QRS complex in 70 percent of cases and a slower rate and wide QRS in the others. This form of complete AV block is often transient, may be responsive to pharmacological antagonism of adenosine with methylxanthines,[543] [544] and resolves in the majority of patients within a few days. The mortality may approach 15 percent unless right ventricular infarction is present, in which case the mortality associated with complete AV block may be more than doubled. In patients with anterior infarction, third-degree AV block often occurs suddenly, 12 to 24 hours after the onset of infarction, although it is usually preceded by intraventricular

block and often Mobitz type II (not first-degree or Mobitz type I) AV block (see Table 35-20) . Such patients have unstable escape rhythms with wide QRS complexes and rates less than 40 beats/min; ventricular systole may occur quite suddenly. The mortality in this group of patients is extremely high, 70 to 80 percent. PROGNOSIS.

This depends on the extent and secondarily on the anatomical site of the myocardial injury.[539] [545] Patients with inferior infarction often have concomitant ischemia or infarction of the AV node secondary to hypoperfusion of the AV nodal artery. However, the His-Purkinje system usually escapes injury in such individuals. Patients with inferior MI who develop AV block usually have lesions in both the right and left anterior descending coronary arteries. Likewise, patients with inferior MI and AV block have larger infarcts and more depressed right ventricular and left ventricular function than do patients with inferior infarct and no AV block. As already noted, junctional escape rhythms with narrow QRS complexes occur commonly in this setting. In patients with anterior infarction, AV block usually develops as a result of extensive septal necrosis that involves the bundle branches. The high mortality in this group of patients with slow idioventricular rhythm and wide QRS complexes is the consequence of extensive myocardial necrosis resulting in severe left ventricular failure and often shock. Although data suggest that complete AV block is not an independent risk factor for mortality, whether temporary transvenous pacing per se improves survival of patients with anterior AMI remains controversial. Some investigators contend that ventricular pacing is useless when employed to correct complete AV block in patients with anterior infarction in view of the poor prognosis in this group

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regardless of therapy. However, pacing may protect against transient hypotension with its attendant risks of extending infarction and precipitating malignant ventricular tachyarrhythmias. Also, pacing protects against asystole, a particular hazard in patients with anterior infarction and infranodal block. Improved survival with pacing probably occurs in only a small fraction of patients with complete AV block and anterior wall infarcts because the extensive destruction of the myocardium that almost invariably accompanies this condition results in a very high mortality rate, even in paced patients. Given these considerations, an extremely large series of patients would be required to demonstrate the small reduction of mortality that might be achieved by pacing. The absence of data supporting such an effect, however, by no means excludes the possibility that it may be present. Pacing is not usually needed in patients with inferior wall infarction and complete AV block that is often transient in nature, but it is indicated if the ventricular rate is very slow (< 40 to 50 beats/min), if ventricular irritability or hypotension is present, or if pump failure develops; atropine is only rarely of value in these patients. Only when complete heart block develops in less than 6 hours after the onset of symptoms is atropine likely

to abolish the AV block or cause acceleration of the escape rhythm. In such cases the AV block is more likely to be transient and related to increases in vagal tone than the more persistent block seen later in the course of MI, which generally requires cardiac pacing. Intraventricular Block

In the prethrombolytic era, studies of intraventricular conduction disturbances, such as a block within one or more of the three subdivisions (fascicles) of the His-Purkinje system (the anterior and posterior divisions of the left bundle and the right bundle), had been reported to occur in 5 to 10 percent of patients with AMI.[532] [546] [547] Several series in the thrombolytic era suggest that intraventricular blocks occur in 2 to 5 percent of patients with AMI.[540] [548] The right bundle branch and the left posterior division have a dual blood supply from the left anterior descending and right coronary arteries, whereas the left anterior division is supplied by septal perforators originating from the left anterior descending coronary artery. Not all conduction blocks observed in patients with AMI can be considered to be complications of infarcts because almost half are already present at the time the first ECG is recorded, and they may represent antecedent disease of the conduction system.[547] [549] Compared with patients without conduction defects, AMI patients with bundle branch blocks have more comorbid conditions; are less likely to receive therapies such as thrombolytics, aspirin, and beta blockers; and have an increased in-hospital mortality rate.[550] ISOLATED FASCICULAR BLOCKS.

Isolated left anterior divisional block is unlikely to progress to complete AV block.[546] [551] [552] Mortality is increased in these patients, although not as much as in patients with other forms of conduction block. The posterior fascicle is larger than the anterior fascicle, and, in general, a larger infarct is required to block it. As a consequence, mortality is markedly increased. Complete AV block is not a frequent complication of either form of isolated divisional block.[546] [551] [552] RIGHT BUNDLE BRANCH BLOCK.

This defect alone occurs in approximately 2 percent of patients with AMI and may lead to AV block because it is often a new lesion, associated with anteroseptal infarction.[547] Isolated right bundle branch block is associated with an increased mortality risk in patients with anterior MI even if complete AV block does not occur, but this appears to be the case only if it is accompanied by congestive heart failure.[547] [551] [553] BIFASCICULAR BLOCK.

The combination of right bundle branch block with either left anterior or posterior divisional block or the combination of left anterior and posterior divisional blocks (i.e., left bundle branch block) is known as bidivisional or bifascicular block. If a new block occurs in two of the three divisions of the conduction system, the risk of developing complete AV block is quite high. Mortality is also high because of the occurrence of

severe pump failure secondary to the extensive myocardial necrosis required to produce such an extensive intraventricular block.[548] [552] Left bundle branch block occurs in 2 to 5 percent of patients with AMI. Although the latter defect progresses to complete AV block only half as frequently as does right bundle branch block, it is associated with as high a mortality as right bundle branch block and the other two forms of bifascicular block[551] and with a high late mortality. Patients with intraventricular conduction defects, particularly right bundle branch block, account for the majority of patients who develop ventricular fibrillation late in their hospital stay. However, the high mortality in these patients occurs even in the absence of high-grade AV block and appears to be related to cardiac failure and massive infarction rather than to the conduction disturbance. [550] Preexisting bundle branch block or divisional block is less often associated with the development of complete heart block in patients with AMI than are conduction defects acquired during the course of the infarct.[551] Bidivisional block in the presence of prolongation of the PR interval (first-degree AV block) may indicate disease of the third subdivision rather than of the AV node. In such cases, termed "trifascicular block," nearly 40 percent progress to complete heart block, a risk that is considerably greater than the risk of complete heart block without first-degree AV block.[546] Complete bundle branch block (either left or right), the combination of right bundle branch block and left anterior divisional (fascicular) block, and any of the various forms of trifascicular block are all more often associated with anterior than inferoposterior infarction. All these forms are more frequent with large infarcts and in older patients and have a higher incidence of other accompanying arrhythmias than is seen in patients without bundle branch block. Asystole

This arrhythmia has been reported to occur in 1 to 14 percent of patients with AMI admitted to CCUs. This wide variation in incidence reflects differences in the definition of this event. The lower incidence rates include only patients who develop asystole either as a primary event or after abnormalities of AV or intraventricular conduction, whereas the higher rates include patients who develop asystole as a terminal complication. In either event, the mortality is very high. The presence of apparent ventricular asystole on monitor displays of continuously recorded ECGs may be misleading, because the mechanism may in fact be fine ventricular fibrillation. Because of the predominance of ventricular fibrillation as the cause of cardiac arrest in this setting, initial therapy should include electrical countershock, even if definitive ECG documentation of this arrhythmia is not available. In the rare instance in which asystole can be documented to be the responsible electrophysiological disturbance, immediate transcutaneous pacing (or stimulation with a transvenous pacemaker if one is already in place) is indicated.[52] Use of Pacemakers in AMI (See also Chap. 24)

TEMPORARY PACING.

Just as is the case for complete AV block, transvenous ventricular pacing has not resulted in statistically demonstrable improvement in prognosis among patients with AMI who develop intraventricular

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conduction defects. However, temporary pacing is advisable in some of these patients because of the high risk of developing complete AV block. This includes patients with new bilateral (bifascicular) bundle branch block (i.e., right bundle branch block with left anterior or posterior divisional block and alternating right and left bundle branch block); first-degree AV block adds to this risk. Isolated new block in only one of the three fascicles even with PR interval prolongation and preexisting bifascicular block and normal PR interval poses somewhat less risk; these patients should be monitored closely, with insertion of a temporary pacemaker deferred unless higher-degree AV block occurs. It has been proposed on the basis of results of an analysis of several large series of well-characterized patients that the risk of developing complete heart block after AMI can be predicted.[552] The presence (new or preexisting) of any of the following conduction disturbances is considered a risk factor: first-degree AV block, Mobitz type I second-degree AV block, Mobitz type II second-degree AV block, left anterior hemiblock, left posterior hemiblock, right bundle branch block, and left bundle branch block. Each risk factor was assigned a score of 1, and the risk score was calculated as the sum of these ECG risk factors. The incidence of complete heart block occurred as follows: risk score 0, 1.2 to 6.8 percent incidence; risk score 1, 7.8 to 10.4 percent incidence; risk score 2, 25.0 to 30.1 percent incidence; and risk score 3, 36 percent or greater incidence.[552] Some authorities have pointed out deficiencies in this scoring system in that Mobitz type II AV block is assigned a score of only 1 point but appears to carry more significance; also there is no differentiation between preexisting and newly appearing bundle branch block. We believe that failure to demonstrate improved prognosis statistically does not belie the potential value of pacemaker therapy; it probably reflects the overriding impact on mortality of the extensive infarction responsible for the development of the conduction abnormality and the large number of patients required to permit statistical documentation of reduction of mortality. In assessing the need for temporary pacing (see Table 35-21) , the clinician must keep in mind that between 10 and 20 percent of patients develop pacemaker-related complications. A pericardial friction rub develops in approximately 5 percent of patients but does not necessarily indicate cardiac perforation, nor is such a finding an indication for withdrawal of the pacemaker electrode. Arrhythmias requiring cardioversion, right ventricular perforation, and local infectious complications occur in 1 to 3 percent of

cases. Pacemaker malfunction also occurs rather frequently and is, in part, related to the experience of the clinical team in managing the device and its insertion. Although external temporary cardiac pacing was introduced in 1952, its widespread clinical use did not occur until relatively recently owing to technical refinements making the technique safe, quickly applicable, and relatively well tolerated. Noninvasive external temporary cardiac pacing is now possible routinely in conscious patients and is acceptable to many but not all patients because of the discomfort.[554] Used in a standby mode, it is virtually free of complications and contraindications and provides an important alternative to transvenous endocardial pacing.[52] Once it is clinically evident that continuous pacing is required, external pacing, which is generally not well tolerated for more than minutes to hours, should be replaced by a temporary transvenous pacemaker. PERMANENT PACING.

The question of permanent pacing in survivors of AMI associated with conduction defects is still controversial (see Table 35-21) . Patients with inferior infarction with transient type II second-degree block or complete AV block without an associated intraventricular conduction defect do not appear to require permanent pacing. Some contend that prophylactic pacing makes little difference in the long-term survival of patients with AMI and bundle branch block complicated by transient high-degree block. On the other hand, in a retrospective multicenter study, survivors of AMI and bundle branch block who experienced transient high-degree (Mobitz type II second-degree or third-degree) block had a high incidence of recurrent high-degree AV block and sudden death, and this incidence was reduced by insertion of a permanent demand pacemaker.[546] [551] Thus, these findings suggest a role for prophylactic permanent pacing in patients with AMI and bundle branch block with transient high-degree AV block. The question of the advisability of permanent pacemaker insertion is complicated by the fact that not all sudden deaths in this population are due to recurrent high-degree block. A high incidence of late in-hospital ventricular fibrillation occurs in CCU survivors with anteroseptal MI complicated by either right or left bundle branch block. If the propensity for this arrhythmia continued, ventricular fibrillation rather than asystole due to failure of AV conduction and of the infranodal pacemaker could be responsible for late sudden death. Long-term pacing is often helpful when complete heart block persists throughout the hospital phase in a patient with AMI, when sinus node function is markedly impaired, or when Mobitz II second- or third-degree block occurs intermittently.[52] When high-grade AV block is associated with newly acquired bundle branch block or other criteria of impairment of conduction system function, prophylactic long-term pacing may be justified as well. Thus, despite the difficulty of proving that long-term pacing improves survival after MI because of the high mortality associated with extensive infarction frequently responsible for high degrees of heart block, prophylactic long-term pacing is prudent.

SUPRAVENTRICULAR TACHYARRHYTHMIAS (See also Chap. 25) SINUS TACHYCARDIA.

This arrhythmia is typically associated with augmented sympathetic activity and may provoke transient hypertension or hypotension. Common causes are anxiety, persistent pain, left ventricular failure, fever, pericarditis, hypovolemia, pulmonary embolism, and the administration of cardioaccelerator drugs such as atropine, epinephrine, or dopamine; rarely it occurs in patients with atrial infarction. Sinus tachycardia is particularly common in patients with anterior infarction, especially if there is significant accompanying left ventricular dysfunction. It is an undesirable rhythm in patients with AMI because it results in an augmentation of myocardial oxygen consumption, as well as a reduction in the time available for coronary perfusion, thereby intensifying myocardial ischemia and/or external myocardial necrosis. Persistent sinus tachycardia may signify persistent heart failure and under these circumstances is a poor prognostic sign associated with an excess mortality.[52] An underlying cause should be sought and appropriate treatment instituted (e.g., analgesics for pain, diuretics for heart failure, oxygen, beta blockers and nitroglycerin for ischemia, and aspirin for fever or pericarditis. Administration of beta-adrenoceptor blocking agents, may be helpful in the treatment of sinus tachycardia, particularly when this arrhythmia is a manifestation of hyperdynamic circulation, which is seen particularly in young patients with an initial MI without extensive cardiac damage. However, beta blockade is contraindicated in patients in whom the sinus tachycardia is a manifestation of hypovolemia or of pump failure, the latter reflected by a systolic arterial pressure below 100 mm Hg, rales involving more than one third of the lung fields, a pulmonary capillary wedge pressure exceeding 20 to 25 mm Hg, or a cardiac index below approximately 2.2 liters/min/m2 . A possible exception to this is a patient in whom persistent ischemia is believed to be the cause or the result of tachycardia: cautious administration of an ultrashort-acting beta-adrenoceptor blocker such as esmolol (25 to 200 mug/kg/min) may be tried to ascertain the patient's response to slowing of the heart rate.[188] ATRIAL PREMATURE CONTRACTIONS.

Atrial premature contractions, and the atrial tachyarrhythmias (paroxysmal supraventricular tachycardia, atrial flutter, and atrial fibrillation) that they often herald, may be caused by atrial distention secondary to increases in left ventricular diastolic pressure, by pericarditis with its associated atrial epicarditis, or, less commonly, by ischemic injury to the atria and sinus node. Atrial premature beats per se are not associated with an increase in

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mortality, and cardiac output is unaffected. No specific therapy is needed, but it should be kept in mind that these beats may indicate excessive autonomic stimulation or the

presence of overt or occult heart failure--conditions that may be assessed by physical examination, chest roentgenography, and echocardiography. PAROXYSMAL SUPRAVENTRICULAR TACHYCARDIA.

This arrhythmia occurs in less than 10 percent of patients with AMI but requires aggressive management because of the rapid ventricular rate. [462] Augmentation of vagal tone by manual carotid sinus stimulation may restore sinus rhythm. The drug of choice for paroxysmal supraventricular tachycardia in the non-AMI patient is adenosine (6 to 12 mg).[462] Few data exist to guide therapy with adenosine in the AMI patient, but we believe that it can be used safely provided that hypotension (systolic pressure 100 mm Hg) is not present before its administration. Intravenous verapamil (5 to 10 mg), diltiazem (15 to 20 mg), and metoprolol (5 to 15 mg) are suitable alternatives in patients without significant left ventricular dysfunction. In the presence of congestive heart failure or hypotension, direct-current countershock or rapid atrial stimulation via a transvenous intraatrial electrode should be used. Although digitalis glycosides may be useful in augmenting vagal tone, thereby terminating the arrhythmia, their effect is often delayed. ATRIAL FLUTTER AND FIBRILLATION.

Atrial flutter is the least common major atrial arrhythmia associated with AMI. Atrial flutter is usually transient, and in AMI it is typically a consequence of augmented sympathetic stimulation of the atria, often occurring in patients with left ventricular failure or pulmonary emboli in whom the arrhythmia intensifies hemodynamic deterioration.[500] [555]

Atrial fibrillation is far more common than flutter, occurring in 10 to 20 percent of patients with AMI.[556] [557] As with atrial premature contractions and atrial flutter, fibrillation is usually transient and tends to occur in patients with left ventricular failure but is also observed in patients with pericarditis and ischemic injury to the atria and right ventricular infarction.[63] [558] The increased ventricular rate and the loss of the atrial contribution to left ventricular filling result in a significant reduction in cardiac output. Atrial fibrillation during AMI is associated with increased mortality and stroke, particularly in patients with anterior wall infarction.[557] [559] However, because it is more common in patients with clinical and hemodynamic manifestations of extensive infarction and a poor prognosis, atrial fibrillation is probably a marker of poor prognosis, with only a small independent contribution to increased mortality. Management.

Atrial flutter and fibrillation in patients with AMI are treated in a manner similar to these conditions in other settings (see Chap. 23) . Because of the possibility that the rapid ventricular rate and hypotension associated with these arrhythmias can increase infarct size and because of the important role played by atrial contraction in the support of cardiac output in patients with AMI, treatment must be prompt, especially when the ventricular rate exceeds 100 beats/min. When hemodynamic decompensation is prominent, electrical cardioversion is indicated, beginning with 25 to 50 J for atrial flutter

and 50 to 100 J for atrial fibrillation, with gradual increase if the initial shock is not successful. For patients without hemodynamic compromise, the first maneuver should be to slow the ventricular rate. Ideally, a beta-adrenoceptor blocker (e.g., metoprolol in 5-mg intravenous boluses every 5 to 10 minutes to a total dose of 15 to 20 mg, followed by 25 to 50 mg orally every 6 hours) should be used because of the combined effects of ischemia and sympathetic tone that are usually present in patients with atrial fibrillation. If there is concern about the patient's ability to tolerate beta blockade, esmolol may be used. Intravenous doses of verapamil or diltiazem are attractive alternatives because of their ability to slow the ventricular rate promptly, but they should be used with caution if at all in patients with pulmonary congestion. In patients with congestive heart failure, digitalis is the principal agent used to slow the ventricular response, although the onset of its effect may be delayed for several hours. Digitalis may be supplemented by small intravenous doses of a beta blocker, which also prolongs the AV nodal refractory period: 1 to 4 mg of propranolol in divided doses is often quite effective in reducing the ventricular rate and is well tolerated, even in patients with mild heart failure and a rapid ventricular rate. An additional important option for the treatment of atrial flutter is the use of rapid atrial stimulation through a transvenous intraatrial electrode. Because of the increased risk of embolism in atrial fibrillation, intravenous anticoagulation with heparin should be instituted in the absence of any contraindications. Attention should be directed to the management of the underlying cause (usually heart failure), and then a decision must be made about the advisability of antiarrhythmic therapy to restore and maintain sinus rhythm. In patients who have acute atrial flutter or fibrillation without a history of atrial fibrillation and in whom congestive symptoms are either absent or easily controlled, we usually administer intravenous procainamide (2 to 4 mg/min) for 24 to 48 hours. The goal is to achieve pharmacological cardioversion or secondarily to establish a therapeutic concentration of the drug in preparation for direct-current cardioversion. In view of the mounting evidence of an increased risk of proarrhythmia from antiarrhythmic drugs prescribed for atrial fibrillation, as well as an adverse interaction between recurrent ischemia and antiarrhythmic drugs, we are reluctant to prescribe type I antiarrhythmic agents over the intermediate or long term in patients with AMI. [510] [560] Amiodarone appears to be an increasingly attractive antiarrhythmic drug for suppression of recurrences of atrial fibrillation. This drug is also useful for prevention of ventricular arrhythmias and can block the AV node should atrial fibrillation recur, both desirable features after AMI. It may be prescribed in a low dose (200 mg/d), thereby reducing the risk of toxicity. Although experience is limited, we believe that amiodarone is a logical choice for suppression of atrial fibrillation after AMI; often only a short course of treatment (6 weeks) is needed because the risk of atrial fibrillation decreases as time passes after infarction. Patients with recurrent episodes of atrial fibrillation should be treated with oral anticoagulants (to reduce the risk of stroke), even if sinus rhythm is present at the time of hospital discharge, because no antiarrhythmic regimen can be relied on to be completely effective in suppressing atrial fibrillation. In the absence of contraindications, the majority of patients should receive a beta blocker after AMI; in addition to their several other beneficial effects in MI and post-MI patients, these agents are helpful in

slowing the ventricular rate should atrial fibrillation recur. JUNCTIONAL RHYTHMS.

These arrhythmias are often transient, occur during the first 48 hours of the infarction, typically develop and terminate gradually, and are characterized by QRS complexes that resemble those of normally conducted beats. Retrograde P waves may be evident, or AV dissociation may occur, with the junctional rate slightly in excess of the underlying sinus rate. Junctional rhythms fall into two categories: 1. AV junctional rhythm at a rate of 35 to 60 beats/min in which the AV junctional tissue simply assumes the role of the dominant pacemaker when the sinus node is depressed. This arrhythmia is generally a benign protective escape rhythm that is commonly seen among patients with a slow sinus rate in the presence of inferior MI. When there is hemodynamic impairment, transvenous sequential AV pacing may be required to facilitate ventricular performance and maintain adequate peripheral perfusion. 2. Accelerated junctional rhythm (nonparoxysmal junctional tachycardia) is less common and occurs when there is increased automaticity of the junctional tissue, which 1195

usurps the role of pacemaker, usually appearing at a rate of 70 to 130 beats/min. This arrhythmia is seen more commonly with inferior than anterior AMI and may also appear in patients with digitalis intoxication. In studies conducted during the prethrombolytic era, the appearance of accelerated junctional rhythm in the setting of anterior infarction was associated with a poor prognosis, but this was not observed when it occurred in patients with inferior infarction. OTHER COMPLICATIONS Recurrent Chest Discomfort

Evaluation of postinfarction chest discomfort may be complicated by previous abnormalities on the ECG and a vague description of the discomfort by the patient who either may be exquisitely sensitive to fleeting discomfort or may deny a potential recrudescence of symptoms. The critical task for clinicians is to distinguish recurrent angina or infarction from nonischemic causes of discomfort that might be caused by infarct expansion, pericarditis, pulmonary embolism, and noncardiac conditions. Important diagnostic maneuvers include a repeat physical examination, repeat ECG, and assessment of the response to sublingual nitroglycerin, 0.4 mg. (The use of noninvasive diagnostic evaluation for recurrent ischemia in patients whose symptoms only appear with moderate levels of exertion is discussed on page 1199 .)

RECURRENT ISCHEMIA AND INFARCTION.

The incidence of postinfarction angina without reinfarction is between 20 and 30 percent.[349] It does not appear to be reduced by the use of thrombolytic therapy as the management strategy during the acute phase [19] but has been reported to be lower in patients who undergo primary PTCA for AMI, especially if stents are used.[337] When accompanied by ST segment and T wave changes in the same leads where Q waves have appeared, it may be due to occlusion of an initially patent vessel, reocclusion of an initially recanalized vessel, or coronary spasm. Extension of the original zone of necrosis or reinfarction in a separate myocardial zone can be a difficult diagnosis, especially within the first 24 hours after the index event.[79] It is more convenient to refer to both extension and reinfarction collectively under the more general term recurrent infarction. Circulating cardiac markers may still be elevated from the initial infarction, and it may not be possible to distinguish the ECG changes that are part of the normal evolution after the index infarction from those due to recurrent infarction. Because the cardiac-specific troponins (see p. 1134) remain elevated for more than 1 week after the index event, they are of less value for diagnosing recurrent infarction than are more rapidly rising and falling markers such as CK-MB. Within the first 18 to 24 hours after the initial infarction, when serum cardiac markers may not have returned to the normal range, recurrent infarction should be strongly considered when there is repeat ST segment elevation on the ECG. Although pericarditis remains a possibility in such patients, the two can usually be distinguished by the presence of a rub and the lack of responsiveness to nitroglycerin in patients with pericardial discomfort. Beyond the first 24 hours, cardiac markers such as CK-MB have usually returned to the normal range; thus, recurrent infarction may be diagnosed either by reelevation of the CK-MB above the upper limit of normal and increased by at least 50 percent of the previous value or by the appearance of new Q waves on the ECG.[52] Because of variations in patient populations and definitions of recurrent infarction, estimates of the incidence of this complication vary; recent large thrombolytic trials report reinfarction rates of 5 to 6 percent.[20] [22] Reinfarction is more common in patients with diabetes mellitus and those with a previous MI, but it cannot be predicted reliably from the angiographic appearance of the coronary artery early after infarction, at least when thrombolytic therapy has been given. Regardless of whether postinfarction angina is persistent or limited, its presence is important because short-term morbidity is higher among such patients; mortality may be increased if the recurrent ischemia is accompanied by ECG changes and hemodynamic compromise.[52] [561] Recurrent infarction (due in many cases to reocclusion of the infarct-related coronary artery) carries serious adverse prognostic information because it is associated with a twofold to fourfold higher rate of in-hospital complications (congestive heart failure, heart block) and mortality. The mortality rate at 1 to 3 years after the initial infarction is higher in those patients who suffered from recurrent infarction during their index hospitalization.[562] Presumably, the higher mortality is

related to the larger mass of myocardium whose function becomes compromised. Of the standard therapies that are routinely prescribed during the acute phase of AMI, aspirin and beta blockers have been associated with a reduction in the incidence of recurrent infarction.[52] [349] [563] The data on heparin are less convincing. Management.

As with the acute phase of treatment of AMI, algorithms for management of patients with recurrent ischemic discomfort at rest center on the 12-lead ECG (Fig. 35-51) . Those patients with ST segment reelevation should either receive repeat thrombolysis[52] [564] or be referred for urgent catheterization and PTCA. Insertion of an intraaortic balloon pump may help stabilize the patient while other procedures are being arranged. For patients believed to have recurrent ischemia who do not have evidence of hemodynamic compromise, an attempt should be made to control symptoms with sublingual or intravenous nitroglycerin and intravenous beta blockade to slow the heart rate to 60 beats/min. When hypotension, congestive heart failure, or ventricular arrhythmias develop during recurrent ischemia, urgent catheterization and revascularization are indicated. Pericardial Effusion and Pericarditis (See also Chap. 50.)

PERICARDIAL EFFUSION.

Effusions are generally detected echocardiographically, and their incidence varies with technique, criteria, and laboratory expertise. Effusions are more common in patients with anterior MI and with larger infarcts and when congestive heart failure is present. [565] The majority of pericardial effusions that are

Figure 35-51 Treatment of recurrent ischemic events. (From Cannon CP, Ganz LI, Stone PH: Complicated myocardial infarction. In Rippe JM, Irwin RS, Fink MP, Cerra FB [eds]: Intensive Care Medicine. 3rd ed. Boston, Little, Brown & Co, 1995.)

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seen after AMI do not cause hemodynamic compromise; when tamponade occurs, it is usually due to ventricular rupture or hemorrhagic pericarditis.[99] The reabsorption rate of a postinfarction pericardial effusion is slow, with resolution often taking several months. The presence of an effusion does not indicate that pericarditis is present; although they may occur together, the majority of effusions occur without other evidence of pericarditis.

PERICARDITIS.

When secondary to transmural AMI, pericarditis may produce pain as early as the first day and as late as 6 weeks after MI. The pain of pericarditis may be confused with that resulting from postinfarction angina, recurrent infarction, or both. An important distinguishing feature is the radiation of the pain to either trapezius ridge, a finding that is nearly pathognomonic of pericarditis and rarely seen with ischemic discomfort.[99] Transmural MI, by definition, extends to the epicardial surface and is responsible for local pericardial inflammation. An acute fibrinous pericarditis (pericarditis epistenocardica) occurs commonly after transmural infarction, but the majority of patients do not report any symptoms from this process.[99] Although transient pericardial friction rubs are relatively common among patients with transmural infarction within the first 48 hours, pain or ECG changes occur much less often. However, the development of a pericardial rub appears to be correlated with a larger infarct and greater hemodynamic compromise. The discomfort of pericarditis usually becomes worse during a deep inspiration, but it may be relieved or diminished when the patient sits up and leans forward. Although anticoagulation clearly increases the risk for hemorrhagic pericarditis early after MI, this complication has not been reported with sufficient frequency during heparinization or after thrombolytic therapy to warrant absolute prohibition of such agents when a rub is present, but the detection of a pericardial effusion on an echocardiogram is usually an indication for discontinuation of anticoagulation.[99] In patients in whom continuation or initiation of anticoagulant therapy is strongly indicated (such as during cardiac catheterization or after coronary angioplasty), heightened monitoring of clotting parameters and observation for clinical signs of possible tamponade are needed. Late pericardial constriction due to anticoagulant-induced hemopericardium has been reported. Treatment of pericardial discomfort consists of aspirin, but usually in higher doses than prescribed routinely after infarction: doses of 650 mg orally every 4 to 6 hours may be needed. Nonsteroidal antiinflammatory agents and corticosteroids should be avoided because they may interfere with myocardial scar formation. [566] DRESSLER SYNDROME.

Also known as the postmyocardial infarction syndrome,[567] Dressler syndrome usually occurs 1 to 8 weeks after infarction. Its incidence is difficult to define because it often blends imperceptibly with the more common early post-MI pericarditis. Dressler cited an incidence of 3 to 4 percent of all AMI patients in 1957, but the incidence has decreased dramatically since that time. Clinically, patients with Dressler syndrome present with malaise, fever, pericardial discomfort, leukocytosis, an elevated ESR, and a pericardial effusion. At autopsy, patients with this syndrome usually demonstrate localized fibrinous pericarditis containing polymorphonuclear leukocytes.[567] The cause of this syndrome is not clearly established, although the detection of antibodies to cardiac tissue has raised the notion of an immunopathological process. Treatment is with aspirin, 650 mg, as often as every 4 hours. Glucocorticosteroids or nonsteroidal antiinflammatory agents are

best avoided in patients with Dressler syndrome within 4 weeks of AMI because of their potential to impair infarct healign, to cause ventricular rupture,[568] and to increase coronary vascular resistance. Aspirin in large doses is effective. Four weeks after AMI, nonsteroidal antiinflammatory agents and in occasional patients corticosteroids are necessary to control what may be severe, recurrent symptoms. Venous Thrombosis and Pulmonary Embolism

Almost all pulmonary emboli originate from thrombi in the veins of the lower extremities (see Chap. 52) ; much less commonly, they originate from mural thrombi overlying an area of right ventricular infarction. Bed rest and heart failure predispose to venous thrombosis and subsequent pulmonary embolism, and both of these factors occur commonly in patients with AMI, particularly those with large infarcts. Several decades ago, at a time when patients with AMI were routinely subjected to prolonged periods of bed rest, significant pulmonary embolism was found in more than 20 percent of patients with MI coming to autopsy, and massive pulmonary embolism accounted for 10 percent of deaths from AMI.[569] In recent years, with early mobilization and the widespread use of low-dose anticoagulant prophylaxis, especially using low-molecular-weight heparins, pulmonary embolism has become an uncommon cause of death in this condition. When pulmonary embolism does occur in patients with AMI, management is generally along the lines described for noninfarction patients. Left Ventricular Aneurysm

The term left ventricular aneurysm (often termed true aneurysm) is generally reserved for a discrete, dyskinetic area of the left ventricular wall with a broad neck (to differentiate it from pseudoaneurysm due to a contained myocardial rupture). True left ventricular aneurysms probably develop in less than 5 to 10 percent of all patients with AMI and perhaps somewhat more frequently in patients with transmural infarction (especially anterior).[57] The wall of the true aneurysm is thinner than the rest of the left ventricle (Fig. 35-46) , and it is usually composed of fibrous tissue as well as necrotic muscle, occasionally mixed with viable myocardium. Aneurysm formation presumably occurs when intraventricular tension stretches the noncontracting infarcted heart muscle, thus producing infarct expansion; a relatively weak, thin layer of necrotic muscle; and fibrous tissue that bulges with each cardiac contraction. With the passage of time, the wall of the aneurysm becomes more densely fibrotic, but it continues to bulge with systole, causing some of the left ventricular stroke volume during each systole to be ineffective. When an aneurysm is present after anterior MI, there is generally a total occlusion of a poorly collateralized left anterior descending coronary artery. An aneurysm is rarely seen with multivessel disease when there are either extensive collaterals or a nonoccluded left anterior descending artery. Aneurysms usually range from 1 to 8 cm in diameter. They occur approximately four times more often at the apex and in the anterior wall than in the inferoposterior wall. The overlying pericardium is usually densely adherent to the wall of the aneurysm, which may even become partially calcified after several years. True left ventricular aneurysms (in contrast to pseudoaneurysms) rarely rupture soon after development. Late rupture, when the true

aneurysm has become stabilized by the formation of dense fibrous tissue in its wall, almost never occurs. Mortality in patients with a left ventricular aneurysm is up to six times higher than in patients without aneurysms, even when compared with that in patients with comparable left ventricular ejection fraction.[570] Death in these patients is often sudden and presumably related to the high incidence of ventricular tachyarrhythmias that occur with aneurysms.[510] The presence of persistent ST segment elevation in an ECG area of infarction, classically thought to suggest aneurysm formation, actually indicates a large infarct but does not necessarily imply an aneurysm. The diagnosis of aneurysm is best made noninvasively by an echocardiographic study by radionuclide ventriculography or at the time of cardiac catheterization by left ventriculography. With the loss of shortening from the area of the aneurysm, the remainder of the ventricle must be hyperkinetic in order to compensate. With relatively large aneurysms, complete compensation is impossible. The stroke volume falls or, if maintained, it is at the expense of an increase in end-diastolic volume, which in turn leads to increased wall

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tension and myocardial oxygen demand. Heart failure may ensue, and angina may appear or worsen. TREATMENT.

Aggressive management of AMI, including coronary thrombolysis, may diminish the incidence of ventricular aneurysms. Surgical aneurysmectomy (Fig. 35-52) generally is successful only if there is relative preservation of contractile performance in the nonaneurysmal portion of the left ventricle. In such circumstances, when the operation is performed for worsening heart failure or angina, operative mortality is relatively low and clinical improvement can be expected.[571] Left Ventricular Thrombus and Arterial Embolism

Mural thrombi occur in approximately 20 percent of patients with AMI who do not receive anticoagulant therapy; the incidence rises to 40 percent with anterior infarction and to as high as 60 percent in patients with large anterior infarcts that involve the apex of the left ventricle.[346] The most convenient and accurate method for diagnosing left ventricular thrombosis is two-dimensional echocardiography (see Chap. 7) . It is hypothesized that endocardial inflammation during the acute phase of infarction provides a thrombogenic surface for clots to form in the left ventricle. With extensive transmural infarction of the septum, however, mural thrombi may overlie infarcted myocardium in both ventricles. Prospective studies have suggested that patients who develop a mural thrombus early (within 48 to 72 hours of infarction) have an extremely poor early prognosis,[494] with a high mortality from the complications of a large infarction

(shock, reinfarction, rupture, and ventricular tachyarrhythmia), rather than emboli from the left ventricular thrombus. Although a mural thrombus adheres to the endocardium overlying the infarcted myocardium, superficial portions of it can become detached and produce systemic arterial emboli. Although estimates vary based on patient selection, about 10 percent of mural thrombi result in systemic embolization.[346] Echocardiographically detectable features that suggest a given thrombus is more likely to embolize include increased mobility and protrusion into the ventricular chamber, visualization in multiple views, and contiguous zones of akinesis and hyperkinesis. MANAGEMENT.

Over the past decade six randomized trials involving only 560 patients tested whether anticoagulant therapy reduced the incidence of left ventricular thrombus formation. [572] [573] Collectively, these smaller trials showed that anticoagulation (intravenous heparin or high-dose subcutaneous heparin) reduced the development of thrombi by 50 percent, but, because of the low event rate, it was not possible to demonstrate a reduction in the incidence of systemic embolism. Additional data from thrombolytic trials suggest that thrombolysis reduces the rate of thrombus formation and the character of the thrombi so that they are less protuberant. Of note, however, the data from thrombolytic trials are difficult to interpret because of the confounding effect of antithrombotic therapy with heparin.[573] Recommendations for anticoagulation vary considerably,[574] [575]

Figure 35-52 Surgical repair of ventricular aneurysm. In this case the aneurysm is located at the apex (A). The aneurysmal segment is resected, and felt pledget strips are used to reinforce interrupted suture closure of the apex (B). Completed repair partially restores apical geometry (C). (Courtesy of Dr. David Adams, Division of Cardiac Surgery, Brigham and Women's Hospital.)

and thrombolysis has precipitated fatal embolization. Nevertheless, anticoagulation for 3 to 6 months with warfarin is advocated for many patients with demonstrable mural thrombi. Based on the available data, it is our practice to recommend anticoagulation (intravenous heparin to elevate the activated partial thromboplastin time one and one-half to two times control, followed by a minimum of 3 to 6 months of warfarin) in the following clinical situations: (1) an embolic event has already occurred or (2) the patient has a large anterior infarction whether or not a thrombus is visualized echocardiographically. We are also inclined to follow the same anticoagulation practice in patients with infarctions other than those in the anterior distribution if a thrombus or large wall motion abnormality is detected. Aspirin, although probably not capable of affecting thrombus size in most patients, may prevent further platelet deposition on existing thrombi and also is protective against recurrent ischemic events. It should be prescribed in conjunction with warfarin to patients who are candidates for long-term anticoagulation therapy based on the

indications discussed earlier.




Convalescence, Discharge, and Post-Myocardial Infarction Care Prolonged hospitalization and enforced bed rest for any illness may lead to complications (particularly in elderly patients) such as constipation, decubitus ulcers, excessive resorption of bone with formation of renal calculi, atelectasis, thrombophlebitis, pulmonary emboli, urinary retention, mild anemia due to repetitive blood sampling for diagnostic tests, impaired oral intake of fluids, bleeding from the gastrointestinal tract due to stress ulcers, and deconditioning of cardiovascular reflex responses to postural changes. Because of the precarious status of the heart recovering from AMI, avoidance of such complications is of primary importance. For example, constipation may lead to straining,

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transitory reduction of venous return and diminution of cardiac output, impaired coronary perfusion, and ventricular arrhythmias, occasionally culminating in ventricular fibrillation. Early use of a bedside commode, stool softeners, and a bed-chair regimen appear to be useful in avoiding many of the difficulties encountered previously among patients with AMI confined to bed for several weeks. Although concern has been raised from studies in animals that early physical activity might unfavorably influence ventricular remodeling, perhaps by causing infarct extension, no evidence indicates that this concern is relevant to patients, and early mobilization appears to be warranted in most stable AMI patients. For the patient with an uncomplicated AMI, washing and personal care may begin within the first 12 to 24 hours. If the convalescence continues uneventfully, limited ambulation within the room can be begun on the second or third day (see Table 35-12) (Table Not Available) . Once

early ambulatory activities are begun, advancement in the activity should depend on the patient's condition. A shower may be allowed some time after the third day. TIMING OF HOSPITAL DISCHARGE.

The time of discharge from the hospital is variable. Patients who have undergone aggressive reperfusion protocols and have no significant ventricular arrhythmias, recurrent ischemia, or congestive heart failure have been safely discharged in less than 5 days. More commonly, discharge occurs 5 or 6 days after admission for patients who experience no complications, who can be followed readily at home, and whose family setting is conducive to convalescence. Most complications that would preclude early discharge occur within the first day or two of admission; therefore, patients suitable for early discharge can be identified early during the hospitalization. [410] [576] However, as noted previously, even if no complications have occurred by hospital day 3, many clinicians find it useful to keep the patient hospitalized for another 1 to 2 days to finalize the discharge prescriptions, provide additional patient education, and confirm the adequacy of the patient's support systems at home.[411] For patients who have experienced a complication, discharge is deferred until their condition has been stable for several days and it is clear that they are responding appropriately to necessary medications such as antiarrhythmic agents, vasodilators, or positive inotropic agents or that they have undergone the appropriate work-up for recurrent ischemia. COUNSELING.

Before discharge from the hospital, all patients should receive detailed instruction concerning physical activity. Initially, this should consist of ambulation at home but avoidance of isometric exercise such as lifting; several rest periods should be taken daily. In addition, the patient should be given fresh nitroglycerin tablets and instructed in their use and should receive careful instructions about the use of any other medications prescribed. As convalescence progresses, graded resumption of activity should be encouraged. Many approaches have been used, ranging from formal rigid guidelines to general advice advocating moderation and avoidance of any activity that evokes symptoms. Sexual counseling is often overlooked during recovery from MI and should also be included as part of the educational process. Such counseling should begin early after AMI and should include the recommendation that sexual activity be resumed after successful completion of either early submaximal or later symptom-limited exercise stress testing.[52] Some evidence indicates that behavioral alteration is possible after recovery from MI and that this may improve prognosis. A cardiac rehabilitation program with supervised physical exercise and an educational component has been recommended for most MI patients after discharge. Although the overall clinical benefit of such programs continues to be debated, there is little question that most people derive considerable knowledge and psychological security from such interventions and they continue to be endorsed by experienced clinicians.[52] Meta-analyses of randomized trials of medically supervised rehabilitation programs versus usual care that were conducted in an era before the

widespread use of beta-adrenoceptor blockers and thrombolytics have shown a reduction in cardiovascular death but no change in the incidence of nonfatal reinfarction.[577] Given the relationship between a history of depression and risk for AMI,[578] interest has arisen in psychosocial intervention programs in the convalescent phase of AMI.[579] [580] Psychosocial intervention programs alone have not been proven to be helpful, but they are a useful adjunct to standard cardiac rehabilitation programs after AMI.[581] [581A] More detailed information on physical and psychological aspects of rehabilitation of patients convalescing from AMI is discussed in Chapter 38 . RISK STRATIFICATION The process of risk stratification after AMI occurs in several stages: initial presentation, in-hospital course (CCU, intermediate care unit), and at the time of hospital discharge. The tools used to form an integrated assessment of the patient consist of baseline demographic information,[268A] serial ECGs and serum cardiac marker measurements, hemodynamic monitoring data, a variety of noninvasive tests, and, if performed, the findings at cardiac catheterization.[414] [582] INITIAL PRESENTATION.

Certain demographic and historical factors are associated with a poor prognosis in patients with AMI, including female gender, age older than 70 years, a history of diabetes mellitus, prior angina pectoris, and previous MI.[414] Diabetes mellitus, in particular, appears to confer a threefold to fourfold increase in risk. Whether this is due to accelerated atherosclerosis or some other characteristic induced by the diabetic state (such as a larger infarct size) is unclear. (Surviving diabetic patients also experience a more complicated post-MI course, including a greater incidence of postinfarction angina, infarct extension, and heart failure.)[52] In addition to playing a central role in the decision pathway for management of patients with AMI based on the presence or absence of ST segment elevation, the 12-lead ECG carries important prognostic information. Mortality is greater in patients experiencing anterior wall MI than after inferior MI, even when corrected for infarct size. [52] Patients with right ventricular infarction complicating inferior infarction, as suggested by ST segment elevation in V4 R, have a greater mortality rate than patients sustaining an inferior infarction without right ventricular involvement.[63] Patients with multiple leads showing ST segment elevation and those with a high sum of ST segment elevation have an increased mortality, especially if their infarct is anterior.[582] Patients whose ECG demonstrates persistent advanced heart block (e.g., Mobitz type II, second-degree, or third-degree AV block) or new intraventricular conduction abnormalities (bifascicular or trifascicular) in the course of an AMI have a worse prognosis than do patients without these abnormalities. The influence of high degrees of heart block is particularly important in patients with right ventricular infarction, for such patients have a markedly increased mortality. Other ECG findings that augur poorly are persistent horizontal or downsloping ST segment depression, Q waves in multiple leads, evidence of right ventricular infarction accompanying inferior infarction,[63] ST segment depressions in anterior leads in patients with inferior infarction,[583] and atrial arrhythmias (especially

atrial fibrillation). Data from the thrombolytic era have confirmed that important determinants of short- and long-term prognosis appear

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to be similar in patients who have received thrombolytic therapy compared with those who have not.[414] A constellation of clinical factors can be detected at the time of presentation to help select patients at particularly high risk of death in the first 4 to 6 weeks after AMI (see Fig. 35-27, p. 1151 ). HOSPITAL COURSE.

Soon after CCUs were instituted, it became apparent that left ventricular function is an important early determinant of survival. Hospital mortality from AMI depends directly on the severity of left ventricular dysfunction.[414] Risk stratification by means of clinical findings, estimation of infarct size, and, in appropriate patients, invasive hemodynamic monitoring in the CCU (see p. 1174 ) provides an assessment of the likelihood of a complicated hospital course[584] and may also identify important abnormalities such as hemodynamically significant mitral regurgitation that convey an adverse long-term prognosis. Recurrent ischemia and infarction after AMI, either in the same location as the index infarction or "at a distance," influence prognosis adversely. Poor prognosis comes from the loss of viable myocardium, with the resulting larger area of infarction creating a greater compromise in ventricular function. Postinfarction angina generally connotes a less favorable prognosis because it indicates the presence of jeopardized myocardium.[582] In the current era of aggressive revascularization, early postinfarction angina often leads to early interventions that tend to improve outcome, diminishing the long-term impact and significance of angina early after AMI.[585] Assessment at Hospital Discharge

Both short-term and long-term survival after AMI depend on three factors: (1) resting left ventricular function, (2) residual potentially ischemic myocardium, and (3) susceptibility to serious ventricular arrhythmias. The most important of these factors is the state of left ventricular function[586] (see Fig. 35-41) . The second most important factor is how the severity and extent of the obstructive lesions in the coronary vascular bed perfusing residual viable myocardium impacts the risk of recurrent infarction, additional myocardial damage, and serious ventricular arrhythmias.[582] Thus, survival relates to the quantity of myocardium that has become necrotic and the quantity at risk of becoming necrotic. At one extreme, the prognosis is best for the patient with normal intrinsic coronary vessels whose completed infarction constitutes a small fraction (5 percent) of the left ventricle as a consequence of a coronary embolus and who has no jeopardized myocardium. At the other extreme is the patient with a massive infarct with left ventricular failure whose

residual viable myocardium is perfused by markedly obstructed vessels. Obviously, progression of atherosclerosis or lowering of perfusion pressure in these vessels impairs the function and viability of the residual myocardium on which left ventricular function depends. The situation may not be hopeless even in such a patient, however, because revascularization may reduce the threat to the jeopardized myocardium. The third risk factor, the susceptibility to serious arrhythmias, is reflected in ventricular ectopic activity and other indicators of electrical instability such as reduced heart rate variability or baroreflex sensitivity and an abnormal signal-averaged ECG. All of these identify patients at increased risk of death. In addition, as noted earlier, patients with an occluded infarct-related artery late (e.g., 1 to 2 weeks) after AMI have a higher long-term mortality. [74] Persistent occlusion of the culprit artery is associated with an increased incidence of abnormal late potentials on the ECG[587] and appears to have an adverse prognostic effect independent of the level of ventricular function (Fig. 35-53) .[224] ASSESSMENT OF LEFT VENTRICULAR FUNCTION.

Left ventricular ejection fraction may be the most easily assessed

Figure 35-53 Impact of patency of the infarct-related artery on long-term mortality. In patients with a patent infarct-related coronary artery at 2 weeks after infarction, the long-term mortality is significantly reduced compared with that of patients with an occluded infarct-related vessel. The beneficial effect of infarct-related artery patency was independent of the number of obstructed coronary arteries or of left ventricular function. (From Lamas GA, Flaker GC, Mitchell G, et al: Effect of infarct artery patency on prognosis after acute myocardial infarction. Circulation 92:1101, 1995. Copyright 1995, American Heart Association.)

measurement of left ventricular function, and this measurement is extremely useful for risk stratification (see Fig. 35-41) . However, imaging of the left ventricle at rest may not distinguish adequately between infarcted, irreversibly damaged myocardium and stunned or hibernating myocardium. To circumvent this difficulty, a variety of techniques has been investigated to assess the extent of residual viable myocardium, including exercise and pharmacological stress echocardiography, stress radionuclide ventricular angiography, perfusion imaging in conjunction with pharmacological stress, and positron emission tomography (see Chap. 13) . All of these techniques can be performed safely in postinfarction patients. Because no study has clearly shown one imaging modality to be superior to others, clinicians should be guided in their selection of ventricular imaging technique by the availability and level of expertise with a given modality at their local institution.[414] In patients with low left ventricular ejection fraction, the measurement of exercise capacity is useful for further identifying those patients at particularly high risk and also for establishing safe exercise limits after discharge.[588] Patients with a good exercise capacity despite a reduced ejection fraction have a better long-term outcome than those who cannot perform more than modest exercise.

ASSESSMENT OF MYOCARDIAL ISCHEMIA.

Because of the potent adverse consequences of recurrent MI after AMI,[562] it is important to assess a patient's risk for future ischemia and infarction. Given the increasing array of pharmacological, interventional catheterization, and surgical options available to modify the likelihood of developing recurrent episodes of myocardial ischemia, most clinicians find it helpful to identify patients at risk for provocable myocardial ischemia before discharge. A predischarge evaluation for ischemia allows clinicians to select patients who might benefit from catheterization and revascularization after

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AMI and to assess the adequacy of medical therapy for those patients who are suitable for a more conservative management strategy. Although it may be argued that coronary arteriography for risk stratification after AMI has the advantage of permitting simultaneous identification and treatment (angioplasty) of coronary obstructions, important limitations of this strategy should be noted.[589] As discussed previously (see p. 1116 ), the coronary artery plaques that are most likely to rupture (and produce future events) are those that are lipid laden and have a thin fibrous cap. These plaques cannot be adequately identified with arteriography because they may be associated with less than a 75 percent stenosis of the coronary artery lumen at the time of angiography after an index AMI. Furthermore, coronary arteriography does not provide information on the functional significance of coronary lesions. Previous studies comparing routine use of coronary angiography versus selected use only in patients with spontaneous or provoked ischemia showed no advantage to the routine catheterization strategy with respect to 6-week mortality and reinfarction.[52] [589] An exercise test also offers the clinician an opportunity to formulate a more precise exercise prescription and is helpful in boosting patients' confidence in their ability to conduct their daily activities after discharge. Patients who are unable to exercise may be evaluated using a pharmacological stress protocol such as an infusion of dobutamine or dipyridamole with echocardiography or perfusion imaging. Treadmill exercise testing after AMI has traditionally used a submaximal protocol that requires the patient to exercise until symptoms of angina appear, ECG evidence of ischemia is seen, or a target workload (approximately 5 METS) has been reached (see Chap. 6) . It has been proposed that symptom-limited exercise tests may be safely performed before discharge in patients with an uncomplicated postinfarction course in hospital.[590] Variables derived from exercise tests after AMI that have been evaluated for their ability to predict the occurrence of death or recurrent nonfatal infarction include the development and magnitude of ST segment depression, the development of angina, exercise capacity, and the systolic blood pressure response during exercise.[586] Myocardial perfusion with

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Tc sestamibi during exercise or pharmacological (e.g.,

dipyridamole, adenosine, or dobutamine) stress increases the sensitivity for detection of patients at risk for death or recurrent infarction (see Chap. 9) . Similar results have been reported for dipyridamole stress echocardiography. Although perfusion imaging may be helpful for risk stratification in patients with uninterpretable ECGs or the inability to exercise, the regular use of these more expensive procedures in patients with interpretable ECGs and the ability to exercise has been questioned.[414] [591] An increasing number of patients are treated with thrombolysis, angioplasty, or surgery and have a more favorable natural history than that reported in patients who have not undergone aggressive reperfusion and revascularization for AMI.[591] Until clinical trials relating the findings of a postinfarction perfusion imaging test to long-term outcome in cohorts of patients receiving contemporary therapy for AMI are available, we do not advocate the routine use of perfusion imaging for risk stratification after AMI. At present its use should be restricted to patients who are candidates for further revascularization procedures and have physical limitations preventing them from exercising to an adequate workload or those with conduction abnormalities, significant resting ST segment and T wave abnormalities, or repolarization abnormalities on the ECG due to ventricular hypertrophy or digitalis therapy.[592] We have also used perfusion imaging studies when a conventional exercise ECG is mildly abnormal and there is uncertainty about the significance of the finding or uncertainty about the potential culprit vessel or vessels. In such cases perfusion imaging may help guide decisions after catheterization if multiple coronary vessels have important stenoses. The Danish Trial in Acute MI (DANAMI) investigators reported that when patients with provokable ischemia after infarction were randomized to catheterization and revascularization versus conservative medical therapy, they experienced a lower requirement for antianginal medications, less unstable angina, and fewer nonfatal infarctions.[585] ASSESSMENT FOR ELECTRICAL INSTABILITY.

After AMI, patients are at greatest risk for the development of sudden cardiac death due to malignant ventricular arrhythmias over the course of the first 1 to 2 years. [593] [594] Several techniques have been devised to stratify patients into those who are at increased risk of sudden death after AMI: measurement of QT interval dispersion (variability of QT intervals between ECG leads), ambulatory ECG recordings for detection of ventricular arrhythmias (Holter monitoring; see Chap. 22) , invasive electrophysiological testing, recording a signal-averaged ECG (a measure of delayed, fragmented conduction in the infarct zone), and measuring heart rate variability (beat-to-beat variability in RR intervals) or baroreflex sensitivity (slope of a line relating beat-to-beat change in sinus rate in response to alteration of blood pressure).[510] Given the risks associated with routine use of type I antiarrhythmics prescribed to suppress VPBs that are detected on ambulatory ECG recordings, we do not recommend routine Holter monitoring to determine which patients should receive antiarrhythmic therapy after AMI. The value of empirical administration of the type III antiarrhythmic drug amiodarone after infarction is discussed on p. 1204 . A variety of noninvasive tests have been used to assess patients for electrical instability

after AMI.[510] The presence of a filtered QRS complex duration greater than 120 milliseconds and abnormal late potentials recorded on a signal-averaged ECG after AMI have a positive predictive value between 8 and 27 percent and a negative predictive value of over 95 percent for serious arrhythmic events. When viewed in isolation, the signal-averaged ECG suffers from a high false-positive rate, which may be improved by combining it with other variables, such as left ventricular ejection fraction. Electrophysiological testing also appears to suffer from a high false-positive rate and has the additional disadvantage of being invasive. The ability of electrophysiological testing to identify patients at risk for arrhythmic events after AMI appears to be improved if it is performed in patients who also have an ejection fraction less than 40 percent, an abnormal signal-averaged ECG, and VPBs. Depressed heart rate variability (HRV) is an independent predictor of mortality and arrhythmic complications after AMI, especially if cutoffs of standard deviation of the average interval between normal beats below 50 milliseconds and HRV triangular index (a geometric method for integrating the distribution of intervals between normal beats) less than 15 are used. A depressed baroreflex sensitivity value (3.0 msec/mm Hg) is associated with about a threefold increase in the risk of mortality.[595] Despite the increased risk of arrhythmic events after AMI in patients who are found to have abnormal results on one or more of the noninvasive tests described earlier, several points should be emphasized. The low positive predictive value ( 10 vs. placebo PVCs/hr or any run 3 beats VT > 100 beats/min

1) Amiodarone did not affect total cardiac mortality but reduced SD or recurrent VF (p < 0.05)

2) There was concordance between PVC suppression and reduced SD and recurrent VF.

3) Early discontinuation of amiodarone for side effects was common (42.3%). EMIAT

To assess the 1486 efficacy of prophylactic antiarrhythmic therapy in patients with asymptomatic complex ventricular ectopy.

5-21 d post-MI

Amiodarone vs. placebo

1) No difference in overall mortality.

LVEF 40% 18-75 yr

2) Reduction in arrhythmic death in the amiodarone group (p=0.052).

24-hr ambulatory monitoring before entry but not used as part of inclusion criteria 3) Drug discontinuation due to side effects or intolerance was high in the amiodarone group (45% by 2 yr).

PVC=premature ventricular contraction; LVEF=left ventricular ejection fraction; VT=ventricular tachyca VF=ventricular fibrillation; SD=sudden death.

Modified from Tracy CM: Current review of arrhythmia trials. Cardiology Special Edition 5(1):17-23, 19

1206

Figure 35-55 Effect of type III antiarrhythmic drugs after acute myocardial infarction. The results of the

SWORD, EMIAT, and CAMIAT trials are shown with total mortality plotted in the top panels and arrhythmic deaths plotted in the bottom panels. The SWORD trial was stopped prematurely owing to increased total mortality in patients receiving d-sotalol compared with placebo; arrhythmic mortality was also significantly increased. Both the EMIAT and CAMIAT trials showed no significant reduction in total mortality with amiodarone, but there was a reduction in arrhythmic deaths in patients receiving amiodarone. However, the rate of discontinuation due to intolerable side effects was high with amiodarone in both the EMIAT and CAMIAT trials. (Adapted from Waldo AL, Camm AJ, deRuyter H, et al: Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet 348:7-12, 1996; Julian DG, Camm AJ, Frangin G, et al: Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. European Myocardial Infarct Amiodarone Trial Investigators. Lancet 349:667-674, 1997; and Cairns JA, Connolly SJ, Roberts R, Gent M: Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Lancet 349:675-682, 1997.)

1207

events and a trend toward an early (year 1) increase in coronary events.[647] At present, we recommend continuing hormone replacement therapy in postmenopausal women after AMI but not starting it in women who have not been on hormone replacement previously until more data are available and longer-term follow-up in HERS has been reported.




REFERENCES CHANGING PATTERNS OF CARE Chockalignam A, Balaguer-Vintro I: Impending Global Pandemic of Cardiovascular Diseases; Challenges and Opportunities for the Prevention and Control of Cardiovascular Diseases in Developing Countries and Economies in Transition. Barcelona, Prous Science, 1999. 1.

American Heart Association: 1999 Heart and Stroke Statistical Update. Dallas, American Heart Association, 1998. 2.

Bayes de Luna A: International cooperation in world cardiology: The role of the World Heart Federation. Circulation 99:986-989, 1999. 3.

Tunstall-Pedoe H, Mahonen M, Tolonen H, et al, for the WHO MONICA (monitoring trends and determinants in cardiovascular disease) Project: Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10-year results from 37 WHO MONICA Project populations. Lancet 353:1547-1557, 1999. 4.

Braunwald E, Antman EM, Beasley JW, et al: ACC/AHA guidelines for the management of patients with unstable angina: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol 36:970-1062, 2000. 5.

Guidry UC, Evans JC, Larson MG, et al: Temporal trends in event rates after Q-wave myocardial infarction: The Framingham Heart Study. Circulation 100:2054-2059, 1999. 6.

Goldberg RJ, Yarzebski J, Lessard D, Gore JM: A two-decades (1975 to 1995) long experience in the incidence, in-hospital and long-term case-fatality rates of acute myocardial infarction: A community-wide 7.

perspective. J Am Coll Cardiol 33:1533-1539, 1999. Braunwald E: Evolution of the management of acute myocardial infarction: A 20th century saga. Lancet 352:1771-1774, 1998. 8.

9.

Braunwald E, Antman EM: Evidence-based coronary care. Ann Intern Med 126:551-553, 1997.

Iezzoni LI: How much are we willing to pay for information about quality of care? Ann Intern Med 126:391-393, 1997. 10.

Pine M, Norusis M, Jones B, Rosenthal GE: Predictions of hospital mortality rates: A comparison of data sources. Ann Intern Med 126:347-354, 1997. 11.

St Peter RF, Reed MC, Kemper P, Blumenthal D: Changes in the scope of care provided by primary care physicians. N Engl J Med 341:1980-1985, 1999. 12.

Antman E, Lau J, Kupelnick B, et al: A comparison of results of meta-analyses of randomized control trials and recommendations of clinical experts. JAMA 268:240-248, 1992. 13.

Antiplatelet Trialists' Collaboration: Collaborative overview of randomised trials of antiplatelet therapy: I. Prevention of death myocardial infarction and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 308:81-106, 1994. 14.

Fibrinolytic Therapy Trialists (FTT) Collaborative Group: Indications for fibrinolytic therapy in suspected acute myocardial infarction: Collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet 343:311-322, 1994. 15.

Every NR, Frederick PD, Robinson M, et al: A comparison of the National Registry of Myocardial Infarction 2 with the Cooperative Cardiovascular Project. J Am Coll Cardiol 33:1886-1894, 1999. 16.

Hampton JR: The limits of evidence-based cardiovascular therapy. Cardiovasc Drugs Ther 12:487-491, 1998. 17.

Schmid CH, Lau J, McIntosh MW, Cappelleri JC: An empirical study of the effect of the control rate as a predictor of treatment efficacy in meta-analysis of clinical trials. Stat Med 17:1923-1942, 1998. 18.

The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 329:673-682, 1993. 19.

The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators: A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med 337:1118-1123, 1997. 20.

Neuhaus KL: InTime-2 results. Presented at the Scientific Sessions of the American College of Cardiology, New Orleans, March 9, 1999. 21.

Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators: Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: The ASSENT-2 double-blind randomised trial: Assessment of the Safety and Efficacy of a New Thrombolytic Investigators. Lancet 354:716-722, 1999. 22.

23.

Barakat K, Wilkinson P, Deaner A, et al: How should age affect management of acute myocardial

infarction? A prospective cohort study. Lancet 353:955-959, 1999. 23A. Thiemann

DR, Coresh J, Schulman SP, et al: Lack of benefit for intravenous thrombolysis in patients with myocardial infarction who are older than 75 years. Circulation 101:2239-46, 2000. 23B. Ayanian

JZ, Braunwald E: Thrombolytic therapy for patients with myocardial infarction who are older than 75 years. Do the risks outweigh the benefits? Circulation 101:2224-6, 2000. Chen J, Marciniak TA, Radford MJ, et al: Beta-blocker therapy for secondary prevention of myocardial infarction in elderly diabetic patients. Results from the National Cooperative Cardiovascular Project. J Am Coll Cardiol 34:1388-1394, 1999. 24.

European Secondary Prevention Study Group. Translation of clinical trials into practice: A European population-based study of the use of thrombolysis for acute myocardial infarction. Lancet 347:1203-1207, 1996. 25.

Kizer JR, Cannon CP, McCabe CH, et al: Trends in the use of pharmacotherapies for acute myocardial infarction among physicians who design and/or implement randomized trials versus physicians in routine clinical practice: The MILIS-TIMI experience. Multicenter Investigation on Limitation of Infarct Size. Thrombolysis in Myocardial Infarction. Am Heart J 137:79-92, 1999. 26.

McCormick D, Gurwitz JH, Lessard D, et al: Use of aspirin, beta-blockers, and lipid-lowering medications before recurrent acute myocardial infarction: Missed opportunities for prevention? Arch Intern Med 159:561-567, 1999. 27.

Saketkhou BB, Conte FJ, Noris M, et al: Emergency department use of aspirin in patients with possible acute myocardial infarction. Ann Intern Med 127:126-129, 1997. 28.

Goldberg RJ, Gurwitz JH: Disseminating the results of clinical trials to community-based practitioners: Is anyone listening? Am Heart J 137:4-7, 1999. 29.

29A. Gan

SC, Beaver SK, Houck PM, et al: Treatment of acute myocardial infarction and 30-day mortality among women and men. N Engl J Med 343:8-15, 2000. O'Connor GT, Quinton HB, Traven ND, et al: Geographic variation in the treatment of acute myocardial infarction: The Cooperative Cardiovascular Project. JAMA 281:627-633, 1999. 30.

Jollis JG, DeLong ER, Peterson ED, et al: Outcome of acute myocardial infarction according to the specialty of the admitting physician. N Engl J Med 335:1880-1887, 1996. 31.

Frances CD, Go AS, Dauterman KW, et al: Outcome following acute myocardial infarction: Are differences among physician specialties the result of quality of care or case mix? Arch Intern Med 159:1429-1436, 1999. 32.

Chen J, Radford MJ, Wang Y, et al: Do "America's Best Hospitals" perform better for acute myocardial infarction? N Engl J Med 340:286-292, 1999. 33.

Thiemann DR, Coresh J, Oetgen WJ, Powe NR: The association between hospital volume and survival after acute myocardial infarction in elderly patients. N Engl J Med 340:1640-1648, 1999. 34.

Selby JV, Fireman BH, Lundstrom RJ, et al: Variation among hospitals in coronary-angiography practices and outcomes after myocardial infarction in a large health maintenance organization. N Engl J Med 335:1888-1896, 1996. 35.

35A. Canto

JG, Shlipak MG, Rogers WJ, et al: Prevalence, clinical characteristics, and mortality among patients with myocardial infarction presenting without chest pain. JAMA 283:3223-3229, 2000. Kravitz RL: Ethnic differences in use of cardiovascular procedures: New insights and new challenges. Ann Intern Med 130:231-233, 1999. 36.

Malacrida R, Genoni M, Maggioni AP, et al: A comparison of the early outcome of acute myocardial infarction in women and men. The Third International Study of Infarct Survival Collaborative Group. N Engl J Med 338:8-14, 1998. 37.

Vaccarino V, Parsons L, Every NR, et al: Sex-based differences in early mortality after myocardial infarction. National Registry of Myocardial Infarction 2 Participants. N Engl J Med 341:217-225, 1999. 38.

PATHOLOGY Phibbs B, Marcus F, Marriott HJC, et al: Q-wave versus non-Q-wave myocardial infarction: A meaningless distinction. J Am Coll Cardiol 33:576-582, 1999. 39.

Rothwell PM, Villagra R, Gibson R, et al: Evidence of a chronic systemic cause of instability of atherosclerotic plaques. Lancet 355:19-24, 2000. 40.

40A. Maseri

A: From syndromes to specific disease mechanisms. The search for the causes of myocardial infarction. Ital Heart J 1:253-257, 2000. Malek AM, Alper SL, Izumo S: Hemodynamic shear stress and its role in atherosclerosis. JAMA 282:2035-2042, 1999. 41.

Rosenberg RD, Aird WC: Vascular-bed-specific hemostasis and hypercoagulable states. N Engl J Med 340:1555-1564, 1999. 42.

42A. Davies

MJ: The pathophysiology of acute coronary syndromes. Heart 83:361-6, 2000.

42B. Dahlback 43.

B: Blood coagulation. Lancet 355:1627-32, 2000.

Lee RT, Libby P: The unstable atheroma. Arterioscler Thromb Vasc Biol 17:1859-1867, 1997.

Fuster V: 50th anniversary historical article: Acute coronary syndromes: The degree and morphology of coronary stenoses. J Am Coll Cardiol 34:1854-1856, 1999. 44.

1208

Davies MJ: Stability and instability: Two faces of coronary atherosclerosis. Circulation 94:2013-2020, 1996. 45.

Fuster V: Mechanisms of arterial thrombosis: Foundation for therapy. Am Heart J 135:S361-S366, 1998. 46.

Gawaz M, Neumann FJ, Schomig A: Evaluation of platelet membrane glycoproteins in coronary artery disease: Consequences for diagnosis and therapy. Circulation 99:E1-E11, 1999. 47.

48.

Ross R: Atherosclerosis--an inflammatory disease. N Engl J Med 340:115-126, 1999.

Ardissino D, Merlini PA, Ariens R, et al: Tissue-factor antigen and activity in human coronary atherosclerotic plaques. Lancet 349:769-771, 1997. 49.

Kloner RA, Leor J: Natural disaster plus wake-up time: A deadly combination of triggers. Am Heart J 137:779-781, 1999. 50.

Feng DL, Tofler GH: Diurnal physiologic processes and circadian variation of acute myocardial infarction. J Cardiovasc Risk 2:494-498, 1995. 51.

51A. Rentrop

KP: Thrombi in acute coronary syndromes: Revisited and revised. Circulation 101:1619-26,

2000. Ryan TJ, Antman EM, Brooks NH, et al: 1999 update: ACC/AHA Guidelines for the Management of Patients With Acute Myocardial Infarction: Executive Summary and Recommendations: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Circulation 100:1016-1030, 1999. 52.

52A. Fox

KA: Acute coronary syndromes: Presentation-clinical spectrum and management. Heart 84:93,

2000. Goodman SG, Langer A, Ross AM, et al: Non-Q-wave versus Q-wave myocardial infarction after thrombolytic therapy: Angiographic and prognostic insights from the global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries: I. Angiographic substudy. GUSTO-I Angiographic Investigators. Circulation 97:444-450, 1998. 53.

Zaacks SM, Liebson PR, Calvin JE, et al: Unstable angina and non-Q-wave myocardial infarction: Does the clinical diagnosis have therapeutic implications? J Am Coll Cardiol 33:107-118, 1999. 54.

Savonitto S, Ardissino D, Granger CB, et al: Prognostic value of the admission electrocardiogram in acute coronary syndromes. JAMA 281:707-713, 1999. 55.

Hathaway WR, Peterson ED, Wagner GS, et al: Prognostic significance of the initial electrocardiogram in patients with acute myocardial infarction. GUSTO-I Investigators. Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries. JAMA 279:387-391, 1998. 56.

Schoen FJ: The heart. In Cotran FS, Kumar V, Collins T (eds): Pathologic Basis of Disease. 6th ed. Philadelphia, WB Saunders, 1999, pp 543-599. 57.

Vargas SO, Sampson BA, Schoen FJ: Pathologic detection of early myocardial infarction: A critical review of the evolution and usefulness of modern techniques. Mod Pathol 12:635-645, 1999. 58.

Kloner RA, Ellis SG, Lange R, et al: Studies of experimental coronary artery reperfusion: Effects on infarct size, myocardial function, biochemistry, ultrastructure and microvascular damage. Circulation 68:15-18, 1983. 59.

Adams J III, Abendschein D, Jaffe A: Biochemical markers of myocardial injury. Is MB creatine kinase the choice for the 1990s? Circulation 88:750-763, 1993. 60.

DeWood MA, Spores J, Notske RN, et al: Prevalence of total coronary artery occlusion during the early hours of transmural myocardial infarction. N Engl J Med. 303:897-902, 1980. 61.

DeWood MA, Notske RN, Simpson CS, et al: Prevalence and significance of spontaneous thrombolysis in transmural myocardial infarction. Eur Heart J 6:33, 1985. 62.

63.

Kinch JW, Ryan TJ. Right ventricular infarction. N Engl J Med 330:1211-1217, 1994.

63A. Haji

SA, Movahed A: Right ventricular infarction-diagnosis and treatment. Clin Cardiol 23:473-482,

2000. Bowers TR, O'Neill WW, Grines C, et al: Effect of reperfusion on biventricular function and survival after right ventricular infarction. N Engl J Med 338:933-940, 1998. 64.

Hod H, Lew AS, Keltai M, et al: Early atrial fibrillation during evolving myocardial infarction: A consequence of impaired left atrial perfusion. Circulation 75:146-150, 1987. 65.

Kyriakidis M, Barbetseas J, Antonopoulos A, et al: Early atrial arrhythmias in acute myocardial infarction: Role of the sinus node artery. Chest 101:944-947, 1992. 66.

Fujita M, Nakae I, Kihara Y, et al: Determinants of collateral development in patients with acute myocardial infarction. Clin Cardiol 22:595-599, 1999. 67.

PATHOPHYSIOLOGY Swan HJC, Forrester JS, Diamond G, et al: Hemodynamic spectrum of myocardial infarction and cardiogenic shock. Circulation 45:1097, 1972. 68.

Forrester JS, Wyatt HL, Daluz PL, et al: Functional significance of regional ischemic contraction abnormalities. Circulation 54:64, 1976. 69.

Schuster EH, Bulkley BH: Ischemia at a distance after acute myocardial infarction: A cause of early postinfarction angina. Circulation 62:509-515, 1980. 70.

White HD, Norris RM, Brown MA, et al: Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 76:44-51, 1987. 71.

Pfeffer MA, Braunwald E: Ventricular remodeling after myocardial infarction: Experimental observations and clinical implications. Circulation 81:1161-1172, 1990. 72.

72A. Sutton

MG, Sharpe N: Left ventricular remodeling after myocardial infarction: Pathophysiology and therapy. Circulation 101:2981-2988, 2000. Braunwald E, Pfeffer MA: Ventricular enlargement and remodeling following acute myocardial infarction: Mechanisms and management. Am J Cardiol 68:1D-6D, 1991. 73.

Braunwald E, Kim CB: Late establishment of patency of the infarct-related artery. In Julian D, Braunwald E (eds): Acute Myocardial Infarction. London, WB Saunders, 1994, pp 147-162. 74.

Pfeffer MA, Lamas GA, Vaughan DE, et al: Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 319:80-86, 1988. 75.

Pfeffer JM, Pfeffer MA, Fletcher PJ, Braunwald E: Progressive ventricular remodeling in rat with myocardial infarction. Am J Physiol 260:H1406-H1414, 1991. 76.

Weisman HF, Bush DE, Mannisi JA, et al: Cellular mechanisms of myocardial infarct expansion. Circulation 78:186-201, 1988. 77.

Pfeffer MA: Left ventricular remodeling after acute myocardial infarction. Ann Rev Med 46:455-466, 1995. 78.

Weisman HF, Healy B: Myocardial infarct expansion, infarct extension, and reinfarction: pathophysiologic concepts. Prog Cardiovasc Dis 30:73-110, 1987. 79.

Schmermund A, Lerman LO, Ritman EL, Rumberger JA: Cardiac production of angiotensin II and its pharmacologic inhibition: Effects on the coronary circulation. Mayo Clin Proc 74:503-513, 1999. 80.

Gray BA, Hyde RW, Hodges M, Yu PN: Alterations in lung volume and pulmonary function in relation to hemodynamic changes in acute myocardial infarction. Circulation 59:551, 1979. 81.

81A. Capes

SE, Hunt D, Malmberg K, Gerstein HC: Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: A systemic overview. Lancet 355:773-8, 2000. Vetter NJ, Adams W, Strange RC, Oliver MF: Initial metabolic and hormonal response to acute myocardial infarction. Lancet 1:284, 1974. 82.

Ceremuzynski L: Hormonal and metabolic reactions evoked by acute myocardial infarction. Circ Res 48:767, 1981. 83.

84.

Taegtmeyer H: Metabolic support of the postischaemic heart. Lancet 345:1552-1555, 1995.

Li YH, Teng JK, Tsai WC, et al: Prognostic significance of elevated hemostatic markers in patients with acute myocardial infarction. J Am Coll Cardiol 33:1543-1548, 1999. 85.

Danesh J, Collins R, Appleby P, Peto R: Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: Meta-analyses of prospective studies. JAMA 279:1477-1482, 1998. 86.

Furman MI, Becker RC, Yarzebski J, et al: Effect of elevated leukocyte count on in-hospital mortality following acute myocardial infarction. Am J Cardiol 78:945-948, 1996. 87.

87A. Kyne

L, Hausdorff JM, Knight E, et al: Neutrophilia and congestive heart failure after acute myocardial infarction. Am Heart J 139:94-100, 2000. Braunwald E: Acute myocardial infarction--the value of being prepared. N Engl J Med 334:51-52, 1996. 88.

CLINICAL FEATURES Stewart RA, Robertson MC, Wilkins GT, et al: Association between activity at onset of symptoms and outcome of acute myocardial infarction. J Am Coll Cardiol 29:250-253, 1997. 89.

Giri S, Thompson PD, Kiernan FJ, et al: Clinical and angiographic characteristics of exertion-related acute myocardial infarction. JAMA 282:1731-1736, 1999. 90.

Gullette EC, Blumenthal JA, Babyak M, et al: Effects of mental stress on myocardial ischemia during daily life. JAMA 277:1521-1526, 1997. 91.

Hlatkly MA, Lam LC, Lee KL, et al: Job strain and the prevalence and outcome of coronary artery disease. Circulation 92:327-333, 1995. 92.

Lee TH, Marcantonio ER, Mangione CM, et al: Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 100:1043-1049, 1999. 93.

Poldermans D, Boersma E, Bax JJ, et al: The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. N Engl J Med 341:1789-1794, 1999. 94.

Maseri A, L'Abbate A, Baroldi G, et al: Coronary vasospasm as a possible cause of myocardial infarction. N Engl J Med 299:1271, 1978. 95.

Lange RL, Reid MS, Tresch DD, et al: Nonatheromatous ischemic heart disease following withdrawal from chronic industrial nitroglycerin exposure. Circulation 46:666, 1972. 96.

Muller JE, Abela GS, Nesto RW, Tofler GH: Triggers, acute risk factors and vulnerable plaques: The lexicon of a new frontier. J Am Coll Cardiol 23:809-813, 1994. 97.

Spencer FA, Goldberg RJ, Becker RC, Gore JM: Seasonal distribution of acute myocardial infarction in the second National Registry of Myocardial Infarction. J Am Coll Cardiol 31:1226-1233, 1998. 98.

1209

98A. Canto

JG, Every NR, Magid DJ, et al: The volume of primary angioplasty procedures and survival after acute myocardial infarction. National Registry of Myocardial Infarction 2 Investigators. N Engl J Med 342:1573-80, 2000. 98B. Sheifer

SE, Gersh BJ, Yanez ND 3rd, et al: Prevalence, predisposing factors, and prognosis of clinically unrecognized myocardial infarction in the elderly. J Am Coll Cardiol 35:119-26, 2000. Spodick DH: Pericardial complications of myocardial infarction. In Francis GS, Alpert JS (eds): Coronary Care. Boston, Little, Brown & Co, 1995, pp 333-341. 99.

Goyal RK. Changing focus on unexplained esophageal chest pain. Ann Intern Med 124:1008-1011, 1996. 100.

Balaban DH, Yamamoto Y, Liu J, et al: Sustained esophageal contraction: A marker of esophageal chest pain identified by intraluminal ultrasonography. Gastroenterology 116:29-37, 1999. 101.

102.

McGuire DK, Granger CB: Diabetes and ischemic heart disease. Am Heart J 138:366-375, 1999.

103.

Webb SW, Adgey AA, Pantridge JF: Autonomic disturbance at onset of acute myocardial infarction.

BMJ 818:89, 1982. Killip T, Kimball JT: Treatment of myocardial infarction in a coronary care unit: A two year experience with 250 patients. Am J Cardiol 20:457-464, 1967. 104.

Pedoe-Tunstall H, Kuulasmaa K, Amouyel P, et al: Myocardial infarction and coronary deaths in the World Health Organization MONICA Project. Circulation 90:583-612, 1994. 105.

Fox AC, Levin RI: Ruptured plaques and leaking cells: Cost-effectiveness in the diagnosis of acute coronary syndromes. Ann Intern Med 131:968-970, 1999. 106.

Ravkilde J, Horder M, Gerhardt W, et al: Diagnostic performance and prognostic value of serum troponin T in suspected acute myocardial infarction. Scand J Clin Lab Invest 53:677-685, 1993. 107.

Ellis AK: Serum protein measurements and the diagnosis of acute myocardial infarction. Circulation 83:1107-1109, 1991. 108.

Mair J, Dienstl F, Puschendorf B: Cardiac troponin T in the diagnosis of myocardial injury. Crit Rev Clin Lab Sci 29:31-57, 1992. 109.

Puleo PR, Meyer D, Wathen C, et al: Use of a rapid assay of subforms of creatine kinase MB to diagnose or rule out acute myocardial infarction. N Engl J Med 331:561-566, 1994. 110.

Antman EM, Grudzien C, Sacks DB: Evaluation of a rapid bedside assay for detection of serum cardiac troponin T. JAMA 273:1279-1282, 1995. 111.

Roberts R: Enzymatic estimation of infarct size: Thrombolysis induced its demise: Will it now rekindle its renaissance? Circulation 81:707-710, 1990. 112.

Adams JE, Bodor GS, Davila-Roman VG, et al: Cardiac troponin I: A marker with high specificity for cardiac injury. Circulation 88:101-106, 1993. 113.

Apple FS: Tissue specificity of cardiac troponin I, cardiac troponin T and creatine kinase-MB. Clin Chim Acta 284:151-159, 1999. 114.

Christenson RH, Vaidya H, Landt Y, et al: Standardization of creatine kinase-MB (CK-MB) mass assays: The use of recombinant CK-MB as a reference material. Clin Chem 45:1414-1423, 1999. 115.

Ohman EM, Tardiff BE: Periprocedural cardiac marker elevation after percutaneous coronary artery revascularization: Importance and implications. JAMA 277:495-497, 1997. 116.

Wu AH, Apple FS, Gibler WB, et al: National Academy of Clinical Biochemistry Standards of Laboratory Practice: Recommendations for the use of cardiac markers in coronary artery diseases. Clin Chem 45:1104-1121, 1999. 117.

Roberts R, Kleiman N: Earlier diagnosis and treatment of acute myocardial infarction necessitates the need for a "new diagnostic mind-set." Circulation 89:872-881, 1994. 118.

Zimmerman J, Fromm R, Meyer D, et al: Diagnostic marker cooperative study for the diagnosis of myocardial infarction. Circulation 99:1671-1677, 1999. 119.

120.

Apple FS: Creatine kinase isoforms and myoglobin: Early detection of myocardial infarction and

reperfusion. Coron Artery Dis 10:75-79, 1999. de Lemos JA, Antman EM, Schroder R, et al: Very early risk stratification after thrombolytic therapy using a bedside myoglobin assay and the 12-lead ECG. Am Heart J, in press. 121.

122.

Hamm CW: New serum markers for acute myocardial infarction. N Engl J Med 331:607-608, 1994.

The Joint European Society of Cardiology/American College of Cardiology Committee: Myocardial infarction redefined--A consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. J Am Coll Cardiol 36:959-969, 2000. 123.

Jaffe AS, Ravkilde J, Roberts R, et al: It's time for a change to a troponin standard. Circulation 102:1216-1220, 2000. 123A.

Hamm CW, Goldmann BU, Heeschen C, et al: Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin I. N Engl J Med 337:1648-1653, 1997. 124.

Hamm CW, Braunwald E: A classification of unstable angina revisited. Circulation 102:118-122, 2000. 124A.

Katrukha AG, Bereznikova AV, Esakova TV, et al: Troponin I is released in bloodstream of patients with acute myocardial infarction not in free form but as complex. Clin Chem 43:1379-1385, 1997. 125.

Tanasijevic MJ, Cannon CP, Antman EM, et al: Myoglobin, creatine-kinase-MB and cardiac troponin-I 60-minute ratios predict infarctrelated artery patency after thrombolysis for acute myocardial infarction: Results from the Thrombolysis in Myocardial Infarction study (TIMI) 10B. J Am Coll Cardiol 34:739-747, 1999. 126.

Stewart JT, French JK, Theroux P, et al: Early noninvasive identification of failed reperfusion after intravenous thrombolytic therapy in acute myocardial infarction. J Am Coll Cardiol 31:1499-1505, 1998. 127.

Panteghini M, Apple FS, Christenson RH, et al: Use of biochemical markers in acute coronary syndromes. IFCC Scientific Division, Committee on Standardization of Markers of Cardiac Damage. International Federation of Clinical Chemistry. Clin Chem Lab Med 37:687-693, 1999. 128.

Heeschen C, Hamm CW, Goldmann B, et al: Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban. PRISM Study Investigators. Platelet Receptor Inhibition in Ischemic Syndrome Management. Lancet 354:1757-1762, 1999. 129.

Del Carlo CH, O'Connor CM: Cardiac troponins in congestive heart failure. Am Heart J 138:646-653, 1999. 130.

Polanczyk CA, Kuntz KM, Sacks DB, et al: Emergency department triage strategies for acute chest pain using creatine kinase-MB and troponin I assays: A cost-effectiveness analysis. Ann Intern Med 131:909-918, 1999. 131.

Adams JE, Sicard GA, Allen BT, et al: Diagnosis of perioperative myocardial infarction with measurement of cardiac troponin I. N Engl J Med 330:670-674, 1994. 132.

Ohman EM, Armstrong PW, White HD, et al: Risk stratification with a point-of-care cardiac troponin T test in acute myocardial infarction. Am J Cardiol 84:1281-1286, 1999. 133.

Szczeklik A, Musial J, Undas A, et al: Inhibition of thrombin generation by simvastatin and lack of additive effects of aspirin in patients with marked hypercholesterolemia. J Am Coll Cardiol 33:1286-1293, 1999. 134.

Dangas G, Badimon JJ, Smith DA, et al: Pravastatin therapy in hyperlipidemia: Effects on thrombus formation and the systemic hemostatic profile. J Am Coll Cardiol 33:1294-1304, 1999. 135.

Amsterdam EA: The rationale for early initiation of cholesterol lowering therapy after myocardial infarction. Prev Cardiol 2:38-41, 1999. 136.

137.

Bayes de Luna A: Clinical Electrocardiography: A Textbook. Armonk, NY, Futura Publishing, 1998.

Panju AA, Hemmelgarn BR, Guyatt GH, Simel DL: Is this patient having a myocardial infarction? JAMA 280:1256-1263, 1998. 138.

Engelen DJ, Gorgels AP, Cheriex EC, et al: Value of the electrocardiogram in localizing the occlusion site in the left anterior descending coronary artery in acute anterior myocardial infarction. J Am Coll Cardiol 34:389-395, 1999. 139.

Wellens HJ: The value of the right precordial leads of the electrocardiogram. N Engl J Med 340:381-383, 1999. 140.

Holmvang L, Clemmensen P, Wagner G, Grande P: Admission standard electrocardiogram for early risk stratification in patients with unstable coronary artery disease not eligible for acute revascularization therapy: A TRIM substudy. ThRombin Inhibition in Myocardial Infarction. Am Heart J 137:24-33, 1999. 141.

Sgarbossa EB, Pinski SL, Barbagelata A, et al: Electrocardiographic diagnosis of evolving acute myocardial infarction in the presence of left bundle-branch block. N Engl J Med 334:481-487, 1996. 142.

Cooksey JD, Dunn M, Massie E: Clinical Vectorcardiography and Electrocardiography. Chicago, Year Book Medical Publishers, 1977. 143.

Bosimini E, Giannuzzi P, Temporelli PL, et al: Electrocardiographic evolutionary changes and left ventricular remodeling after acute myocardial infarction: Results of the GISSI-3 Echo substudy. J Am Coll Cardiol 35:127-35, 2000. 143A.

Levine HD: Subendocardial infarction in retrospect: Pathologic, cardiographic, and ancillary features. Circulation 72:790, 1985. 144.

Cheitlin MD, Alpert JS, Armstrong WF, et al: ACC/AHA guidelines for the clinical application of echocardiography: Executive summary. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on Clinical Application of Echocardiography): Developed in collaboration with the American Society of Echocardiography. J Am Coll Cardiol 29:862-879, 1997. 145.

Reimold SC, Antman EM: Noninvasive cardiac imaging in chest pain syndromes. J Thromb Thrombol 6:239-252, 1998. 146.

Mirvis DM: Physiologic bases for anterior ST segment depression in patients with acute inferior wall myocardial infarction. Am Heart J 116:1308, 1988. 147.

Lopez-Sendon J, Coma-Canella I, Alcasena S, et al: Electrocardiographic findings in acute right ventricular infarction: Sensitivity and specificity of electrocardiographic alterations in right precordial leads 148.

V4R, V3R, V1, V2, and V3. J Am Coll Cardiol 6:1273-1279, 1985. Geft IL, Shah PK, Rodriguez L, et al: ST elevations in leads V1 to V5 may be caused by right coronary artery occlusion and acute right ventricular infarction. Am J Cardiol 53:991, 1984. 149.

Brattler A, Karliner JS, Higgins CB, et al: The initial chest x-ray in acute myocardial infarction: Prediction of early and late mortality and survival. Circulation 61:1004, 1980. 150.

151.

Schwaiger M, Melin J: Cardiological applications of nuclear medicine. Lancet 354:661-666, 1999.

Gotte MJ, van Rossum AC, Marcus JT, et al: Recognition of infarct localization by specific changes in intramural myocardial mechanics. Am Heart J 138:1038-1045, 1999. 152.

Konermann M, Sanner BM, Horstmann E, et al: Changes of the left ventricle after myocardial infarction--estimation with cine magnetic resonance imaging during the first six months. Clin Cardiol 20:201-212, 1997. 153.

1210

Hasche ET, Fernandes C, Freedman SB, Jeremy RW: Relation between ischemia time, infarct size, and left ventricular function in humans. Circulation 92:710-719, 1995. 154.

Gibbons RJ, Miller TD, Christian TF: Infarct size measured by single photon emission computed tomographic imaging with (99m)Tc-sestamibi: A measure of the efficacy of therapy in acute myocardial infarction. Circulation 101:101-108, 2000. 155.

Miller TD, Christian TF, Hopfenspirger MR, et al: Infarct size after acute myocardial infarction measured by quantitative tomographic 99m Tc sestamibi imaging predicts subsequent mortality. Circulation 92:334-341, 1995. 156.

MANAGEMENT National Heart Attack Alert Program Coordinating Committee--60 Minutes to Treatment Working Group. Emergency department: Rapid identification and treatment of patients with acute myocardial infarction. Ann Emerg Med 23:311-329, 1994. 157.

National Heart Attack Alert Program Coordinating Committee Working Group on Educational Strategies to Prevent Prehospital Delay in Patients at High Risk for Acute Myocardial Infarction. Educational strategies to prevent prehospital delay in patients at high risk for acute myocardial: A report by the National Heart Attack Alert Program. J Thromb Thrombol 6:000-000, 1998. 158.

Goff DC Jr, Feldman HA, McGovern PG, et al: Prehospital delay in patients hospitalized with heart attack symptoms in the United States: The REACT trial. Am Heart J 138:1046-1057, 1999. 159.

Cannon CP, Sayah AJ, Walls RM: Prehospital thrombolysis: An idea whose time has come. Clin Cardiol 22:IV10-IV19, 1999. 160.

Hand M, Brown C, Horan M, Simons-Morton D: The National Heart Attack Alert Program: Progress at 5 years in educating providers, patients and the public, and future directions. J Thromb Thrombol 6:9-17, 161.

1998. National Heart Attack Alert Program Coordinating Committee: Access to timely and optimal care of patients with acute coronary syndromes--community planning considerations: A report by the National Heart Attack Alert Program. J Thromb Thrombol 6:19-46, 1998. 162.

Lombardi G, Gallagher J, Gennis P: Outcome of out-of-hospital cardiac arrest in New York City. The Pre-Hospital Arrest Survival Evaluation (PHASE) Study. JAMA 271:678-683, 1994. 163.

Sandler DA: Paramedic direct admission of heart-attack patients to a coronary-care unit. Lancet 352:1198, 1998. 164.

National Heart Attack Alert Program: 9-1-1: Rapid Identification and Treatment of Acute Myocardial Infarction (NIH publication 94-3302). Department of Health and Human Services Public Health Service, National Institutes of Health. Bethesda, MD, National Heart, Lung, and Blood Institute, 1994, pp 1-16. 165.

Weaver WD, Cerqueira M, Hallstrom AP, et al: Prehospital-initiated vs. hospital-initiated thrombolytic therapy. The Myocardial Infarction Triage and Intervention Trial. JAMA 270:1211-1216, 1993. 166.

The European Myocardial Infarction Project Group: Prehospital thrombolytic therapy in patients with suspected acute myocardial infarction. N Engl J Med 329:383-389, 1993. 167.

Morrison LJ, Verbeek PR, McDonald AC, et al: Mortality and prehospital thrombolysis for acute myocardial infarction: A meta-analysis. JAMA 283:2686-92, 2000. 167A.

National Heart Attack Alert Program: Emergency Department: Rapid Identification and Treatment of Patients with Acute Myocardial Infarction (NIH publication 93-3278). Bethesda, MD, National Heart, Lung, and Blood Institute, 1993. 168.

National Heart Attack Alert Program: Emergency Medical Dispatching: Rapid Identification and Treatment of Acute Myocardial Infarction (NIH publication 94-3287). Bethesda, MD, National Heart, Lung, and Blood Institute, 1994, pp 1-14. 169.

National Heart Attack Alert Program: Staffing and Equipping Emergency Medical Services Systems: Rapid Identification and Treatment of Acute Myocardial Infarction (NIH publication 93-3304). Bethesda, MD, National Heart, Lung, and Blood Institute, 1994, pp 1-20. 170.

Canto JG, Rogers WJ, Bowlby LJ, et al: The prehospital electrocardiogram in acute myocardial infarction: Is its full potential being realized? National Registry of Myocardial Infarction 2 Investigators. J Am Coll Cardiol 29:498-505, 1997. 171.

Rawles JM: Quantification of the benefit of earlier thrombolytic therapy: Five-year results of the Grampian Region Early Anistreplase Trial (GREAT). J Am Coll Cardiol 30:1181-1186, 1997. 172.

The pre-hospital management of acute heart attacks. Recommendations of a Task Force of The European Society of Cardiology and The European Resuscitation Council. Eur Heart J 19:1140-1164, 1998. 173.

Selker HP, Zalenski RJ, Antman EM, et al: An evaluation of technologies for identifying acute cardiac ischemia in the emergency department: Executive summary of a National Heart Attack Alert Program Working Group Report. Ann Emerg Med 29:1-12, 1997. 174.

174A.

Lee TH, Goldman L: Evaluation of the patient with acute chest pain. N Engl J Med 342:1187, 2000.

Pope JH, Aufderheide TP, Ruthazer R, et al: Missed diagnoses of acute cardiac ischemia in the emergency department. N Engl J Med 342:1163-70, 2000. 174B.

Selker HP, Griffith JL, Beshansky JR, et al: Patient-specific predictions of outcomes in myocardial infarction for real-time emergency use: A thrombolytic predictive instrument. Ann Intern Med 127:538-556, 1997. 175.

Lambrew CT, Bowlby LJ, Rogers WJ, et al: Factors influencing the time to thrombolysis in acute myocardial infarction. Time to Thrombolysis Substudy of the National Registry of Myocardial Infarction-1. Arch Intern Med 157:2577-2582, 1997. 176.

Zalenski RJ, Selker HP, Cannon CP, et al: National Heart Attack Alert Program position paper: Chest pain centers and programs for the evaluation of acute cardiac ischemia. Ann Emerg Med 35:462-471, 2000. 177.

Shlipak MG, Lyons WL, Go AS, et al: Should the electrocardiogram be used to guide therapy for patients with left bundle-branch block and suspected myocardial infarction? JAMA 281:714-719, 1999. 178.

Cannon CP, Gibson CM, Lambrew CT, et al: Longer thrombolysis door-to-needle times are associated with increased mortality in acute myocardial infarction: An analysis of 85,589 patients in the National Registry of Myocardial Infarction 2 & 3. J Am Coll Cardiol 35(Suppl. A):376A, 2000. 179.

Cannon CP, Gibson CM, Lambrew CT, et al: Relationship of symptom-onset-to-balloon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 283:2941-7, 2000. 179A.

The TIMI IIIB Investigators: Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction: Results of the TIMI IIIB Trial. Circulation 89:1545-1556, 1994. 180.

Ornato JP: Chest pain emergency centers: Improving acute myocardial infarction care. Clin Cardiol 22:IV3-IV9, 1999. 181.

Farkouh ME, Smars PA, Reeder GS, et al: A clinical trial of a chest-pain observation unit for patients with unstable angina. Chest Pain Evaluation in the Emergency Room (CHEER) Investigators. N Engl J Med 339:1882-1888, 1998. 182.

Nichol G, Walls R, Goldman L, et al: A critical pathway for management of patients with acute chest pain who are at low risk for myocardial ischemia: Recommendations and potential impact. Ann Intern Med 127:996-1005, 1997. 183.

Roberts RR, Zalenski RJ, Mensah EK, et al: Costs of an emergency department-based accelerated diagnostic protocol vs hospitalization in patients with chest pain: A randomized controlled trial. JAMA 278:1670-1676, 1997. 184.

Antman EM: General hospital management. In Julian DG, Braunwald E (eds): Management of Acute Myocardial Infarction. London, WB Saunders, 1994, pp 29-70. 185.

Chamberlain D: E-blockers and calcium antagonists. In Julian D, Braunwald E (eds): Management of Acute Myocardial Infarction. London, WB Saunders, 1994, pp 193-221. 186.

187.

Hjalmarson A, Elmfeldt D, Herlitz J, et al: Effect on mortality of metoprolol in acute myocardial

infarction, a double-blind randomized trial. Lancet 2:823-827, 1981. Kirshenbaum JM, Kloner RA, Antman EM, Braunwald E: Use of an ultra short-acting beta-blocker in patients with acute myocardial ischemia. Circulation 72:873-880, 1985. 188.

Maroko P, Radvany P, Braunwald E, Hale S: Reduction of infarct size by oxygen inhalation following acute coronary occlusion. Circulation 52:360, 1975. 189.

190.

Califf RM, Bengtson JR: Cardiogenic shock. N Engl J Med 330:1724-1730, 1994.

191.

Pfeffer M: ACE inhibition in acute myocardial infarction. N Engl J Med 332:118-120, 1995.

Maroko PR, Braunwald E: Modification of myocardial infarct size after coronary occlusion. Ann Intern Med 79:720-733, 1973. 192.

Martin GV, Kennedy JW: Choice of thrombolytic agent. In Julian D, Braunwald E (eds): Management of Acute Myocardial Infarction. London, WB Saunders, 1994, pp 71-105. 193.

Taegtmeyer H: Energy metabolism of the heart: From basic concepts to clinical applications. Curr Probl Cardiol 19:57-116, 1994. 194.

Bolli R: Oxygen-derived free radicals and postischemic myocardial dysfunction ("stunned myocardium"). J Am Coll Cardiol 12:239-249, 1988. 195.

196.

Bolli R: Myocardial "stunning" in man. Circulation 86:1671-1691, 1992.

Przyklenk K, Kloner RA: Oxygen radical scavenging agents as adjuvant therapy with tissue plasminogen activator in a canine model of coronary thrombolysis. Cardiovasc Res 27:925-934, 1993. 197.

Tomai F, Crea F, Chiariello L, Gioffre PA: Ischemic preconditioning in humans: Models, mediators, and clinical relevance. Circulation 100:559-563, 1999. 198.

Przyklenk K, Bauer B, Ovize M, et al: Regional ischemic "preconditioning" protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 87:893-899, 1993. 199.

Lee SH, Wolf PL, Escudero R, et al: Early expression of angiogenesis factors in acute myocardial ischemia and infarction. N Engl J Med 342:626-33, 2000. 199A.

Latini R, Tognoni G, Maggioni AP, et al: Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: Systematic overview of individual data from 96,712 randomized patients. Angiotensin-converting Enzyme Inhibitor Myocardial Infarction Collaborative Group. J Am Coll Cardiol 35:1801-7, 2000. 199B.

Gersh BJ, Anderson JL: Thrombolysis and myocardial salvage: Results of clinical trials and the animal paradigm--paradoxic or predictable? Circulation 88:296-306, 1993. 200.

1211

201.

Ottani F, Galvani M, Ferrini D, Nicolini FA: Clinical relevance of prodromal angina before acute

myocardial infarction. Int J Cardiol 68(Suppl 1):S103-S108, 1999. Bolli R, Marban E: Molecular and cellular mechanisms of myocardial stunning. Physiol Rev 79:609-634, 1999. 202.

Murphy AM, Kogler H, Georgakopoulos D, et al: Transgenic mouse model of stunned myocardium. Science 287:488-91, 2000. 202A.

Gerber BL, Wijns W, Vanoverschelde JL, et al: Myocardial perfusion and oxygen consumption in reperfused noninfarcted dysfunctional myocardium after unstable angina: Direct evidence for myocardial stunning in humans. J Am Coll Cardiol 34:1939-1946, 1999. 203.

Kloner RA, Przyklenk K: Understanding the jargon: A glossary of terms used (and misused) in the study of ischaemia and reperfusion. Cardiovasc Res 27:162-166, 1993. 204.

Theroux P: Myocardial cell protection: A challenging time for action and a challenging time for clinical research. Circulation 101:2874-2876, 2000. 204A.

205.

Kloner RA: Does reperfusion injury exist in humans? J Am Coll Cardiol 21:537-545, 1993.

Ito H, Tomooka T, Sakai N, et al: Lack of myocardial perfusion immediately after successful thrombolysis: A predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation 85:1699-1705, 1992. 206.

207.

Davies CH, Ormerod OJ: Failed coronary thrombolysis. Lancet 351:1191-1196, 1998.

Antman E: Magnesium in acute myocardial infarction: Overview of available evidence. Am Heart J 132:487-494, 1996. 208.

Kloner RA, Yellon D: Does ischemic preconditioning occur in patients? J Am Coll Cardiol 24:1133-1142, 1994. 209.

Meisel SR, Shapiro H, Radnay J, et al: Increased expression of neutrophil and monocyte adhesion molecules LFA-1 and Mac-1 and their ligand ICAM-1 and VLA-4 throughout the acute phase of myocardial infarction: Possible implications for leukocyte aggregation and microvascular plugging. J Am Coll Cardiol 31:120-125, 1998. 210.

Horwitz LD, Kong Y, Robertson AD: Timing of treatment for myocardial reperfusion injury. J Cardiovasc Pharmacol 33:19-29, 1999. 211.

TIMI Study Group: Comparison of invasive and conservative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) Phase II Trial. N Engl J Med 320:618-627, 1989. 212.

Roberts R, Rogers WJ, Meuller HS, for the TIMI Investigators: Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction: Results of the Thrombolysis in Myocardial Infarction (TIMI) II-B Study. Circulation 83:422-437, 1991. 213.

Murry CE, Jennings RB, Reimer KA: Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation 74:1124-1136, 1986. 214.

215.

Sato T: Signalign in late preconditioning: Involvement of mitochondrial K(ATP) channels. Circ Res

85:1113-1114, 1999. Ito H, Taniyama Y, Iwakura K, et al: Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction. J Am Coll Cardiol 33:654-660, 1999. 216.

Ueda Y, Kitakaze M, Komamura K, et al: Pravastatin restored the infarct size-limiting effect of ischemic preconditioning blunted by hypercholesterolemia in the rabbit model of myocardial infarction. J Am Coll Cardiol 34:2120-2125, 1999. 217.

Kloner RA, Shook T, Antman EM, et al: Prospective temporal analysis of the onset of preinfarction angina versus outcome: An ancillary study in TIMI-9B. Circulation 97:1042-1045, 1998. 218.

Noda T, Minatoguchi S, Fujii K, et al: Evidence for the delayed effect in human ischemic preconditioning: Prospective multicenter study for preconditioning in acute myocardial infarction. J Am Coll Cardiol 34:1966-1974, 1999. 219.

Califf RM, O'Neill W, Stack RS, et al: Failure of simple clinical characteristics to predict perfusion status after intravenous thrombolysis. Ann Intern Med 108:658-662, 1988. 220.

Solomon SD, Ridker PM, Antman EM: Ventricular arrhythmias in trials of thrombolytic therapy for acute myocardial infarction: A meta-analysis. Circulation 88:2575-2581, 1993. 221.

Kim C, Braunwald E: Potential benefits of late reperfusion of infarcted myocardium: The open artery hypothesis. Circulation 88:2426-2436, 1993. 222.

Hochman JS, Choo H: Limitation of myocardial infarct expansion by reperfusion independent of myocardial salvage. Circulation 75:299-306, 1987. 223.

Lamas GV, Flaker GC, Mitchell G, et al: Effect of infarct artery patency on prognosis after acute myocardial infarction. Circulation 92:1101-1109, 1995. 224.

White HD, Cross DB, Elliott JM, et al: Long-term prognostic importance of patency of the infarct-related coronary artery after thrombolytic therapy for acute myocardial infarction. Circulation 89:61-67, 1994. 225.

Wilson JM: Reversible congestive heart failure caused by myocardial hibernation. Tex Heart Inst J 26:19-27, 1999. 226.

Gang ES, Lew AS, Hong M, et al: Decreased incidence of ventricular late potentials after successful thrombolytic therapy for acute myocardial infarction. N Engl J Med 321:712-716, 1989. 227.

Horvitz LL, Pietrolungo JF, Suri RS, et al: An open infarct-related artery is associated with a lower risk of lethal ventricular arrhythmias in patients with a left ventricular aneurysm. Circulation 86:I-315, 1992. 228.

CORONARY THROMBOLYSIS Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI): Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1:397-401, 1986. 229.

Franzosi MG, Santoro E, De Vita C, et al: Ten-year follow-up of the first megatrial testing thrombolytic therapy in patients with acute myocardial infarction: Results of the Gruppo Italiano per lo Studio della 230.

Sopravvivenza nell'Infarto-1 study. The GISSI Investigators. Circulation 98:2659-2665, 1998. 231.

Califf RM: Ten years of benefit from a one-hour intervention. Circulation 98:2649-2651, 1998.

Van de Werf F, Ludbrook PA, Bergmann SR, et al: Coronary thrombolysis with tissue-type plasminogen activator in patients with evolving myocardial infarction. N Engl J Med 310:609-613, 1984. 232.

Kennedy J, Ritchie J, Davis K, et al: The Western Washington randomized trial of intracoronary streptokinase in acute myocardial infarction: A 12-month follow-up report. N Engl J Med 312:1073-1078, 1985. 233.

234.

Tiefenbrunn AJ, Sobel BE: Thrombolysis and myocardial infarction. Fibrinolysis 5:1-15, 1991.

TIMI Study Group: The Thrombolysis in Myocardial Infarction (TIMI) Trial: Phase I findings. N Engl J Med 312:932-936, 1985. 235.

Chesebro JH, Knatterud G, Roberts R, et al: Thrombolysis in Myocardial Infarction (TIMI) Trial, phase 1: A comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Circulation 76:142-154, 1987. 236.

Antman EM, Giugliano RP, Gibson CM, et al: Abciximab facilitates the rate and extent of thrombolysis: Results of the thrombolysis in myocardial infarction (TIMI) 14 trial. The TIMI 14 Investigators. Circulation 99:2720-2732, 1999. 237.

The GUSTO Angiographic Investigators: The comparative effects of tissue plasminogen activator, streptokinase, or both on coronary artery patency, ventricular function and survival after acute myocardial infarction. N Engl J Med 329:1615-1622, 1993. 238.

Lenderink T, Simoons ML, Van Es G-A, et al: Benefit of thrombolytic therapy is sustained throughout five years and is related to TIMI perfusion grade 3 but not grade 2 flow at discharge. Circulation 92:1110-1116, 1995. 239.

Gibson CM: Primary angioplasty, rescue angioplasty, and new devices. In Hennekens CH (ed): Clinical Trials in Cardiovascular Disease: A Companion to Braunwald's Heart Disease. Philadelphia, WB Saunders, 1999, pp 185-197. 240.

Fath-Ordoubadi F, Huehns TY, Al-Mohammad A, Beatt KJ: Significance of the Thrombolysis in Myocardial Infarction scoring system in assessing infarct-related artery reperfusion and mortality rates after acute myocardial infarction. Am Heart J 134:62-68, 1997. 241.

Gibson CM, Murphy SA, Rizzo JM, et al: Relationship between TIMI frame count and clinical outcomes after thrombolytic administration. Thrombolysis In Myocardial Infarction (TIMI) Study Group. Circulation 99:1945-1950, 1999. 242.

Gibson CM, Murphy S, Menown IB, et al: Determinants of coronary blood flow after thrombolytic administration. TIMI Study Group. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol 34:1403-1412, 1999. 243.

Ito H, Okamura A, Iwakura K, et al: Myocardial perfusion patterns related to thrombolysis in myocardial infarction perfusion grades after coronary angioplasty in patients with acute anterior wall myocardial infarction. Circulation 93:1993-1999, 1996. 244.

245.

Wu KC, Zerhouni EA, Judd RM, et al: Prognostic significance of microvascular obstruction by

magnetic resonance imaging in patients with acute myocardial infarction. Circulation 97:765-772, 1998. Schroder R, Wegscheider K, Schroder K, et al: Extent of early ST segment elevation resolution: A strong predictor of outcome in patients with acute myocardial infarction and a sensitive measure to compare thrombolytic regimens. A substudy of the International Joint Efficacy Comparison of Thrombolytics (INJECT) trial. J Am Coll Cardiol 26:1657-1664, 1995. 246.

Schroder K, Wegscheider K, Neuhaus KL, et al: Significance of initial ST segment changes for thrombolytic treatment in first inferior myocardial infarction. Heart 77:506-511, 1997. 247.

Wegscheider K, Neuhaus KL, Dissmann R, et al: Prognostic significance of ST segment change in acute myocardial infarct. Herz 24:378-388, 1999. 248.

Schroder R, Zeymer U, Wegscheider K, Neuhaus KL: Comparison of the predictive value of ST segment elevation resolution at 90 and 180 min after start of streptokinase in acute myocardial infarction: A substudy of the hirudin for improvement of thrombolysis (HIT)-4 study. Eur Heart J 20:1563-1571, 1999. 249.

van't Hof AW, Liem A, de Boer MJ, Zijlstra F: Clinical value of 12-lead electrocardiogram after successful reperfusion therapy for acute myocardial infarction. Zwolle Myocardial Infarction Study Group. Lancet 350:615-619, 1997. 250.

Matetzky S, Freimark D, Chouraqui P, et al: The distinction between coronary and myocardial reperfusion after thrombolytic therapy by clinical markers of reperfusion. J Am Coll Cardiol 32:1326-1330, 1998. 251.

Matetzky S, Novikov M, Gruberg L, et al: The significance of persistent ST elevation versus early resolution of ST segment elevation after primary PTCA. J Am Coll Cardiol 34:1932-1938, 1999. 252.

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Langer A, Krucoff MW, Klootwijk P, et al: Prognostic significance of ST segment shift early after resolution of ST elevation in patients with myocardial infarction treated with thrombolytic therapy: The GUSTO-I ST Segment Monitoring Substudy. J Am Coll Cardiol 31:783-789, 1998. 253.

Drew BJ, Krucoff MW: Multilead ST-segment monitoring in patients with acute coronary syndromes: A consensus statement for healthcare professionals. ST-Segment Monitoring Practice Guideline International Working Group. Am J Crit Care 8:372-386, 1999. 254.

Agati L, Voci P, Hickle P, et al: Tissue-type plasminogen activator therapy versus primary coronary angioplasty: Impact on myocardial tissue perfusion and regional function 1 month after uncomplicated myocardial infarction. J Am Coll Cardiol 31:338-343, 1998. 255.

256.

Gassler JP, Topol EJ: Reperfusion revisited: Beyond TIMI 3 flow. Clin Cardiol 22:IV20-IV29, 1999.

Horcher J, Blasini R, Martinoff S, et al: Myocardial perfusion in acute coronary syndrome. Circulation 99:E15, 1999. 257.

Lepper W, Hoffmann R, Kamp O, et al: Assessment of myocardial reperfusion by intravenous myocardial contrast echocardiography and coronary flow reserve after primary percutaneous transluminal 257A.

coronary angiography in patients with acute myocardial infarction. Circulation 101:2368-74, 2000. Stewart RE, Miller DD, Bowers TR, et al: PET perfusion and vasodilator function after angioplasty for acute myocardial infarction. J Nucl Med 38:770-777, 1997. 258.

Iwakura K, Ito H, Nishikawa N, et al: Early temporal changes in coronary flow velocity patterns in patients with acute myocardial infarction demonstrating the "no-reflow" phenomenon. Am J Cardiol 84:415-419, 1999. 259.

Neumann FJ, Blasini R, Schmitt C, et al: Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after the placement of coronary-artery stents in acute myocardial infarction. Circulation 98:2695-2701, 1998. 260.

Schomig A, Kastrati A, Dirschinger J, et al: Coronary stenting plus platelet glycoprotein IIb/IIIa blockade compared with tissue plasminogen activator in acute myocardial infarction. N Engl J Med 343:385-391, 2000. 260A.

Gibson CM, Cannon CP, Murphy SA, et al: Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs. Circulation 101:124-130, 2000. 261.

Mahaffey KW, Puma JA, Barbagelata NA, et al: Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction: Results of a multicenter, randomized, placebo-controlled trial: The Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial. J Am Coll Cardiol 34:1711-1720, 1999. 262.

Weaver WD: Time to thrombolytic treatment: Factors affecting delay and their influence on outcome. J Am Coll Cardiol 25:3S-9S, 1995. 263.

Boersma E, Maas AC, Deckers JW, Simoons ML: Early thrombolytic treatment in acute myocardial infarction: Reappraisal of the golden hour. Lancet 348:771-775, 1996. 264.

LATE (Late Assessment of Thrombolytic Efficacy) Study Group: Late Assessment of Thrombolytic Efficacy (LATE) Study with alteplase 6-24 hours after onset of acute myocardial infarction. Lancet 342:759-766, 1993. 265.

EMERAS (Estudio Multicentrico Estreptoquinasa Republicas de America del Sur) Collaborative Group: Randomized trial of late thrombolysis in acute myocardial infarction. Lancet 342:767-772, 1993. 266.

ISIS-3 (Third International Study of Infarct Survival) Collaborative Group: ISIS-3: A randomized trial of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. Lancet 339:753-770, 1992. 267.

Chandra NC, Ziegelstein RC, Rogers WJ, et al: Observations of the treatment of women in the United States with myocardial infarction: A report from the National Registry of Myocardial Infarction-I. Arch Intern Med 158:981-988, 1998. 268.

Morrow DA, Antman EM, Charlesworth A, et al: The TIMI risk score for ST elevation myocardial infarction: A convenient, bedside, clinical score for risk assessment at presentation: An InTIME II substudy. Circulation, in press. 268A.

Lee KL, Woodlief LH, Topol EJ, et al: Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction: Results from an international trial of 41,021 patients. GUSTO-I Investigators. Circulation 91:1659-1668, 1995. 269.

Wilcox RG, von der Lippe G, Olsson CG, et al: Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet 1:525-530, 1988. 270.

ISAM (Intravenous Streptokinase in Acute Myocardial Infarction) Study Group: A prospective trial of intravenous streptokinase in acute myocardial infarction (ISAM). N Engl J Med 314:1465-1471, 1986. 271.

Becker RC, Gore JM, Lambrew C, et al: A composite view of cardiac rupture in the United States National Registry of Myocardial Infarction. J Am Coll Cardiol 27:1321-1326, 1996. 272.

Meijer A, Verheugt FWA, Werter CJPJ, et al: Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: A prospective placebo-controlled angiographic study: Results of the APRICOT Study. Circulation 87:1524-1530, 1993. 273.

Collins R, Peto R, Baigent C, Sleight P: Aspirin, heparin, and fibrinolytic therapy in suspected acute myocardial infarction. N Engl J Med 336:847-860, 1997. 274.

Cannon CP, McCabe CH, Diver DJ, et al: Comparison of front-loaded recombinant tissue-type plasminogen activator, anistreplase and combination thrombolytic therapy for acute myocardial infarction: Results of the Thrombolysis in Myocardial Infarction (TIMI) 4 trial. J Am Coll Cardiol 24:1602-1610, 1994. 275.

Van de Werf FJ: The ideal fibrinolytic: Can drug design improve clinical results? Eur Heart J 20:1452-1458, 1999. 276.

The Continuous Infusion versus Double-Bolus Administration of Alteplase (COBALT) Investigators: A comparison of continuous infusion of alteplase with double-bolus administration for acute myocardial infarction. The Continuous Infusion versus Double-Bolus Administration of Alteplase (COBALT) Investigators. N Engl J Med 337:1124-1130, 1997. 277.

278.

Ware JH, Antman EM: Equivalence trials. N Engl J Med 337:1159-1161, 1997.

279.

White HD: Thrombolytic therapy and equivalence trials. J Am Coll Cardiol 31:494-496, 1998.

Neuhaus KL, von Essen R, Vogt A, et al: Dose finding with a novel recombinant plasminogen activator (BM 06.022) in patients with acute myocardial infarction: Results of the German Recombinant Plasminogen Activator Study. A study of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausarzte (ALKK). J Am Coll Cardiol 24:55-60, 1994. 280.

Tebbe U, von Essen R, Smolarz A, et al: Open, noncontrolled dose-finding study with a novel recombinant plasminogen activator (BM 06.022) given as a double bolus in patients with acute myocardial infarction. Am J Cardiol 72:518-524, 1993. 281.

Smalling RW, Bode C, Kalbfleisch J, et al: More rapid, complete, and stable coronary thrombolysis with bolus administration of reteplase compared with alteplase infusion in acute myocardial infarction. RAPID Investigators. Circulation 91:2725-2732, 1995. 282.

Bode C, Smalling RW, Berg G, et al: Randomized comparison of coronary thrombolysis achieved with double-bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction. The RAPID II Investigators. Circulation 94:891-898, 1996. 283.

International Joint Efficacy Comparison of Thrombolytics: Randomised, double-blind comparison of reteplase double-bolus administration with streptokinase in acute myocardial infarction (INJECT): Trial to 284.

investigate equivalence. Lancet 346:329-336, 1995. den Heijer P, Vermeer F, Ambrosioni E, et al: Evaluation of a weight-adjusted single-bolus plasminogen activator in patients with myocardial infarction: A double-blind, randomized angiographic trial of lanoteplase versus alteplase. Circulation 98:2117-2125, 1998. 285.

Keyt BA, Paoni NF, Refino CJ, et al: A faster-acting and more potent form of tissue plasminogen activator. Proc Natl Acad Sci U S A 91:3670-3674, 1994. 286.

Cannon CP, McCabe CH, Gibson CM, et al: TNK-tissue plasminogen activator in acute myocardial infarction: Results of the Thrombolysis in Myocardial Infarction (TIMI) 10A dose-ranging trial. Circulation 95:351-356, 1997. 287.

Cannon CP, Gibson CM, McCabe CH, et al: TNK-tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: Results of the TIMI 10B trial. Thrombolysis in Myocardial Infarction (TIMI) 10B Investigators. Circulation 98:2805-2814, 1998. 288.

Van de Werf F, Cannon CP, Luyten A, et al: Safety assessment of single-bolus administration of TNK tissue-plasminogen activator in acute myocardial infarction: The ASSENT-1 trial. The ASSENT-1 Investigators. Am Heart J 137:786-791, 1999. 289.

PRIMI Trial Study Group: Randomised double-blind trial of recombinant pro-urokinase against streptokinase in acute myocardial infarction. Lancet 1:863-868, 1989. 290.

Michels R, Hoffmann H, Windeler J, et al: A double-blind multicenter comparison of the efficacy and safety of saruplase and urokinase in the treatment of acute myocardial infarction: Report of the SUTAMI study group. J Thromb Thrombol 2:117-124, 1995. 291.

Bar FW, Meyer J, Vermeer F, et al: Comparison of saruplase and alteplase in acute myocardial infarction: SESAM Study Group. The Study in Europe with Saruplase and Alteplase in Myocardial Infarction. Am J Cardiol 79:727-732, 1997. 292.

Vermeer F, Bosl I, Meyer J, et al: Saruplase is a safe and effective thrombolytic agent; Observations in 1,698 patients: Results of the PASS study. Practical Applications of Saruplase Study. J Thromb Thrombol 8:143-150, 1999. 293.

Tebbe U, Michels R, Adgey J, et al: Randomized, double-blind study comparing saruplase with streptokinase therapy in acute myocardial infarction: The COMPASS Equivalence Trial. Comparison Trial of Saruplase and Streptokinase (COMPASS) Investigators. J Am Coll Cardiol 31:487-493, 1998. 294.

Bar WF, Hopkins G, Dickhoet S: The Bolus versus Infusion in Rescueplase (saruplase) Development (BIRD) Study in 2410 patients with myocardial infarction. Circulation 98:I-505, 1998. 295.

Collen D. Staphylokinase: A potent, uniquely fibrin-selective thrombolytic agent. Nat Med 4:279-284, 1998. 296.

Vanderschueren S, Barrios L, Kerdsinchai P, et al: A randomized trial of recombinant staphylokinase versus alteplase for coronary artery patency in acute myocardial infarction. The STAR Trial Group. Circulation 92:2044-2049, 1995. 297.

Armstrong PW, Burton JR, Palisaitis D, et al: Collaborative Angiographic Patency Trial of Recombinant Staphylokinase (CAPTORS). Circulation 100:I-650, 1999. 298.

White HD, Norris RM, Brown MA, et al: Effect of intravenous streptokinase on left ventricular function and early survival after acute myocardial infarction. N Engl J Med 317:850-855, 1987. 299.

1213

St. John Sutton M, Pfeffer MA, Plappert T, et al: Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction: The protective effects of captopril. Circulation 89:68-75, 1994. 300.

Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico: GISSI-2: A factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12,490 patients with acute myocardial infarction. Lancet 336:65-71, 1990. 301.

Antman EM, for the TIMI 9A Investigators: Hirudin in acute myocardial infarction: Safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A trial. Circulation 90:1624-1630, 1994. 302.

The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa Investigators: A randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. Circulation 90:1631-1637, 1994. 303.

Sane DC, Califf RM, Topol EJ, et al: Bleeding during thrombolytic therapy for acute myocardial infarction: Mechanisms and management. Ann Intern Med 111:1010, 1989. 304.

Gore JM, Granger CB, Simoons ML, et al: Stroke after thrombolysis: Mortality and functional outcomes in the GUSTO-I Trial. Circulation 92:2811-2818, 1995. 305.

Maggioni AP, Franzosi MG, Santoro E, et al: The risk of stroke in patients with acute myocardial infarction after thrombolytic and antithrombotic treatment. N Engl J Med 327:1-6, 1992. 306.

Simoons ML, Maggioni AP, Knatterud G, et al: Individual risk assessment for intracranial haemorrhage during thrombolytic therapy. Lancet 342:1523-1528, 1993. 307.

ISIS-2 (Second International Study of Infarct Survival) Collaborative Group: Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 2:349-360, 1988. 308.

Gurwitz JH, Gore JM, Goldberg RJ, et al: Risk for intracranial hemorrhage after tissue plasminogen activator treatment for acute myocardial infarction: Participants in the National Registry of Myocardial Infarction 2. Ann Intern Med 129:597-604, 1998. 309.

Kleiman NS, Terrin M, Mueller H, et al: Mechanisms of early death despite thrombolytic therapy: Experience from the Thrombolysis in Myocardial Infarction Investigation Phase II (TIMI II) Study. J Am Coll Cardiol 19:1129-1135, 1992. 310.

311.

Hennekens C: The need for wider utilization of thrombolytic therapy. Clin Cardiol 20:III26-III31, 1997.

Berkowitz SD, Granger CB, Pieper KS, et al: Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction: The Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries (GUSTO) I Investigators. Circulation 95:2508-2516, 312.

1997. 313.

Lee TH: Cost effectiveness of tissue plasminogen activator. N Engl J Med 332:1443-1444, 1995.

Simoons ML, Arnold AE: Tailored thrombolytic therapy: A perspective. Circulation 88:2556-2564, 1993. 314.

Brodie BR, Stuckey TD, Hansen C, et al: Benefit of late coronary reperfusion in patients with acute myocardial infarction and persistent ischemic chest pain. Am J Cardiol 74:538-543, 1994. 315.

CATHETER-BASED REPERFUSION Dangas G, Stone GW: Primary mechanical reperfusion in acute myocardial infarction: The United States experience. Semin Intervent Cardiol 4:21-33, 1999. 316.

Antoniucci D, Valenti R, Trapani M, Moschi G: Current role of stenting in acute myocardial infarction. Am Heart J 138:147-152, 1999. 317.

Grines CL: Should thrombolysis or primary angioplasty be the treatment of choice for acute myocardial infarction? Primary angioplasty--the strategy of choice. N Engl J Med 335:1313-1316, 1996. 318.

Weaver WD, Simes RJ, Betriu A, et al: Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review. JAMA 278:2093-2098, 1997. 319.

Grines CL, Ellis SG, Jones M, et al: Primary coronary angioplasty vs. thrombolytic therapy for acute myocardial infarction (MI): Long term follow-up of ten randomized trials. Circulation 100:I-499, 1999. 320.

Stone GW, Grines CL, Rothbaum D, et al: Analysis of the relative costs and effectiveness of primary angioplasty versus tissue-type plasminogen activator: The Primary Angioplasty in Myocardial Infarction (PAMI) trial. The PAMI Trial Investigators. J Am Coll Cardiol 29:901-907, 1997. 321.

Grines CL, Marsalese DL, Brodie B, et al: Safety and cost-effectiveness of early discharge after primary angioplasty in low risk patients with acute myocardial infarction. PAMI-II Investigators. Primary Angioplasty in Myocardial Infarction. J Am Coll Cardiol 31:967-972, 1998. 322.

Antoniucci D, Valenti R, Santoro GM, et al: Systematic primary angioplasty in octogenarian and older patients. Am Heart J 138:670-674, 1999. 323.

Grines CL, Ellis S, Jones M, et al: Primary coronary angioplasty vs. thrombolytic therapy for treatment of acute myocardial infarction (MI): Findings from the PCAT collaboration. Eur Heart J 20:170, 1999. 324.

Berger AK, Schulman KA, Gersh BJ, et al: Primary coronary angioplasty vs thrombolysis for the management of acute myocardial infarction in elderly patients. JAMA 282:341-348, 1999. 325.

Nunn CM, O'Neill WW, Rothbaum D, et al: Long-term outcome after primary angioplasty: Report from the primary angioplasty in myocardial infarction (PAMI-I) trial. J Am Coll Cardiol 33:640-646, 1999. 326.

Zijlstra F, Hoorntje JC, de Boer MJ, et al: Long-term benefit of primary angioplasty as compared with thrombolytic therapy for acute myocardial infarction. N Engl J Med 341:1413-1419, 1999. 327.

The Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) Angioplasty Substudy Investigators: A clinical trial comparing primary coronary angioplasty 328.

with tissue plasminogen activator for acute myocardial infarction. N Engl J Med 336:1621-1628, 1997. Yusuf S, Pogue J: Primary angioplasty compared with thrombolytic therapy for acute myocardial infarction. JAMA 278:2110-2111, 1997. 329.

Zahn R, Schuster S, Schiele R, et al: Differences in patients with acute myocardial infarction treated with primary angioplasty or thrombolytic therapy. Maximal Individual Therapy in Acute Myocardial Infarction (MITRA) Study Group. Clin Cardiol 22:191-199, 1999. 330.

Ashmore RC, Luckasen GJ, Larson DG, et al: Immediate angioplasty for acute myocardial infarction: A community hospital's experience. J Invas Cardiol 11:61-65, 1999. 331.

Wharton TP Jr, McNamara NS, Fedele FA, et al: Primary angioplasty for the treatment of acute myocardial infarction: Experience at two community hospitals without cardiac surgery. J Am Coll Cardiol 33:1257-1265, 1999. 332.

Grines CL: Transfer of high-risk myocardial infarction patients for primary PTCA. J Invas Cardiol 9:13B-19B, 1997. 333.

Ferguson JJ. Meeting Highlights: Highlights of the 21st Congress of the European Society of Cardiology. Circulation 100:e126-e131, 1999. 334.

Peterson LR, Chandra NC, French WJ, et al: Reperfusion therapy in patients with acute myocardial infarction and prior coronary artery bypass graft surgery (National Registry of Myocardial Infarction-2). Am J Cardiol 84:1287-1291, 1999. 335.

336.

Jacobs AK: Coronary stents--have they fulfilled their promise? N Engl J Med 341:2005-2006, 1999.

Grines CL, Cox DA, Stone GW, et al: Coronary angioplasty with or without stent implantation for acute myocardial infarction. N Engl J Med 341:1949-1956, 1999. 337.

Ellis SG, da Silva ER, Heyndrickx G, et al: Randomized comparison of rescue angioplasty with conservative management of patients with early failure of thrombolysis for acute anterior myocardial infarction. Circulation 90:2280-2284, 1994. 338.

Llevadot J, Giugliano RP, McCabe CH, et al: Degree of residual stenosis in the culprit coronary artery after thrombolytic administration (Thrombolysis In Myocardial Infarction [TIMI] trials). Am J Cardiol 85:1409-1413, 2000. 338A.

Michels KB, Yusuf S: Does PTCA in acute myocardial infarction affect mortality and reinfarction rates? A quantitative overview (meta-analysis) of the randomized clinical trials. Circulation 91:476-485, 1995. 339.

Topol EJ, Califf RM, George BS, et al: A randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med 317:581-588, 1987. 340.

Rogers WJ, Baim DS, Gore JM, et al: Comparison of immediate invasive, delayed invasive, and conservative strategies after tissue-type plasminogen activator: Results of the Thrombolysis in Myocardial Infarction (TIMI) Phase II-A Trial. Circulation 81:1457-1476, 1990. 341.

The TIMI Research Group: Immediate vs delayed catheterization and angioplasty following thrombolytic therapy for acute myocardial infarction: TIMI II A results. JAMA 260:2849-2858, 1988. 342.

SWIFT (Should We Intervene Following Thrombolysis) Trial Study Group: SWIFT trial of delayed elective intervention v. conservative treatment after thrombolysis with anistreplase in acute myocardial infarction. BMJ 302:555-560, 1991. 343.

Ross AM, Coyne KS, Reiner JS, et al: A randomized trial comparing primary angioplasty with a strategy of short-acting thrombolysis and immediate planned rescue angioplasty in acute myocardial infarction: The PACT trial. PACT investigators. Plasminogen-activator Angioplasty Compatibility Trial. J Am Coll Cardiol 34:1954-1962, 1999. 344.

Keeley EC, Weaver WD: Combination therapy for acute myocardial infarction. J Am Coll Cardiol 34:1963-1965, 1999. 345.

Keeley EC, Hillis LD: Left ventricular mural thrombus after acute myocardial infarction. Clin Cardiol 19:83, 1996. 346.

Rankin JM, Spinelli JJ, Carere RG, et al: Improved clinical outcome after widespread use of coronary-artery stenting in Canada. N Engl J Med 341:1957-1965, 1999. 347.

Pomes Iparraguirre H, Conti C, Grancelli H, et al: Prognostic value of clinical markers of reperfusion in patients with acute myocardial infarction treated by thrombolytic therapy. Am Heart J 134:631-638, 1997. 348.

Goldman LE, Eisenberg MJ: Identification and management of patients with failed thrombolysis after acute myocardial infarction. Ann Intern Med 132:556-65, 2000. 348A.

The TIMI Study Group: Comparison of invasive and conservative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction: Results of the Thrombolysis in Myocardial Infarction (TIMI) phase II trial. N Engl J Med 320:618-627, 1989. 349.

1214

Stone GW, Marsalese D, Brodie BR, et al: A prospective, randomized evaluation of prophylactic intraaortic balloon counterpulsation in high risk patients with acute myocardial infarction treated with primary angioplasty. Second Primary Angioplasty in Myocardial Infarction (PAMI-II) Trial Investigators. J Am Coll Cardiol 29:1459-1467, 1997. 350.

van't Hof AW, Liem AL, DeBoer MJ, et al: A randomized comparison of intra-aortic balloon pumping after primary coronary angioplasty in high-risk patients with acute myocardial infarction. Eur Heart J 20:659-665, 1999. 351.

Kereiakes DJ, Topol EJ, George BS, et al: Favorable early and long-term prognosis following coronary bypass surgery therapy for myocardial infarction: Results of a multicenter trial. TAMI Study Group. Am Heart J 118:199-207, 1989. 352.

ANTITHROMBOTIC AND ANTIPLATELET THERAPY Kagen L, Scheidt S, Butt A: Serum myoglobin in myocardial infarction: The "staccato phenomenon": Is acute myocardial infarction in man an intermittent event? Am J Med 62:86, 1977. 353.

The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb investigators: A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 335:775-782, 1996. 354.

Bleich SD, Nichols T, Schumacher RR, et al: Effect of heparin on coronary patency after thrombolysis with tissue plasminogen activator in acute myocardial infarction. Am J Cardiol 66:1412-1417, 1990. 355.

Hsia J, Hamilton WP, Kleiman N, et al: A comparison between heparin and low-dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction. N Engl J Med 323:1433-1437, 1990. 356.

de Bono DP, Simoons MI, Tijssen J, et al: Effect of early intravenous heparin on coronary patency, infarct size, and bleeding complications after alteplase thrombolysis: Results of a randomized double blind European Cooperative Study Group trial. Br Heart J 67:122-128, 1992. 357.

Verheugt FW, Liem A, Zijlstra F, et al: High dose bolus heparin as initial therapy before primary angioplasty for acute myocardial infarction: Results of the Heparin in Early Patency (HEAP) pilot study. J Am Coll Cardiol 31:289-293, 1998. 358.

Liem A, Zijlstra F, Ottervanger JP, et al: High dose heparin as pre-treatment for primary angioplasty in acute myocardial infarction: The Heparin in EArly Patency (HEAP) randomized trial. J Am Coll Cardiol 35:600-604, 2000. 359.

Cairns JA, Theroux P, Lewis HD Jr, et al: Antithrombotic agents in coronary artery disease. Chest 114:611S-633S, 1998. 360.

Vaitkus P, Barnathan E: Embolic potential, prevention and management of mural thrombus complicating anterior myocardial infarction: A meta-analysis. J Am Coll Cardiol 22:1004-1009, 1993. 361.

Warkentin TE, Levine MN, Hirsh J, et al: Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 332:1374-1376, 1995. 362.

Krumholz HM, Hennen J, Ridker PM, et al: Use and effectiveness of intravenous heparin therapy for treatment of acute myocardial infarction in the elderly. J Am Coll Cardiol 31:973-979, 1998. 363.

Giugliano RP, Cutler SS, Llevadot J: Risk of intracranial hemorrhage with accelerated tPA: Importance of the heparin dose. Circulation 100 (Suppl 1):I-1650, 1999. 364.

365.

Weitz JI: Low-molecular-weight heparins. N Engl J Med 337:688-698, 1997.

Neuhaus KL, von Essen R, Tebbe U, et al: Safety observations from the pilot phase of the randomized r-Hirudin for Improvement of Thrombolysis (HIT-III) study: A study of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausarzte (ALKK). Circulation 90:1638-1642, 1994. 366.

Antman EM: Hirudin in acute myocardial infarction. Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial. Circulation 94:911-921, 1996. 367.

Antman EM, Bittl JA: Direct thrombin inhibitors. In Hennekens CH (ed): Clinical Trials in Cardiovascular Disease: A Companion to Braunwald's Heart Disease. Philadelphia, WB Saunders, 1999, pp 145-165. 368.

Fung AY, Lorch G, Cambier PA, et al: Efegatran sulfate as an adjunct to streptokinase versus heparin as an adjunct to tissue plasminogen activator in patients with acute myocardial infarction. 369.

ESCALAT Investigators. Am Heart J 138:696-704, 1999. White HD, Aylward PE, Frey MJ, et al: Randomized, double-blind comparison of hirulog versus heparin in patients receiving streptokinase and aspirin for acute myocardial infarction (HERO). Hirulog Early Reperfusion/Occlusion (HERO) Trial Investigators. Circulation 96:2155-2161, 1997. 370.

French JK, White HD: Antithrombin agents as adjuncts to thrombolytic therapy. J Thromb Thrombol 8:159-166, 1999. 371.

Leadley RJ Jr, Kasiewski CJ, Bostwick JS, et al: Comparison of enoxaparin, hirulog, and heparin as adjunctive antithrombotic therapy during thrombolysis with rtPA in the stenosed canine coronary artery. Thromb Haemost 78:1278-1285, 1997. 372.

Glick A, Kornowski R, Michowich Y, et al: Reduction of reinfarction and angina with use of low-molecular-weight heparin therapy after streptokinase (and heparin) in acute myocardial infarction. Am J Cardiol 77:1145-1148, 1996. 373.

Frostfeldt G, Ahlberg G, Gustafsson G, et al: Low molecular weight heparin (dalteparin) as adjuvant treatment of thrombolysis in acute myocardial infarction--a pilot study: Biochemical markers in acute coronary syndromes (BIOMACS II). J Am Coll Cardiol 33:627-633, 1999. 374.

Zed PJ: Low-molecular-weight heparin should replace unfractionated heparin in the management of acute coronary syndromes. J Thromb Thrombol 8:79-87, 1999. 375.

Antman EM, Cohen M, Radley D, et al: Assessment of the treatment effect of enoxaparin for unstable angina/non-Q-wave myocardial infarction. TIMI 11B-ESSENCE meta-analysis. Circulation 100:1602-1608, 1999. 376.

White HD, Yusuf S: Issues regarding the use of heparin following streptokinase therapy. J Thromb Thrombol 2:5-10, 1995. 377.

Hochman JS, Wali AU, Gavrila D, et al: A new regimen for heparin use in acute coronary syndromes. Am Heart J 138:313-318, 1999. 378.

Becker RC, Spencer FA, Li Y, et al: Thrombin generation after the abrupt cessation of intravenous unfractionated heparin among patients with acute coronary syndromes: Potential mechanisms for heightened prothrombotic potential. J Am Coll Cardiol 34:1020-1027, 1999. 379.

380.

Falk E, Shah PK, Fuster V: Coronary plaque disruption. Circulation 92:657-671, 1995.

Shimomura H, Ogawa H, Arai H, et al: Serial changes in plasma levels of soluble P-selectin in patients with acute myocardial infarction. Am J Cardiol 81:397-400, 1998. 381.

Antiplatelet Trialists' Collaboration: Collaborative overview of randomised trials of antiplatelet therapy: II. Maintenance of vascular graft or arterial patency by antiplatelet therapy. BMJ 308:159-168, 1994. 382.

Antiplatelet Trialists' Collaboration: Collaborative overview of randomised trials of antiplatelet therapy: III. Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. BMJ 308:235-246, 1994. 383.

Zusman RM, Chesebro JH, Comerota A, et al: Antiplatelet therapy in the prevention of ischemic vascular events: Literature review and evidence-based guidelines for drug selection. Clin Cardiol 22:559-573, 1999. 384.

Weber C, Springer TA: Neutrophil accumulation on activated, surface-adherent platelets in flow is mediated by interaction of Mac-1 with fibrinogen bound to alphaIIb/beta3 and stimulated by platelet-activating factor. J Clin Invest 100:2085-2093, 1997. 385.

Mickelson JK, Ali MN, Kleiman NS, et al: Chimeric 7E3 Fab (ReoPro) decreases detectable CD11b on neutrophils from patients undergoing coronary angioplasty. J Am Coll Cardiol 33:97-106, 1999. 386.

Nordt TK, Moser M, Kohler B, et al: Augmented platelet aggregation as predictor of reocclusion after thrombolysis in acute myocardial infarction. Thromb Haemost 80:881-886, 1998. 387.

388.

Topol EJ, Byzova TV, Plow EF: Platelet GPIIb-IIIa blockers. Lancet 353:227-231, 1999.

Gurbel PA, Serebruany VL, Shustov AR, et al: Effects of reteplase and alteplase on platelet aggregation and major receptor expression during the first 24 hours of acute myocardial infarction treatment. GUSTO-III Investigators. Global Use of Strategies to Open Occluded Coronary Arteries. J Am Coll Cardiol 31:1466-1473, 1998. 389.

Vorchheimer DA, Badimon JJ, Fuster V: Platelet glycoprotein IIb/IIIa receptor antagonists in cardiovascular disease. JAMA 281:1407-1414, 1999. 390.

Harrington RA: Overview of clinical trials of glycoprotein IIb-IIIa inhibitors in acute coronary syndromes. Am Heart J 138:S276-S286, 1999. 391.

Kleiman N, Ohman EM, Califf RM, et al: Profound inhibition of platelet aggregation with monoclonal antibody 7E3 Fab after thrombolytic therapy: Results of the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 8 pilot study. J Am Coll Cardiol 22:381-389, 1993. 392.

Ohman EM, Kleiman NS, Gacioch G, et al: Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrin receptor blockade with Integrilin in acute myocardial infarction. Results of a randomized, placebo-controlled, dose-ranging trial. IMPACT-AMI Investigators. Circulation 95:846-854, 1997. 393.

394.

SK Eptifibatide Trial. Eur Heart J 2000.

The PARADIGM Investigators: Combining thrombolysis with the platelet glycoprotein IIb/IIIa inhibitor lamifiban: Results of the Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction (PARADIGM) trial. J Am Coll Cardiol 32:2003-2010, 1998. 395.

Antman EM, Gibson CM, de Lemos JA, et al: For the Thrombolysis in Myocardial Infarction (TIMI) 14 Investigators. Combination reperfusion therapy with abciximab and reduced dose reteplase: Results from TIMI 14. Eur Heart J 2000, in press. 396.

de Lemos JA, Antman EM, ibson CM, et al: Abciximab improves both epicardial flow and myocardial reperfusion in ST-elevation myocardial infarction. Observations from the TIMI 14 trial. Circulation 101:239-43, 2000. 396A.

Brener SJ, Lopez JF, Vrobel TR, et al: Eptifibatide markedly enhances arterial patency after low-dose tissue plasminogen activator in acute myocardial infarction. J Am Coll Cardiol, submitted for publication. 397.

Strategies for Patency Enhancement in the Emergency Department (SPEED) Group: Trial of abciximab with and without low-dose reteplase for acute myocardial infarction. Circulation 101:2788-2794, 2000. 398.

Gold HK, Garabedian HD, Dinsmore RE, et al: Restoration of coronary flow in myocardial infarction by intravenous chimeric 7E3 antibody without exogenous plasminogen activators: Observations in animals and humans. Circulation 95:1755-1759, 1997. 399.

Lefkovits J, Ivanhoe RJ, Califf RM, et al: Effects of platelet glycoprotein IIb/IIIa receptor blockade by a chimeric monoclonal antibody (abciximab) on acute and six-month outcomes after percutaneous transluminal coronary angioplasty for acute myocardial infarction. EPIC investigators. Am J Cardiol 77:1045-1051, 1996. 400.

1215

van den Merkhof LF, Zijlstra F, Olsson H, et al: Abciximab in the treatment of acute myocardial infarction eligible for primary percutaneous transluminal coronary angioplasty. Results of the Glycoprotein Receptor Antagonist Patency Evaluation (GRAPE) pilot study. J Am Coll Cardiol 33:1528-1532. 1999. 401.

Brener SJ, Barr LA, Burchenal JE, et al: Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT) Investigators. Circulation 98:734-741, 1998. 402.

Montalescot G, Barragan P, Wittenberg O, et al: Abciximab associated with primary angioplasty and stenting in acute myocardial infarction: The ADMIRAL study, 30-day final results. Circulation 18:I-87, 1999. 403.

404.

CADILLAC Study Presented at 72nd Scientific Sessions of AHA, Atlanta, GA, 1999.

405.

White HD: Future of reperfusion therapy for acute myocardial infarction. Lancet 354:695-697, 1999.

Kennedy JW, Stadius ML: Combined thrombolytic and platelet glycoprotein IIb/IIIa inhibitor therapy for acute myocardial infarction: Will pharmacological therapy ever equal primary angioplasty? Circulation 99:2714-2716, 1999. 406.

Harrington RA, Kleiman NS, Granger CB, et al: Relation between inhibition of platelet aggregation and clinical outcomes. Am Heart J 136:S43-S50, 1998. 407.

HOSPITAL MANAGEMENT Daida H, Kottke TE, Backes RJ, et al: Are coronary-care unit changes in therapy associated with improved survival of elderly patients with acute myocardial infarction? Mayo Clin Proc 72:1014-1021, 1997. 408.

Lee TH, Cook EF, Weisberg MC, et al: Impact of the availability of a prior electrocardiogram on the triage of the patient with acute chest pain. J Gen Intern Med 5:381-388, 1990. 409.

Newby KL, Eisenstein EL, Califf RM, et al: Cost-effectiveness of early discharge after acute myocardial infarction after uncomplicated myocardial infarction. N Engl J Med 342:749-785, 2000. 410.

Antman EM, Kuntz KM: The length of the hospital stay after myocardial infarction. N Engl J Med 342:808-810, 2000. 411.

Kirchhoff KT, Holm K, Foreman MD, Rebenson-Piano M: Electrocardiographic response to ice water ingestion. Heart Lung 19:41-48, 1990. 412.

413.

Levine SA, Lown B: "Armchair" treatment of acute coronary thrombosis. JAMA 148:1365, 1952.

Peterson ED, Shaw LJ, Califf RM: Risk stratification after myocardial infarction. Ann Intern Med 126:561-582, 1997. 414.

The MIAMI Trial Research Group: Metoprolol in acute myocardial infarction: Arrhythmias. Am J Cardiol 56:35G-38G, 1985. 415.

The MIAMI Trial Research Group: Metoprolol in acute myocardial infarction: Enzymatic estimation of infarct size. Am J Cardiol 56:27G-29G, 1985. 416.

Chae CU, Hennekens CH: Beta blockers. In Hennekens CH (ed): Clinical Trials in Cardiovascular Disease: A Companion to Braunwald's Heart Disease. Philadelphia, WB Saunders, 1999, pp 76-94. 417.

ISIS-1 (First International Study of Infarct Survival) Collaborative Group: Mechanisms for the early mortality reduction produced by beta-blockade started early in acute myocardial infarction: ISIS-1. Lancet 1:921-923, 1988. 418.

Krumholz HM, Radford MJ, Wang Y, et al: Early beta-blocker therapy for acute myocardial infarction in elderly patients. Ann Intern Med 131:648-654, 1999. 419.

Yusuf S, Peto R, Lewis J, et al: Beta blockade during and after myocardial infarction: An overview of the randomized trials. Prog Cardiovasc Dis 27:335-371, 1985. 420.

Pfeiffer MA, Braunwald E, Moye LA, et al: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 327:669-677, 1992. 421.

The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators: Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 342:821-828, 1993. 422.

Ambrosioni E, Borghi C, Magnani B, on behalf of the SMILE Study Investigators: Effects of the early administration of zofenopril on mortality and morbidity in patients with anterior myocardial infarction. Results of the Survival of Myocardial Infarction Long-Term Evaluation Trial. N Engl J Med 332:280-285, 1995. 423.

Kobler L, Torp-Pedersen C, Carlsen JE, et al: A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 333:1670-1676, 1995. 424.

ISIS-4 Collaborative Group: ISIS-4: A randomized factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet 345:669-685, 1995. 425.

Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico: GISSI-3: Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet 343:1115-1122, 1994. 426.

427.

Swedberg K, Held P, Kjekshus J, et al, on behalf of the CONSENSUS II Study Group: Effects of early

administration of enalapril on mortality in patients with acute myocardial infarction. Results of the Cooperative North Scandinavian Enalapril Survival Study II (CONSENSUS II). N Engl J Med 327:678-684, 1992. Chinese Cardiac Study Collaborative Group: Oral captopril versus placebo among 13,634 patients with suspected myocardial infarction: Interim report from the Chinese Cardiac Study (CCS-1). Lancet 345:686-687, 1995. 428.

ACE Inhibitor Myocardial Infarction Collaborative Group: Indications for ACE inhibitors in the early treatment of acute myocardial infarction: Systematic overview of individual data from 100,000 patients in randomized trials. Circulation 97:2202-2212, 1998. 429.

Pfeffer MA: ACE inhibitors in acute myocardial infarction: Patient selection and timing. Circulation 97:2192-2194, 1998. 430.

Rutherford JD, Pfeffer MA, Moye LA, et al: Effects of captopril on ischemic events after myocardial infarction: Results of the Survival and Ventricular Enlargement Trial. Circulation 90:1731-1738, 1994. 431.

Pfeffer MA: Enhancing cardiac protection after myocardial infarction: Rationale for newer clinical trials of angiotensin receptor blockers. Am Heart J 139:S23-S28, 2000. 431A.

Dickstein K, Kjekshus J: Comparison of the effects of losartan and captopril on mortality in patients after acute myocardial infarction: The OPTIMAAL trial design. Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan. Am J Cardiol 83:477-481, 1999. 432.

Lindsay HSJ, Zaman AG, Cowan JC: ACE inhibitors after myocardial infarction: Patient selection or treatment for all? Br Heart J 73:397-400, 1995. 433.

Pfeffer MA, Greaves SC, Arnold JM, et al: Early versus delayed angiotensin-converting enzyme inhibition therapy in acute myocardial infarction: The healign and early afterload reducing therapy trial. Circulation 95:2643-2651, 1997. 434.

435.

Jugdutt BI: Nitrates in myocardial infarction. Cardiovasc Drugs Ther 8:635-646, 1994.

436.

Abrams J: The role of nitrates in coronary heart disease. Arch Intern Med 155:357-364, 1995.

Yusuf S, Held P, Furberg C: Update of effects of calcium antagonists in myocardial infarction or angina in light of the second Danish Verapamil Infarction Trial (DAVIT-II) and other recent studies. Am J Cardiol 67:1295-1297, 1991. 437.

Furberg CD, Psaty BM, Meyer JV: Nifedipine: Dose-related increase in mortality in patients with coronary heart disease. Circulation 92:1326-1331, 1995. 438.

Rogers W, Bowlby L, Chandra N, et al: Treatment of myocardial infarction in the United States (1990 to 1993). Observations from the National Registry of Myocardial Infarction. Circulation 90:2103-2114, 1994. 439.

Yusuf S: Calcium antagonists in coronary artery disease and hypertension: Time for reevaluation? Circulation 92:1079-1082, 1995. 440.

Opie LH, Messerli FH: Nifedipine and mortality: Grave defects in the dossier. Circulation 92:1068-1073, 1995. 441.

Report of the Holland Interuniversity Nifedipine/Metoprolol Trial Research Group. Early treatment of unstable angina in the coronary care unit: A randomised, double-blind, placebo-controlled comparison of recurrent ischaemia and thrombolytic therapy in patients treated with nifedipine or metoprolol or both. Br Heart J 56:400, 1986. 442.

The Danish Study Group on Verapamil in Myocardial Infarction: Verapamil in acute myocardial infarction. Eur Heart J 54:516-528, 1984. 443.

Gibson RS, Boden WE, Theroux P, et al: Diltiazem and reinfarction in patients with non-Q wave myocardial infarction: Results of a double-blind, randomized, multicenter trial. N Engl J Med 315:423-429, 1986. 444.

Hansen JF: Treatment with verapamil after an acute myocardial infarction: Review of the Danish studies on verapamil in myocardial infarction (DAVIT I and II). Drugs 2:43-53, 1991. 445.

The Multicenter Diltiazem Postinfarction Trial Research Group: The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 319:385-392, 1988. 446.

The Danish Study Group on Verapamil in Myocardial Infarction: Effect of verapamil on mortality and major events after acute infarction (the Danish Verapamil Infarction Trial II-DAVIT II). Am J Cardiol 66:779, 1990. 447.

Boden WE, van Gilst WH, Scheldewaert RG: Diltiazem in acute myocardial infarction treated with thrombolytic agents: A randomised placebo-controlled trial. Incomplete Infarction Trial of European Research Collaborators Evaluating Prognosis post-Thrombolysis (INTERCEPT). Lancet 355:1751-6, 2000. 448.

Leitch JW, McElduff P, Dobson A, Heller R: Outcome with calcium channel antagonists after myocardial infarction: A community-based study. J Am Coll Cardiol 31:111-117, 1998. 449.

Shechter M, Kaplinsky E, Rabinowitz B: The rationale of magnesium supplementation in acute myocardial infarction: A review of the literature. Arch Intern Med 152:2189-2196, 1992. 450.

Shechter M, Hod H, Kaplinsky E, et al: Magnesium therapy in acute myocardial infarction when patients are not candidates for thrombolytic therapy. Am J Cardiol 75:321-323, 1995. 451.

MAGIC Steering Committee: Rationale and design of the Magnesium in Coronaries (MAGIC) study: A clinical trial to reevaluate the efficacy of early administration of magnesium in acute myocardial infarction. Am Heart J 139: 10-14, 2000. 452.

Rogers WJ, Segall PH, McDaniel HG, et al: Prospective randomized trial of glucose-insulin-potassium in acute myocardial infarction. Am J Cardiol 43:801, 1979. 453.

1216

Fath-Ordoubadi F, Beatt KJ: Glucose-insulin-potassium therapy for treatment of acute myocardial infarction: An overview of randomized placebo-controlled trials. Circulation 96:1152-1156, 1997. 454.

Diaz R, Paolasso EA, Piegas LS, et al: Metabolic modulation of acute myocardial infarction. The ECLA (Estudios Cardiologicos Latinoamerica) Collaborative Group. Circulation 98:2227-2234, 1998. 455.

Apstein CS: Glucose-insulin-potassium for acute myocardial infarction: Remarkable results from a new prospective, randomized trial. Circulation 98:2223-2226, 1998. 456.

Opie LH: Proof that glucose-insulin-potassium provides metabolic protection of ischaemic myocardium? Lancet 353:768-769, 1999. 457.

Malmberg K, Ryden L, Efendic S, et al: Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI Study): Effects on mortality at 1 year. J Am Coll Cardiol 26:57-65, 1995. 458.

Collaborative Organization for RheothRx Evaluation (CORE). Effects of RheothRx on mortality, morbidity, left ventricular function, and infarct size in patients with acute myocardial infarction. Circulation 96:192-201, 1997. 459.

HALT-AMI Trial Presented at 72nd Scientific Sessions of the American Heart Association, Atlanta, GA, Nov. 1999. 460.

HEMODYNAMIC DISTURBANCES Swan HJC, Ganz W, Forrester JS, et al: Catheterization of the heart in man with use of a flow-directed balloon-tipped catheter. N Engl J Med 283:447, 1970. 461.

462.

Ganz LI, Friedman PL: Supraventricular tachycardia. N Engl J Med 332:162-173, 1995.

Mermel LA: Prevention of intravascular catheter-related infections. Ann Intern Med 132:391-402, 2000. 462A.

Veenstra DL, Saint S, Saha S, et al: Efficacy of antiseptic-impregnated central venous catheters in preventing catheter-related bloodstream infection: A meta-analysis. JAMA 281:261-267, 1999. 463.

Ali AS, Rybicki BA, Alam M, et al: Clinical predictors of heart failure in patients with first acute myocardial infarction. Am Heart J 138:1133-1139, 1999. 464.

Handley DA, Anderson AJ, Koester J, Snider ME: New millennium bronchodilators for asthma: Single-isomer beta agonists. Curr Opin Pulm Med 6:43-49, 2000. 465.

Marchionni N, Pini R, Vanucci A, et al: Hemodynamic effects of digoxin in acute myocardial infarction in man: A randomized controlled trial. Am Heart J 109:63-68, 1985. 466.

Moss AJ, Davis HT, Conard DL, et al: Digitalis-associated cardiac mortality after myocardial infarction. Circulation 64:1150-1156, 1981. 467.

Ryan TJ, Bailey KR, McCabe CH, et al: The effects of digitalis on survival in high-risk patients with coronary artery disease. Circulation 67:735-742, 1983. 468.

Digitalis Subcommittee of the Multicenter Post-Infarction Research Group. The mortality risk associated with digitalis treatment after myocardial infarction. Cardiovasc Drugs Ther 1:125-132, 1987. 469.

Bigger JT, Fleiss JL, Rolnitzky LM et al: Effect of digitalis treatment on survival after acute myocardial infarction. Am J Cardiol 55:623-630, 1985. 470.

Muller JE, Turi ZG, Stone PH, et al: Digoxin therapy and mortality after myocardial infarction. N Engl J Med 314:265-271, 1986. 471.

Maekawa K, Liang CS, Hood WBJ. Comparison of dobutamine and dopamine in acute myocardial infarction: Effects of systemic hemodynamics, plasma catecholamines, blood flows and infarct size. Circulation 67:750, 1983. 472.

473.

Barry WL, Sarembock IJ: Cardiogenic shock: Therapy and prevention. Clin Cardiol 21:72-80, 1998.

Hochman JS, Buller CE, Sleeper LA, et al, for the SHOCK Investigators: Cardiogenic shock complicating acute myocardial infarction--Etiologies, management and outcome: A report from the SHOCK Trial Registry. J Am Coll Cardiol 36(3, suppl 1):1063-1070, 2000. 473A.

Scheidt S, Ascheim R, Killip T: Shock after acute myocardial infarction: A clinical and hemodynamic profile. Am J Cardiol 26:556-564, 1970. 474.

Goldberg RJ, Samad NA, Yarzebski J, et al: Temporal trends in cardiogenic shock complicating acute myocardial infarction. N Engl J Med 340:1162-1168, 1999. 475.

Hasdai D, Califf RM, Thompson TD, et al: Predictors of cardiogenic shock after thrombolytic therapy for acute myocardial infarction. J Am Coll Cardiol 35:136-43, 2000. 475A.

Holmes DR Jr, Bates ER, Kleiman NS, et al: Contemporary reperfusion therapy for cardiogenic shock: The GUSTO-I trial experience. The GUSTO-I Investigators. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries. J Am Coll Cardiol 26:668-674, 1995. 476.

Zeymer U, Neuhaus KL, Wegscheider K, et al: Effects of thrombolytic therapy in acute inferior myocardial infarction with or without right ventricular involvement. HIT-4 Trial Group. Hirudin for Improvement of Thrombolysis. J Am Coll Cardiol 32:876-881, 1998. 477.

Mueller H, Ayres SM, Conklin EF, et al: The effects of intra-aortic counter pulsation on cardiac performance and metabolism in shock associated with acute myocardial infarction. J Clin Invest 50:1885, 1971. 478.

Holmes DR Jr, Califf RM, Van de Werf F, et al: Difference in countries' use of resources and clinical outcome for patients with cardiogenic shock after myocardial infarction: Results from the GUSTO trial. Lancet 349:75-78, 1997. 479.

Hochman JS, Sleeper LA, Webb JG, et al: Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock. N Engl J Med 341:625-634, 1999. 480.

Shiraki H, Yoshikawa T, Anzai T, et al: Association between preinfarction angina and a lower risk of right ventricular infarction. N Engl J Med 338:941-947, 1998. 481.

Inoue K, Ito H, Kitakaze M, et al: Antecedent angina pectoris as a predictor of better functional and clinical outcomes in patients with an inferior wall acute myocardial infarction. Am J Cardiol 83:159-163, 1999. 482.

Robalino BD, Whitlow PL, Underwood DA, Salcedo EE: Electrocardiographic manifestations of right ventricular infarction. Am Heart J 118:138, 1989. 483.

484.

Hurst JW: Comments about the electrocardiographic signs of right ventricular infarction. Clin Cardiol

21:289-291, 1998. Gewirtz H, Gold HK, Fallon JT, et al: Role of right ventricular infarction in cardiogenic shock associated with inferior myocardial infarction. Br Heart J 42:719, 1979. 485.

Reeder GS: Identification and treatment of complications of myocardial infarction. Lancet 70:880-884, 1995. 486.

Reddy SG, Roberts WC: Frequency of rupture of the left ventricular free wall or ventricular septum among necropsy cases of fatal acute myocardial infarction since introduction of coronary care units. Am J Cardiol 63:906, 1989. 487.

Pohjola-Sintonen S, Muller JE, Stone PH, et al: Ventricular septal and free wall rupture complicating acute myocardial infarction: Experience in the Multicenter Limitation of Infarct Size. Am Heart J 117:809, 1989. 488.

Pappas PJ, Cernaianu AC, Baldino WA, et al: Ventricular free-wall rupture after myocardial infarction. Chest 99:892, 1991. 489.

Figueras J, Cortadellas J, Calvo F, Soler-Soler J: Relevance of delayed hospital admission on development of cardiac rupture during acute myocardial infarction: Study in 225 patients with free wall, septal or papillary muscle rupture. J Am Coll Cardiol 32:135-139, 1998. 490.

Bulkley BH, Roberts WC: Steroid therapy during acute myocardial infarction: A cause of delayed healign and of ventricular aneurysm. Am J Med 56:244, 1974. 491.

Becker RC, Hochman JS, Cannon CP, et al: Fatal cardiac rupture among patients treated with thrombolytic agents and adjunctive thrombin antagonists: Observations from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction 9 Study. J Am Coll Cardiol 33:479-487, 1999. 492.

Crenshaw BS, Granger CB, Birnbaum Y, et al: Risk factors, angiographic patterns, and outcomes in patients with ventricular septal defect complicating acute myocardial infarction. Circulation 101:27-32, 2000. 493.

Held AC, Cole PL, Lipton B, et al: Rupture of the interventricular septum complicating acute myocardial infarction: A multicenter analysis of clinical findings and outcome. Am Heart J 116:1330, 1988. 494.

Figueras J, Cortadellas J, Soler-Soler J: Comparison of ventricular septal and left ventricular free wall rupture in acute myocardial infarction. Am J Cardiol 81:495-497, 1998. 495.

Radford MJ, Johnson RA, Daggett WM, et al: Ventricular septal rupture: A review of clinical and physiologic features and an analysis of survival. Circulation 64:545, 1981. 496.

Manning WJ, Waksmonski CA, Boyle NG: Papillary muscle rupture complicating inferior myocardial infarction: Identification with transesophageal echocardiography. Am Heart J 129:191-193, 1995. 497.

Come PC, Riley MF, Weintraub R, et al: Echocardiographic detection of complete and partial papillary muscle rupture during acute myocardial infarction. Am J Cardiol 56:787, 1985. 498.

Verma R, Freeman I: Images in clinical medicine:. Rupture of papillary muscle during acute myocardial infarction. N Engl J Med 341:247, 1999. 499.

ARRHYTHMIAS Pantridge JF, Adgey AAJ: Pre-hospital coronary care: The mobile coronary care unit. Am J Cardiol 24:666, 1969. 500.

Aufderheide TP: Arrhythmias associated with acute myocardial infarction and thrombolysis. Emerg Med Clin North Am 16:583-600, 1998. 501.

Coronel R, Wilms-Schopman FJ, Janse MJ: Profibrillatory effects of intracoronary thrombus in acute regional ischemia of the in situ porcine heart. Circulation 96:3985-3991, 1997. 502.

Greenspon AJ, Hsu SS, Borge R, et al: Insights into the mechanism of sustained ventricular tachycardia after myocardial infarction in a closed chest porcine model using a multielectrode "basket" catheter. J Cardiovasc Electrophysiol 10:1501-1516, 1999. 503.

Karagueuzian HS, Mandel WJ: Electrophysiologic mechanisms of ischemic ventricular arrhythmias: Experimental and clinical correlations. In Mandel WJ (ed): Cardiac arrhythmias: Their mechanisms, diagnosis, and management. Philadelphia, JB Lippincott, 1995, pp 563-603. 504.

505.

Janse MJ: Ischemia as a trigger for arrhythmias. ACC Curr J Rev 8:15-17, 1999.

Carmeliet E: Cardiac ionic currents and acute ischemia: From channels to arrhythmias. Physiol Rev 79:917-1017, 1999. 506.

Bloor CM, Ehsani A, White FC, Sobel BE: Ventricular fibrillation threshold in acute myocardial infarction and its relation to myocardial infarct size. Cardiovasc Res 9:468, 1975. 507.

1217

Roque F, Amuchastegui LM, Lopez Morillos MA, et al: Beneficial effects of timolol on infarct size and late ventricular tachycardia in patients with myocardial infarction. Circulation 76:610, 1987. 508.

Ruskin J, McHale PA, Harley A, Greenfield JC Jr: Pressure-flow studies in man; Effects of atrial systole on left ventricular function. J Clin Invest 49:472, 1970. 509.

Cannom DS, Prystowsky EN: Management of ventricular arrhythmias: Detection, drugs, and devices. JAMA 281:172-179, 1999. 510.

Antman EM, Berlin JA: Declining incidence of ventricular fibrillation in myocardial infarction: Implications for prophylactic use of lidocaine. Circulation 86:764-773, 1992. 511.

Hine LK, Laird N, Hewitt P, Chalmers TC: Meta-analytic evidence against prophylactic use of lidocaine in acute myocardial infarction. Arch Intern Med 149:2694-2698, 1989. 512.

Sadowski ZP, Alexander JH, Skrabucha B, et al: Multicenter randomized trial and a systematic overview of lidocaine in acute myocardial infarction. Am Heart J 137:792-798, 1999. 513.

514.

Alexander JH, Granger CB, Sadowski Z, et al: Prophylactic lidocaine use in acute myocardial

infarction: Incidence and outcomes from two international trials. The GUSTO-I and GUSTO-IIb Investigators. Am Heart J 137:799-805, 1999. Tan HL, Lie KI: Prophylactic lidocaine use in acute myocardial infarction revisited in the thrombolytic era. Am Heart J 137:770-773, 1999. 515.

Yusuf S, Sleight P, Rossi P, et al: Reduction in infarct size, arrhythmias and chest pain by early intravenous beta blockade in suspected acute myocardial infarction. Circulation 67:12, 1983. 516.

Norris RM, Brown MA, Clark ED, et al: Prevention of ventricular fibrillation during acute myocardial infarction by intravenous propranolol. Lancet 2:833-836, 1984. 517.

Gressin V, Gorgels A, Louvard Y, et al: ST-segment normalization time and ventricular arrhythmias as electrocardiographic markers of reperfusion during intravenous thrombolysis for acute myocardial infarction. Am J Cardiol 71:1436-1439, 1993. 518.

Maggioni AP, Zuanetti G, Franzosi MG, et al: Prevalence and prognostic significance of ventricular arrhythmias after acute myocardial infarction in the fibrinolytic era: GISSI-2 results. Circulation 87:312-322, 1993. 519.

Wolfe CL, Nibley C, Bhandari A, et al: Polymorphous ventricular tachycardia associated with acute myocardial infarction. Circulation 84:1543-1551, 1991. 520.

Gheeraert PJ, Henriques JP, De Buyzere ML, et al: Out-of-hospital ventricular fibrillation in patients with acute myocardial infarction: Coronary angiographic determinants. J Am Coll Cardiol 35:144-50, 2000. 520A.

Campbell RWF, Murray A, Julian DG: Ventricular arrhythmias in first 12 hours of acute myocardial infarction: Natural history study. Br Heart J 46:351-357, 1981. 521.

Newby KH, Thompson T, Stebbins A, et al: Sustained ventricular arrhythmias in patients receiving thrombolytic therapy: Incidence and outcomes. The GUSTO Investigators. Circulation 98:2567-2573, 1998. 522.

Nordehaug JE, Johannessen KA, von der Lippe G: Serum potassium concentration as a risk factor of ventricular arrhythmias early in acute myocardial infarction. Circulation 71:645, 1985. 523.

Volpi A, Maggioni A, Franzosi MG, et al: In-hospital prognosis of patients with acute myocardial infarction complicated by primary ventricular fibrillation. N Engl J Med 317:257-261, 1987. 524.

Volpi A, Cavalli A, Santoro L, Negri E: Incidence and prognosis of early primary ventricular fibrillation in acute myocardial infarction--results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2) database. Am J Cardiol 82:265-271, 1998. 525.

Behar S, Reicher Ress H, Schechter M, et al: Frequency and prognostic significance of secondary ventricular fibrillation complicating acute myocardial infarction. Am J Cardiol 71:152-156, 1993. 526.

Lown B, Fakhro AM, Hood WB, Thorn GW: The coronary care unit: New perspectives and directions. JAMA 199:188-198, 1967. 527.

Harrison DC: Should lidocaine be administered routinely to all patients after acute myocardial infarction? Circulation 58:581-584, 1978. 528.

MacMahon S, Collins R, Peto R, et al: Effects of prophylactic lidocaine in suspected acute myocardial infarction: An overview of results from the randomized, controlled trials. JAMA 260:1910-1916, 1988. 529.

ISIS-1 (First International Study of Infarct Survival) Collaborative Group: Randomized trial of intravenous atenolol among 16,027 cases of suspected acute myocardial infarction. Lancet 2:57-66, 1986. 530.

Nordrehaug JE, Lippe GVD: Hypokalemia and ventricular fibrillation in acute myocardial infarction. Br Heart J 50:525-529, 1983. 531.

Higham PD, Adams PC, Murray A, Campbell RWF: Plasma potassium, serum magnesium and ventricular fibrillation: A prospective study. Q J Med 86:609-617, 1993. 532.

Mark AL: The Bezold-Jarisch reflex revisited: Clinical implications of inhibitory reflexes originating in the heart. J Am Coll Cardiol 1:90, 1983. 533.

Koren G, Weiss AT, Ben-David J, et al: Bradycardia and hypotension following reperfusion with streptokinase (Bezold-Jarish reflex): A sign of coronary thrombolysis and myocardial salvage. Am Heart J 112:468-471, 1986. 534.

Come PC, Pitt B: Nitroglycerin-induced severe hypotension and bradycardia in patients with acute myocardial infarction. Circulation 54:624-628, 1976. 535.

Zuanetti G, Mantini L, Hernandez-Bernal F, et al: Relevance of heart rate as a prognostic factor in patients with acute myocardial infarction: Insights from the GISSI-2 study. Eur Heart J 19(Suppl F):F19-F26, 1998. 536.

Swart G, Brady WJ Jr, DeBehnke DJ, et al: Acute myocardial infarction complicated by hemodynamically unstable bradyarrhythmia: Prehospital and ED treatment with atropine. Am J Emerg Med 17:647-652, 1999. 537.

Simons GR, Sgarbossa E, Wagner G, et al: Atrioventricular and intraventricular conduction disorders in acute myocardial infarction: A reappraisal in the thrombolytic era. Pacing Clin Electrophysiol 21:2651-2663, 1998. 538.

Harpaz D, Behar S, Gottlieb S, et al: Complete atrioventricular block complicating acute myocardial infarction in the thrombolytic era. SPRINT Study Group and the Israeli Thrombolytic Survey Group. Secondary Prevention Reinfarction Israeli Nifedipine Trial. J Am Coll Cardiol 34:1721-1728, 1999. 539.

Archbold RA, Sayer JW, Ray S, et al: Frequency and prognostic implications of conduction defects in acute myocardial infarction since the introduction of thrombolytic therapy. Eur Heart J 19:893-898, 1998. 540.

Goldberg RJ, Zevallos JC, Yarzebski J, et al: Prognosis of acute myocardial infarction complicated by complete heart block (the Worcester Heart Attack Study). Am J Cardiol 69:1135-1141, 1992. 541.

Bilbao FJ, Zabalza IE, Vilanova JR, Froupe J: Atrioventricular block in posterior acute myocardial infarction: A clinicopathologic correlation. Circulation 75:733, 1987. 542.

Bertolet BD, McMurtrie EB, Hill JA, Bellardinelli L: Theophylline for the treatment of atrioventricular block after myocardial infarction. Ann Int Med 123:509-511, 1995. 543.

Altun A, Kirdar C, Ozbay G: Effect of aminophylline in patients with atropine-resistant late advanced atrioventricular block during acute inferior myocardial infarction. Clin Cardiol 21:759-762, 1998. 544.

Lilavie CJ, Gersh PJ: Mechanical and electrical complication of acute myocardial infarction. Mayo Clin Proc 65:709-730, 1990. 545.

Hindman MC, Wagner GS, JaRo M, et al: The clinical significance of bundle branch block complicating acute myocardial infarction: 2. Indications for temporary and permanent pacemaker insertion. Circulation 58:689-699, 1978. 546.

Klein RC, Vera Z, Mason DT: Intraventricular conduction defects in acute myocardial infarction: Incidence, prognosis and therapy. Am Heart J 108:1007-1013, 1984. 547.

Sgarbossa EB, Pinski SL, Topol EJ, et al: Acute myocardial infarction and complete bundle branch block at hospital admission: Clinical characteristics and outcome in the thrombolytic era. GUSTO-I Investigators. Global Utilization of Streptokinase and t-PA [tissue-type plasminogen activator] for Occluded Coronary Arteries. J Am Coll Cardiol 31:105-110, 1998. 548.

Herlitz J, Karlson BW, Bang A, Sjolin M: Mortality and risk indicators for death during five years after acute myocardial infarction among patients with and without ST elevation on admission electrocardiogram. Cardiology 89:33-39, 1998. 549.

Go AS, Barron HV, Rundle AC, et al: Bundle-branch block and in-hospital mortality in acute myocardial infarction. National Registry of Myocardial Infarction 2 Investigators. Ann Intern Med 129:690-697, 1998. 550.

Hindman MC, Wagner GS, JaRo M, et al: The clinical significance of bundle branch block complicating acute myocardial infarction: I. Clinical characteristics, hospital mortality, and one-year follow-up. Circulation 58:679-688, 1978. 551.

Lamas GA, Mueller JE, Turi AG, et al: A simplified method to predict occurrence of complete heart block during acute myocardial infarction. Am J Cardiol 57:1213, 1986. 552.

Scheinman MM, Gonzalez RP: Fascicular block and acute myocardial infarction. JAMA 244:2646-2649, 1980. 553.

Zoll PM, Zoll RH, Falk RH, et al: External non-invasive temporary cardiac pacing: Clinical trials. Circulation 71:937, 1985. 554.

DeSanctis RW, Block P, Hutter AM: Tachyarrhythmias in myocardial infarction. Circulation 45:681, 1972. 555.

Eldar M, Canetti M, Rotstein Z, et al: Significance of paroxysmal atrial fibrillation complicating acute myocardial infarction in the thrombolytic era. SPRINT and Thrombolytic Survey Groups. Circulation 97:965-970, 1998. 556.

Pedersen OD, Bagger H, Kober L, Torp-Pedersen C: The occurrence and prognostic significance of atrial fibrillation/flutter following acute myocardial infarction. TRACE Study group. TRAndolapril Cardiac Evaluation. Eur Heart J 20:748-754, 1999. 557.

Waldecker B: Atrial fibrillation in myocardial infarction complicated by heart failure: Cause or consequence? Eur Heart J 20:710-712, 1999. 558.

Mahaffey KW, Granger CB, Sloan MA, et al: Risk factors for in-hospital nonhemorrhagic stroke in patients with acute myocardial infarction treated with thrombolysis: Results from GUSTO-I. Circulation 559.

97:757-764, 1998. Singh BN: Current antiarrhythmic drugs: An overview of mechanisms of action and potential clinical utility. J Cardiovasc Electrophysiol 10:283-301, 1999. 560.

Betriu A, Califf RM, Bosch X, et al: Recurrent ischemia after thrombolysis: Importance of associated clinical findings. GUSTO-I Investigators. Global Utilization of Streptokinase and t-PA [tissue-plasminogen activator] for Occluded Coronary Arteries. J Am Coll Cardiol 31:94-102, 1998. 561.

Mueller HS, Forman SA, Manegus MA, et al: Prognostic significance of nonfatal reinfarction during 3-year follow-up: Results of the Thrombolysis in Myocardial Infarction (TIMI) Phase II Clinical Trial. J Am Coll Cardiol 26:900-907, 1995. 562.

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Detre KM, Lombardero MS, Brooks MM, et al: The effect of previous coronary-artery bypass surgery on the prognosis of patients with diabetes who have acute myocardial infarction. Bypass Angioplasty Revascularization Investigation Investigators. N Engl J Med 342:989-97, 2000. 562A.

Roux S, Christeller S, Ludin E: Effects of aspirin on coronary reocclusion and recurrent ischemia after thrombolysis: A meta-analysis. J Am Coll Cardiol 19:671-677, 1992. 563.

Simoons ML, Arnout J, van den Brand M, et al: Re-treatment with alteplase for early signs of reocclusion after thrombolysis. The European Cooperative Study Group. Am J Cardiol 71:524-528, 1993. 564.

Correale E, Maggioni AP, Romano S, et al: Pericardial involvement in acute myocardial infarction in the post-thrombolytic era: Clinical meaning and value. Clin Cardiol 20:327-331, 1997. 565.

Kloner R, Fishbein M, Lew H, et al: Mummification of the infarcted myocardium by high dose corticosteroids. Circulation 57:56, 1978. 566.

Dressler W: The post-myocardial infarction syndrome: A report of forty-four cases. Arch Intern Med 103:28, 1959. 567.

Reinecke H, Wichter T, Weyand M: Left ventricular pseudoaneurysm in a patient with Dressler's syndrome after myocardial infarction. Heart 80:98-100, 1998. 568.

Hellerstein HK, Martin JW: Incidence of thromboembolic lesions accompanying myocardial infarction. Am Heart J 33:443, 1947. 569.

Meizlish JL, Berger HJ, Plankey M, et al: Functional left ventricular aneurysm formation after acute anterior transmural myocardial infarction: Incidence, natural history, and prognostic implications. N Engl J Med 311:1001, 1984. 570.

Ha JW, Cho SY, Lee JD, Kang MS: Left ventricular aneurysm after myocardial infarction. Clin Cardiol 21:917, 1998. 571.

Davis MJE, Ireland MA: Effect of early anticoagulation on the frequency of left ventricular thrombi after anterior wall acute myocardial infarction. Am J Cardiol 57:1244-1247, 1986. 572.

Turpie AGG, Robinson JG, Doyle DJ, et al: Comparison of high-dose with low-dose subcutaneous heparin to prevent left ventricular mural thrombosis in patients with acute transmural anterior myocardial infarction. N Engl J Med 320:352-357, 1989. 573.

Halperin JL, Fuster V: Left ventricular thrombus and stroke after myocardial infarction: Toward prevention or perplexity? J Am Coll Cardiol 14:912, 1989. 574.

Stein B, Fuster V, Halperin JL, Chesebro JH: Antithrombotic therapy in cardiac disease: An emerging approach based on pathogenesis and risk. Circulation 80:1501-1513, 1989. 575.

Newby LK, Califf RM, Guerci A, et al: Early discharge in the thrombolytic era: An analysis of criteria for uncomplicated infarction from the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) trial. J Am Coll Cardiol 27:625-632, 1996. 576.

CONVALESCENCE AND POST-MYOCARDIAL INFARCTION CARE O'Connor GT, Buring JE, Yusuf S, et al: An overview of randomized trials of rehabilitation with exercise after myocardial infarction. Circulation 80:234, 1989. 577.

Barefoot JC, Schroll M: Symptoms of depression, acute myocardial infarction, and total mortality in a community sample. Circulation 93:1976-1980, 1996. 578.

Petrie KJ, Weinman J, Sharpe N, Buckley J: Role of patients' view of their illness in predicting return to work and functioning after myocardial infarction: Longitudinal study. BMJ 312:1191-1194, 1996. 579.

Frasure-Smith N, Lesperance F, Prince RH, et al: Randomised trial of home-based psychosocial nursing intervention for patients recovering from myocardial infarction. Lancet 350:473-479, 1997. 580.

Linden W, Stossel C, Maurice J: Psychosocial interventions for patients with coronary artery disease: A meta-analysis. Arch Intern Med 156:745-752, 1996. 581.

Thompson DR, Lewin RJ: Management of the post-myocardial infarction patient: Rehabilitation and cardiac neurosis. Heart 84:101-105, 2000. 581A.

American College of Physicians: Guidelines for risk stratification after myocardial infarction. Ann Intern Med 126:556-560, 1997. 582.

Mukharji J, Murray S, Lewis SE, et al: Is anterior ST depression with acute transmural inferior infarction due to posterior infarction? J Am Coll Cardiol 4:28, 1984. 583.

Fresco C, Carinci F, Maggioni AP, et al: Very early assessment of risk for in-hospital death among 11,483 patients with acute myocardial infarction. Am Heart J 138:1058-1064, 1999. 584.

Madsen JK, Grande P, Saunamaki K, et al: Danish multicenter randomized study of invasive versus conservative treatment in patients with inducible ischemia after thrombolysis in acute myocardial infarction (DANAMI). DANish trial in Acute Myocardial Infarction. Circulation 96:748-755, 1997. 585.

Volpi A, De VC, Franzosi MG, et al: Determinants of 6-month mortality in survivors of myocardial infarction after thrombolysis: Results of the GISSI-2 data base. The Ad hoc Working Group of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-2 Data Base. Circulation 88:416-429, 1993. 586.

Aguirre FV, Kern MJ, Hsia J, et al: Importance of myocardial infarct artery patency on the prevalence of ventricular arrhythmia and late potentials after thrombolysis in acute myocardial infarction. Am J Cardiol 68:1410-1416, 1991. 587.

Fletcher GF, Balady G, Froelicher VF, et al: Exercise standards: A statement for healthcare professionals from the American Heart Association. Circulation 91:580-615, 1995. 588.

Bates DW, Miller E, Bernstein SJ, et al: Coronary angiography and angioplasty after acute myocardial infarction. Ann Intern Med 126:539-550, 1997. 589.

Jain A, Myers GH, Sapin PM, O'Rourke RA: Comparison of symptom-limited and low level exercise tolerance tests early after myocardial infarction. J Am Coll Cardiol 22:1816-1820, 1993. 590.

Committee on Radionuclide Imaging: ACC/AHA Task Force Report: Guidelines for clinical use of cardiac radionuclide imaging. J Am Coll Cardiol 25:521-547, 1995. 591.

Kuntz KM, Tsevat J, Weinstein MC, Goldman I: Expert panel vs decision-analysis recommendations for postdischarge coronary angiography after myocardial infarction. JAMA 282:2246-2251, 1999. 592.

Moss AJ, Davis HT, DeCamilla J, Bayer LW: Ventricular ectopic beats and their relation to sudden and nonsudden cardiac death after myocardial infarction. Circulation 60:998-1003, 1979. 593.

Morganroth J, Bigger JT Jr. Pharmacologic management of ventricular arrhythmias after the Cardiac Arrhythmia Suppression Trial. Am J Cardiol 65:1497-1503, 1990. 594.

La Rovere MT, Bigger JT Jr, Marcus FI, et al: Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet 351:478-484, 1998. 595.

Julian D: The practical implications of clinical trials: Putting it all together. In Julian D, Braunwald E (eds): Management of Acute Myocardial Infarction. London, WB Saunders, 1994, pp 407-415. 596.

Krumholz HM, Cohen BJ, Tsevat J, et al: Cost-effectiveness of a smoking cessation program after myocardial infarction. J Am Coll Cardiol 22:1697-1702, 1993. 597.

Frasure-Smith N, Lesperance F, Talajic M: Depression following myocardial infarction: Impact on 6-month survival. JAMA 270:1819-1825, 1993. 598.

Bucher HC: Social support and prognosis following first myocardial infarction. J Gen Intern Med 9:409-417, 1994. 599.

Gallagher EJ, Viscoli CM, Horwitz RI: The relationship of treatment adherence to the risk of death after myocardial infarction in women. JAMA 270:742-744, 1993. 600.

601.

Knopp RH: Drug treatment of lipid disorders. N Engl J Med 341:498-511, 1999.

LaRosa JC, He J, Vupputuri S: Effect of statins on risk of coronary disease: A meta-analysis of randomized controlled trials. JAMA 282:2340-2346, 1999. 602.

Ansell BJ, Watson KE, Fogelman AM: An evidence-based assessment of the NCEP Adult Treatment Panel II guidelines. National Cholesterol Education Program. JAMA 282:2051-2057, 1999. 603.

Ridker PM, Rifai N, Pfeffer MA, et al: Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 100:230-235, 1999. 604.

Lee TH, Cleeman JI, Grundy SM, et al: Clinical goals and performance measures for cholesterol management in secondary prevention of coronary heart disease. JAMA 283:94-98, 2000. 605.

Rubins HB, Robins SJ, Collins D, et al: Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 341:410-418, 1999. 606.

Gutstein DE, Fuster V: Pathophysiologic bases for adjunctive therapies in the treatment and secondary prevention of acute myocardial infarction. Clin Cardiol 21:161-168, 1998. 607.

Col NF, Yarzebski J, Gore JM, et al: Does aspirin consumption affect the presentation or severity of acute myocardial infarction? Arch Intern Med 155:1386-1389, 1995. 608.

Alhaddad IA, Tkaczevski L, Siddiqui F, et al: Aspirin enhances the benefits of late reperfusion on infarct shape: A possible mechanism of the beneficial effects of aspirin on survival after acute myocardial infarction. Circulation 91:2819-2823, 1995. 609.

Hennekens CH, Dyken ML, Fuster V: Aspirin as a therapeutic agent in cardiovascular disease: A statement for healthcare professionals from the American Heart Association. Circulation 96:2751-2753, 1997. 610.

CAPRIE Steering Committee: A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 348:1329-1339, 1996. 611.

Hall AS, Murray GD, Ball SG: Follow-up study of patients randomly allocated ramipril or placebo for heart failure after acute myocardial infarction: AIRE Extension (AIREX) Study. Acute Infarction Ramipril Efficacy. Lancet 349:1493-1497, 1997. 612.

Torp-Pedersen C, Kober L: Effect of ACE inhibitor trandolapril on life expectancy of patients with reduced left-ventricular function after acute myocardial infarction. TRACE Study Group. Trandolapril Cardiac Evaluation. Lancet 354:9-12, 1999. 613.

Gustafsson I, Torp-Pedersen C, Kober L, et al: Effect of the angiotensin-converting enzyme inhibitor trandolapril on mortality and morbidity in diabetic patients with left ventricular dysfunction after acute myocardial infarction. Trace Study Group. J Am Coll Cardiol 34:83-89, 1999. 614.

Packer M, Poole-Wilson PA, Armstrong PW, et al: Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation 100:rt1-rt7, 1999. 615.

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Domanski MJ, Exner DV, Borkowf CB, et al: Effect of angiotensin converting enzyme inhibition on sudden cardiac death in patients following acute myocardial infarction. A meta-analysis of randomized clinical trials. J Am Coll Cardiol 33:598-604, 1999. 616.

The EUCLID Study Group: Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. Lancet 349:1787-1792, 1997. 617.

The Heart Outcomes Prevention Evaluation and Study Investigators: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 342:145-153, 2000. 618.

Beta-Blocker Pooling Project Research Group: The Beta-Blocker Pooling Project (BBPP): Subgroup findings from randomized trials in postinfarction patients. Eur Heart J 9:8, 1988. 619.

Barron HV, Viskin S, Lundstrom RJ, et al: Effect of beta-adrenergic blocking agents on mortality rate in patients not revascularized after myocardial infarction: Data from a large HMO. Am Heart J 134:608-613, 1997. 620.

Barron HV, Viskin S, Lundstrom RJ, et al: Beta-blocker dosages and mortality after myocardial infarction: Data from a large health maintenance organization. Arch Intern Med 158:449-453, 1998. 621.

Krumholz HM, Radford MJ, Wang Y, et al: National use and effectiveness of beta-blockers for the treatment of elderly patients after acute myocardial infarction: National Cooperative Cardiovascular Project. JAMA 280:623-629, 1998. 622.

Crockett SE, Davis D, Golden WE, et al: Quality Care Alert: Beta Blocker Prophylaxis after Myocardial Infarction. Chicago, American Medical Association, 1998. 623.

Marciniak TA, Ellerbeck EF, Radford MJ, et al: Improving the quality of care for Medicare patients with acute myocardial infarction: Results from the Cooperative Cardiovascular Project. JAMA 279:1351-1357, 1998. 624.

Goldman L, Sia STB, Cook EF, et al: Costs and effectiveness of routine therapy with long-term beta-adrenergic antagonists after acute myocardial infarction. N Engl J Med 319:152, 1988. 625.

Yusuf S, Wittes J, Friedman L: Overview of results of randomized clinical trials in heart disease: I. Treatments following myocardial infarction. JAMA 260:2088-2093, 1988. 626.

Brand DA, Newcomer LN, Freiburger A, et al: Cardiologists' practices compared with practice guidelines: Use of beta-blockade after myocardial infarction. J Am Coll Cardiol 26:1432, 1995. 627.

Freemantle N, Cleland J, Young P, et al: beta Blockade after myocardial infarction: Systematic review and meta regression analysis. BMJ 318:730-737, 1999. 628.

Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) Research Group: Effect of long-term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction. Lancet 343:499-503, 1994. 629.

van Bergen PFMM, Jonker JJC, van Hout BA, et al: Costs and effects of long-term oral anticoagulant treatment after myocardial infarction. JAMA 273:925-928, 1995. 630.

Coumadin Aspirin Reinfarction Study (CARS) Investigators: Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction. Lancet 350:389-396, 1997. 631.

632.

CHAMP Trial Presented at 72nd Scientific Sessions of AHA, Atlanta, GA, 1999.

Teo KK, Yusuf S, Furberg CD: Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction. JAMA 270:1589-1595, 1993. 633.

Epstein AE, Hallstrom AP, Rogers WJ, et al: Mortality following ventricular arrhythmia suppression by encainide, flecainide, and moricizine after myocardial infarction: The original design concept of the Cardiac Arrhythmia Suppression Trial (CAST). JAMA 270:2451-2455, 1993. 634.

Echt DS, Liebson PR, Mitchell LB, et al: Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 324:781-788, 1991. 635.

The Cardiac Arrhythmia Suppression Trial II Investigators: Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med 327:227-233, 1992. 636.

Akiyama T, Pawitan Y, Greenberg H, et al: Increased risk of death and cardiac arrest from encainide and flecainide in patients after non-Q-wave acute myocardial infarction in the Cardiac Arrhythmia Suppression Trial. CAST Investigators. Am J Cardiol 68:1551-1555, 1991. 637.

Krishnan SC, Shivkumar K, Garan H, Ruskin JN: Increased vulnerability of the subendocardium to ischaemic injury: An electrophysiological explanation. Lancet 346:1612-1614, 1995. 638.

Waldo AL, Camm AJ, deRuyter H, et al: Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet 348:7-12, 1996. 639.

Cairns JA, Connolly SJ, Roberts R, Gent M: Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Lancet 349:675-682, 1997. 640.

Julian DG, Camm AJ, Frangin G, et al: Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. European Myocardial Infarct Amiodarone Trial Investigators. Lancet 349:667-674, 1997. 641.

Elizari MV, Martinez JM, Belziti C, et al: Morbidity and mortality following early administration of amiodarone in acute myocardial infarction. GEMICA study investigators, GEMICA Group, Buenos Aires, Argentina. Grupo de Estudios Multicentricos en Argentina. Eur Heart J 21:198-205, 2000. 641A.

The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators: A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med 337:1576-1583, 1997. 642.

Buxton AE, Lee KL, Fisher JD, et al: A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med 341:1882-1890, 1999. 643.

Moss AJ, Hall WJ, Cannom DS, et al: Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 335:1933-1940, 1996. 644.

Mendelsohn ME, Karas RH: The protective effects of estrogen on the cardiovascular system. N Engl J Med 340:1801-1811, 1999. 645.

646.

Sourander L, Rajala T, Raiha I, et al: Cardiovascular and cancer morbidity and mortality and sudden

cardiac death in postmenopausal women on oestrogen replacement therapy (ERT). Lancet 352:1965-1969, 1998. Hulley S, Grady D, Bush T, et al: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 280:605-613, 1998. 647.




GUIDELINES DIAGNOSIS AND MANAGEMENT OF ACUTE MYOCARDIAL INFARCTION Thomas H. Lee Key guidelines for the diagnosis and management of acute myocardial infarction (AMI) have been published by the American College of Emergency Physicians (ACEP)[1] and by an ACC/AHA Committee.[2] Additional influential guidelines on management of patients with acute ischemic heart disease syndromes have been published by the National Heart Attack Alert Program (NHAAP),[3] the Agency for Health Care Policy and Research (AHCPR),[4] and an ACC/AHA task force on unstable angina.[5]

Evaluation of Patients with Acute Chest Pain (Table 35-G-1) In all of these guidelines, the recommended actions in response to the data that are collected during this evaluation are intended to lead to timely care for patients with AMI, unstable angina, aortic dissection, and pulmonary embolus. The ACC/AHA guidelines on unstable angina and non-ST segment elevation MI emphasize that patients with possible acute coronary syndromes should be evaluated at a facility at which a 12-lead electrocardiogram (ECG) can be performed (as opposed to over the telephone). [5] According to these guidelines, patients with suspected acute coronary syndromes of symptom duration of more than 20 minutes, hemodynamic instability, or recent syncope or presyncope are most appropriately seen in an emergency department or specialized chest pain unit. Emergency transport services should be used when available for such patients; private vehicles are acceptable alternatives only if waiting for an emergency

vehicle would impose a long delay. The ACEP statement on the initial evaluation of patients with acute chest pain[1] include "rules" and "guidelines" about the data that should be recorded and the actions that should follow from certain findings. In these guidelines, "rules" are actions that are general principles of good practice; deviation from a "rule" should generally be justified in the record. "Guidelines" are actions that should be considered, but failure to follow a "guideline" does not necessarily imply that care was improper. The ACEP policy statement includes in its appendix forms that can be used to assess compliance with their "rules" and to remind clinicians of their content. The ACEP statement indicates that the routine evaluation of nontraumatic chest pain should include a history that obtains data on the

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TABLE 35--G-1 -- EVALUATION OF ACUTE CHEST PAIN: EXCERPTS FROM THE CLINICAL POLICY OF THE AMERICAN COLLEGE OF EMERGENCY PHYSICIANS (ACEP) (1995) Variable Finding Rule* Guideline

Pain

Ongoing and severe Intravenous access and crushing and substernal or same as Supplemental oxygen previous pain diagnosed Cardiac monitor as MI ECG

Serum cardiac markers CXR Anticoagulation

Aspirin Nitrates Management of ongoing pain Admit Severe or pressure or ECG substernal or exertional or radiating to jaw, neck, shoulder, or arm

Intravenous access Supplemental oxygen Cardiac monitor Serum cardiac markers CXR Nitrates Management of ongoing pain Admit

Tearing, severe, and radiating to back

Large-bore intravenous access Supplemental oxygen

Differential upper extremity blood pressures

Cardiac monitor

Aortic imaging

CXR, ECG

Management of ongoing pain Admit

Similar to that of previous pulmonary embolus

Intravenous access

CXR

Supplemental O2

Admit

Cardiac monitor ABG/oximetry Anticoagulation/pulmonary vascular imaging ECG Indigestion or burning

None

ECG

Indigestion or burning epigastric

None

ECG

Pleuritic

None

CXR ECG

Associated symptoms

Past medical history

Syncope or near-syncope

ECG

Shortness of breath, dyspnea on exertion, paroxysmal nocturnal dyspnea, or orthopnea

ECG

Cardiac monitor Hematocrit ABG/oximetry CXR

Previous MI, coronary ECG artery bypass graft, angioplasty, cocaine use within past 96 hours, previous positive cardiac diagnostic studies Major risk factors for coronary artery disease

ECG

CXR=chest radiograph; ECG=electrocardiogram; ABG=arterial blood gas analysis. From American College of Emergency Physicians: Clinical policy for the initial approach to adults presenting with a chief complaint of chest pain, with no history of trauma. Ann Emerg Med 25:274-299, 1995. *Rule: An action reflecting principles of good practice in most situations. There may be circumstances when a rule need not or cannot be followed; in these situations, it is advisable that deviation from the rule be justified in writing. Inability to comply with rules should be incorporated in institutional policies. Guideline: An action that may be considered, depending on the patient, the circumstances, or other factors. Thus, guidelines are not always followed, and there is no implication that failure to follow a guideline is improper.

character of pain, age, associated symptoms, and past history. The physical examination should include vital signs, a cardiovascular examination, and a pulmonary examination. The performance of an ECG is a "rule" in all but atypical chest pain syndromes. The ACEP statement emphasizes that the decision to admit the patient must be based primarily on clinical judgment. The NHAAP report also includes guidelines for specific functions related to evaluation and treatment of patients with chest pain aimed at improving the speed with which patients with AMI are identified and treated,[3] including recommendations for which patient subsets should be placed on the AMI protocol. For registration staff, the NHAAP guidelines recommend that patients older than age 30 with the following chief complaints receive immediate assessment by the triage nurse and be referred for

further evaluation:

Chest pain, pressure, tightness, or heaviness; radiating pain in neck, jaw, shoulders, back, or one or both arms Indigestion or "heartburn"/nausea and/or vomiting Persistent shortness of breath Weakness/dizziness/lightheadedness/loss of consciousness The triage nurse should immediately assess patients for initiation of the AMI protocol and obtain an ECG if they have any of the following:

Chest pain Associated dyspnea Associated nausea/vomiting Associated diaphoresis For physicians, the NHAAP guidelines offer several clinical recommendations

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and explicitly note that the use of a so-called GI cocktail (usually including an antacid) as a diagnostic test to differentiate between gastrointestinal and cardiac causes of the patient's symptoms is inappropriate because it frequently leads to erroneous conclusions. ECG and aspirin are strongly recommended for patients with new-onset angina that is exertional, but admission is not considered mandatory in the ACEP policy statement. The AHCPR guidelines also indicate that not all patients with unstable angina require admission but recommend that patients with unstable angina be monitored electrocardiographically during their initial evaluation and that those with ongoing rest pain should be placed at bed rest during the initial phase of stabilization.[4]

EARLY RISK STRATIFICATION. The ACC/AHA guidelines for management of unstable angina emphasize the importance of a search for noncoronary causes that might explain the patient's symptoms but recommend that biochemical cardiac markers be performed for all patients with suspected acute coronary syndromes.[5] This recommendation does not

mandate the performance of markers in patients with a very low probability of acute coronary syndromes, for whom discharge without such testing is appropriate.[6] The ACC/AHA task force supports the use of cardiac troponins as a preferred marker for acute ischemic injury (Table 36-G-2) . Specific recommendations for the care of patients with unstable angina are included in the guidelines in Chapter 36 .

Urgent Care of AMI (Table 35-G-2) The 1999 ACC/AHA update of guidelines on AMI[2] seek to ensure timely revascularization of patients who present early in the course of their infarction by setting a goal for timely evaluations of patients with acute chest pain, including performance of an ECG within 10 minutes and administration of thrombolytic therapy for appropriate patients within 30 minutes. To achieve this goal, the NHAAP guidelines[3] recommend measuring the time at which four specific events occur for patients with AMI: 1. 2. 3. 4.

Presentation to the emergency department Performance of the ECG Decision of whether to administer thrombolytic therapy Actual infusion of the thrombolytic agent

Specific time goals can be set for the interval between these events (e.g., 10 minutes). Another critical issue is who gives the order to administer thrombolytic therapy. ACEP guidelines recommend that emergency department physicians be given the authority to administer thrombolytic therapy.[1] In the ACC/AHA guidelines,[2] thrombolytic therapy is considered appropriate (Class I) for up to 12 hours after the onset of symptoms for patients younger than age 75 years and presenting with ST segment elevation or bundle branch block. The ACC/AHA task force considered the weight of evidence in favor of extending the same approach to patients older than 75. Primary intervention with percutaneous transluminal coronary angioplasty (PTCA) was considered an appropriate (Class I) alternative to thrombolytic therapy within the first 12 hours of infarction and beyond for patients with persisting ischemic symptoms. The ACC/AHA guidelines also define goals for speed and volume for operators and institutions performing primary PTCA. Primary PTCA is also endorsed as a strategy for patients with cardiogenic shock due to MI. The ACC/AHA guidelines do not support routine use of angiography TABLE 35--G-2 -- ACC/AHA GUIDELINES FOR INITIAL MANAGEMENT OF ACUTE MYOCARDIAL INFARCTION (AMI) AND ISCHEMIC COMPLICATIONS Indication Class I Class IIa Class IIb Class III

Telephone triage[5]

Patients with symptoms suggesting possible ACS should be evaluated by a medical practitioner in a facility equipped to record a 12-lead ECG and not over the telephone.

Emergency department or outpatient facility presentation

Patients with suspected ACS with symptom duration > 20 minutes, hemodynamic instability, or recent syncope or presyncope should be referred to an emergency department or specialized chest pain unit. Other patients with suspected ACS may be seen initially either in an emergency department, chest pain unit, or an outpatient facility.

[5]

Early risk Patients stratification[5] presenting with chest pain should undergo early risk stratification focusing on anginal symptoms, the presence or absence of traditional risk factors for coronary artery disease, physical findings, and ECG. A 12-lead ECG should be obtained immediately in patients with ongoing chest pain and within 10 minutes of presentation in patients with a history of chest pain consistent with ACS but has resolved by the time of evaluation.

An acceptable but less preferable marker is CK-MB. Mass assays for CK-MB are preferred over activity assays for CK-MB.

Total CK activity, AST, and/or LDH as the serum markers for detecting MI in patients with chest pain suggestive of ACS.

Serum cardiac markers should be measured in all patients presenting with chest pain consistent with ACS. A cardiac-specific troponin is the preferred marker and if available should be measured in all patients. For patients presenting within 6 hours of the onset of symptoms, an early marker, myoglobin, should be measured in addition to a cardiac troponin. In patients with negative serum markers within 6 hours of the onset of pain, another determination should be made at 9 hours. Oxygen

Overt pulmonary Routine congestion administration to all patients Arterial oxygen with desaturation uncomplicated (SaO2 < 90%) MI during the first 2 to 3 hours

Routine administration of supplemental O2 to patients with uncomplicated MI beyond 3 to 6 hours

Intravenous nitroglycerin

For the first 24 to 48 hours in patients with AMI and CHF, large anterior infarction, persistent ischemia, or hypertension Continued use (beyond 48 hours) in patients with recurrent angina or persistent pulmonary congestion

Aspirin

160 to 325 mg on day 1 of AMI and continued indefinitely on a daily basis.

For the first 24 to 48 hours in all patients with AMI who do not have hypotension, bradycardia, or tachycardia. Continued use (beyond 48 hours) in patients with a large or complicated infarction. (Oral or topical preparations may be substituted.) Other antiplatelet agents, such as dipyridamole, ticlopidine, or clopidogrel, may be substituted if true aspirin allergy is present or if the patient is unresponsive to aspirin.

Patients with systolic blood pressure < 90 mm Hg or severe bradycardia (< 50/min)

Atropine

Sinus bradycardia with evidence of low cardiac output and peripheral hypoperfusion or frequent PVCs at onset of symptoms of AMI Acute inferior infarction with type I second- or third-degree AV block associated with symptoms of hypotension, ischemic discomfort, or ventricular arrhythmias Sustained bradycardia and hypotension after administration of nitroglycerin For nausea and vomiting associated with administration of morphine Ventricular asystole

Symptomatic patients with inferior infarction and type I secondor third-degree heart block at the level of the AV node

Administration concomitant with administration of morphine in the presence of sinus bradycardia

Sinus bradycardia > 40 beats/min without signs or symptoms of hypoperfusion or frequent PVCs.

Type II AV block and third-degree AV block Asymptomatic and third-degree AV patients with block with new wide inferior infarction QRS complex and type I presumed due to second-degree AMI. heart block or third-degree heart block at the level of the AV node. Second- or third-degree AV block of uncertain mechanism when pacing is not available.

Thrombolysis ST segment ST segment elevation (> 0.1 elevation, age mV, two or more 75 yr contiguous leads), time to therapy 12 hr, age < 75 yr BBB (obscuring ST segment analysis) and history suggesting AMI Primary percutaneous transluminal coronary angioplasty

As an alternative to thrombolytic therapy in patients with AMI and ST segment elevation or new or presumed new left BBB (LBBB) who can undergo angioplasty of the infarct-related artery within 12 hours of onset of symptoms or beyond 12 hours if ischemic symptoms persist, and performed in a timely fashion* by persons skilled in the procedure and supported by experienced personnel in an appropriate laboratory environment. In patients who are within 36

As a reperfusion strategy in candidates for reperfusion who have a contraindication to thrombolytic therapy

ST segment elevation, time to therapy>12 to 24 hr

ST segment elevation, time to therapy greater than 24 hours, ischemic pain resolved

Blood pressure on ST segment presentation>180 depression only mm Hg systolic and/or > 110 mm Hg diastolic associated with high-risk MI. In patients with Patients with AMI AMI who do not who: present with ST segment 1. Undergo elevation but who elective PTCA have reduced (< of a TIMI grade 2) non-infarct-relat flow in the ed artery at the infarct-related time of AMI artery and when 2. Are beyond 12 PTCA can be hours after performed within onset of 12 hours of onset symptoms and of symptoms. have no evidence of myocardial ischemia 3. Have received thrombolytic therapy and have no symptoms of myocardial ischemia 4. Are eligible for thrombolysis and are undergoing primary angioplasty performed by a low-volume operator in a laboratory without surgical

appropriate laboratory environment.

angioplasty performed by a low-volume operator in a laboratory without surgical backup

In patients who are within 36 hours of an acute ST segment elevation/Q wave or new LBBB MI who develop cardiogenic shock, are < 75 years old, and in whom revascularization can be performed within 18 hours of onset of shock. Early coronary angiography in the ST segment elevation or BBB cohort not undergoing primary PTCA

Patients with cardiogenic shock or persistent hemodynamic instability

Patients with evolving large or anterior infarcts treated with thrombolytic agents in whom it is believed that the artery is not patent and adjuvant PTCA is planned

Routine use of angiography and subsequent PTCA within 24 hours of administration of thrombolytic agents

Emergency or urgent coronary artery bypass graft surgery

Failed PTCA with persistent pain or hemodynamic instability in patients with coronary anatomy suitable for surgery AMI with persistent or recurrent ischemia refractory to medical therapy in patients with coronary anatomy suitable for surgery who are not candidates for PCI. At the time of surgical repair of postinfarction ventricular septal defect or mitral regurgitation

Cardiogenic shock with coronary anatomy suitable for surgery

Failed PTCA and small area of myocardium at risk; hemodynamically stable

When the expected surgical mortality rate equals or exceeds the mortality rate associated with appropriate medical therapy

Early coronary angiography and/or interventional therapy in non-ST segment elevation MI

Patients with persistent or recurrent (stuttering) episodes of symptomatic ischemia, spontaneous or induced, with or without associated ECG changes Presence of shock, severe pulmonary congestion, or continuing hypotension

Glycoprotein IIb/IIIa inhibitors

Patients experiencing an MI without ST segment elevation who have some high-risk features and/or refractory ischemia, provided they do not have a major contraindication due to a bleeding risk

For definition of classes see p. 1353 . ACS=acute coronary syndrome; ECG=electrocardiogram; CK=creatine kinase; CK-MB=MB isoenzyme of creatine kinase; AST=aspartate transaminase; LDH=lactate dehydrogenase; CHF=congestive heart failure; BBB=bundle branch block; PVCs=premature ventricular contractions; AV=atrioventricular; PTCA = percutaneous transluminal coronary angioplasty; PCI=percutaneous coronary intervention Unless otherwise specified, data from Ryan TJ, Antman EM, Brooks NH, et al: 1999 Update: ACC/AHA guidelines for the management of patients with acute myocardial infarction: Executive summary and recommendations: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Circulation 100:1016-1030, 1999. Copyright 1999, American Heart Association.

*Performance standard: balloon inflation within 90 (±30) minutes of admission. Individuals who perform > 75 PTCA procedures per year. Centers that perform > 200 PTCA procedures per year and have cardiac surgical capability.

TABLE 35--G-3 -- ACC/AHA GUIDELINES FOR HEMODYNAMIC MONITORING IN ACUTE MYOCARDIAL INFARCTION (AMI) Indication Class I Class IIa Class IIb Class III Balloon flotation Severe or progressive right-sided heart CHF or pulmonary catheter edema monitoring Cardiogenic shock or progressive hypotension

Hypotension that does not respond promptly to fluid administration in a patient without Suspected mechanical pulmonary complications of AMI congestion (i.e., VSD, papillary muscle rupture, or pericardial tamponade)

Intraarterial pressure monitoring

Patients with severe hypotension (systolic arterial pressure < 80 mm Hg and/or cardiogenic shock Patients receiving vasopressor agents

Patients receiving intravenous sodium nitroprusside or other potent vasodilators

Patients with AMI without cardiac or pulmonary complications

Hemodynamically stable patients receiving intravenous nitroglycerin for myocardial ischemia Patients receiving intravenous inotropic agents

Patients with acute infarction who are hemodynamically stable

Intraaortic Cardiogenic shock not balloon quickly reversed with counterpulsation pharmacological therapy as a stabilizing measure for angiography and prompt revascularization Acute MR or VSD complicating MI as a stabilizing therapy for angiography and repair/revascularization

Signs of hemodynamic instability, poor left ventricular function, or persistent ischemia in patients with large areas of myocardium at risk.

Recurrent intractable ventricular arrhythmias with hemodynamic instability

In patients with successful PTCA after failed thrombolysis or those with three-vessel coronary disease to prevent reocclusion In patients known to have large areas of myocardium at risk with or without active ischemia

Refractory post-MI angina as a bridge to angiography and revascularization CHF=congestive heart failure; VSD=ventricular septal defect; MR=mitral regurgitation; PTCA=percutaneous transluminal coronary angioplasty. For definition of classes see p. 1353 .

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and subsequent PTCA within 24 hours after administration of a thrombolytic agent. Emergency or urgent coronary artery bypass graft (CABG) is endorsed only when patients have severe, persistent ischemia that cannot be addressed by medical therapy and/or PTCA or as part of an effort to correct mechanical complications of MI. Such surgery along with correction of the latter is considered appropriate when these complications cause severe hemodynamic compromise. For patients with AMI without ST segment elevation, the ACC/AHA guidelines consider early coronary angiography appropriate if they have recurrent ischemia, spontaneous or induced, with or without associated ECG changes. In these patients, glycoprotein IIb/IIIa inhibitors are usually appropriate (Class IIa), assuming that patients do not have major contraindications to these agents. (See guidelines in Chapter 36 for more detail.) Oxygen therapy is recommended for patients even in the absence of complications in the first 2 to 3 hours, but the evidence was considered weak for this intervention after 3

to 6 hours. Similarly, routine use of intravenous nitroglycerin in patients with uncomplicated courses is not generally advised (Class IIb).

HEMODYNAMIC MONITORING (Table 35-G-3) Routine use of right-sided heart catheterization or intraarterial pressure monitoring in the absence of cardiac or pulmonary complications is considered inappropriate by the ACC/AHA guidelines. These interventions are considered clearly appropriate (Class I) in patients who have severe hemodynamic derangements or who require vasopressor agents. Intraaortic balloon counterpulsation is endorsed for patients with cardiogenic shock or other major hemodynamic instability and as a bridge to angiography and revascularization in patients with refractory post-MI angina.

Management of Arrhythmias (Table 35-G-4) The ACC/AHA guidelines recommend a rapid response to the development of atrial fibrillation, including prompt electrical cardioversion for TABLE 35--G-4 -- ACC/AHA GUIDELINES FOR MANAGEMENT OF ARRHYTHMIAS IN ACUTE MYOCARDIAL INFARCTION (AMI) Indication Class I Class IIa Class IIb Class III Atrial fibrillation Electrical cardioversion for patients with severe hemodynamic compromise or intractable ischemia Rapid digitalization to slow a rapid ventricular response and improve LV function Intravenous beta adrenoceptor blockers to slow a rapid ventricular response in patients without clinical LV dysfunction, bronchospastic

Either diltiazem or verapamil intravenously to slow a rapid ventricular response if beta-adrenoceptor blocking agents are contraindicated or ineffective

rapid ventricular response in patients without clinical LV dysfunction, bronchospastic disease, or AV block Ventricular tachycardia (VT)/ventricular fibrillation (VF)

VF should be treated with an electric shock with an initial energy of 200 J; if unsuccessful, a second shock of 200 to 300 J should be given, and, if necessary, a third shock of 360 J

Drug-refractory polymorphic VT should be managed by aggressive attempts to reduce myocardial ischemia, including therapies such as beta-adrenoceptor blockade, intraaortic balloon Sustained (> 30 Electrolyte and pumping, and seconds or acid-base emergency causing disturbances PTCA/CABG hemodynamic should be surgery. collapse) corrected to Amiodarone, 150 polymorphic VT prevent recurrent mg infused over should be treated episodes of VF 10 minutes with an when an initial followed by a unsynchronized episode of VF has constant infusion electric shock been treated. of 1.0 mg/min for using an initial up to 6 hours and energy of 200 J; if then a unsuccessful, a maintenance second shock of infusion of 0.5 200 to 300 J mg/min. should be given, and, if necessary, a third shock of 360 J. Episodes of sustained monomorphic VT associated with angina, pulmonary edema, or hypotension (systolic pressure < 90 mm Hg) should be treated with a synchronized electric shock of 100 J initial

Infusions of antiarrhythmic drugs may be used after an episode of VT/VF but should be discontinued after 6 to 24 hours and the need for further arrhythmia management assessed

Treatment of isolated VPBs, couplets, runs of accelerated idioventricular rhythm, and nonsustained VT Prophylactic administration of antiarrhythmic therapy when using thrombolytic agents.

(systolic pressure < 90 mm Hg) should be treated with a synchronized electric shock of 100 J initial energy. Increasing energies may be used if not initially successful. Sustained monomorphic VT not associated with angina, pulmonary edema, or hypotension (systolic pressure < 90 mm Hg) should be treated with one of the following regimens: 1. Lidocaine: bolus 1.0 to 1.5 mg/kg. Supplement al boluses of 0.5 to 0.75 mg/kg every 5 to 10 minutes to a maximum of 3 mg/kg total loading dose may be given as needed. Loading is followed by infusion of 2 to 4 mg/min (30 to 50 mug/kg/min) . 2. Procainamid e: 20 to 30 mg/min loading infusion, up to 12 to 17 mg/kg. This

e: 20 to 30 mg/min loading infusion, up to 12 to 17 mg/kg. This may be followed by an infusion of 1 to 4 mg/min. 3. Amiodarone : 150 mg infused over 10 minutes followed by a constant infusion of 1.0 mg/min for 6 hours and then a maintenanc e infusion of 0.5 mg/min. 4. Synchronize d electrical cardioversio n starting at 50 J (brief anesthesia is necessary).

Atropine

Symptomatic sinus bradycardia (generally, heart rate < 50 beats/min associated with hypotension, ischemia, or escape ventricular arrhythmia).

AV block occurring at an infranodal level (usually associated with anterior MI with a wide-complex escape rhythm).

Ventricular asystole

Asymptomatic sinus bradycardia

Symptomatic AV block occurring at the AV nodal level (second-degree type I or third-degree with a narrow-complex escape rhythm) Temporary pacing: placement of transcutaneous patches and active (demand) transcutaneous pacing

Sinus bradycardia (rate less than 50 beats/min) with hypotension (systolic pressure < 80 mm Hg) unresponsive to drug therapy. Mobitz type II second-degree AV block Third-degree heart block Bilateral BBB (alternating BBB, or RBBB) and alternating LAFB, LPFB (irrespective of time of onset) Newly acquired or age-indeterminate LBBB, LBBB and LAFB, RBBB, and

Stable bradycardia (systolic pressure > 90 mm Hg, no hemodynamic compromise, or compromise responsive to initial drug therapy) Newly acquired or age-indeterminate RBBB

Newly acquired or age-indeterminate first-degree AV block

Uncomplicated AMI without evidence of conduction system disease

(irrespective of time of onset) Newly acquired or age-indeterminate LBBB, LBBB and LAFB, RBBB, and LPFB RBBB or LBBB and first-degree AV block Temporary transvenous pacing

Asystole Symptomatic bradycardia (includes sinus bradycardia with hypotension and type I second-degree AV block with hypotension not responsive to atropine) Bilateral BBB (alternating BBB or RBBB with alternating LAFB/LPFB) (any age) New or indeterminate-age bifascicular block (RBBB with LAFB or LPFB, or LBBB) with first-degree AV block Mobitz type II second-degree AV block

RBBB and LAFB or LPFB (new or indeterminate)

Bifascicular block of indeterminate age

RBBB with first-degree AV block

Type I New or second-degree age-indeterminate AV block with isolated RBBB normal hemodynamics

LBBB, new or indeterminate Incessant VT, for atrial or ventricular overdrive pacing Recurrent sinus pauses (greater than 3 seconds) not responsive to atropine

First-degree AV block

Accelerated idioventricular rhythm BBB or fascicular block known to exist before AMI

Permanent pacing after AMI

Persistent second-degree AV block in the His-Purkinje system with bilateral BBB or complete AV block after AMI Transient advanced (second- or third-degree) AV block and associated BBB Symptomatic AV block at any level

Persistent advanced (second- or third-degree) block at the AV node level

Transient AV conduction disturbances in the absence of intraventricular conduction defects Transient AV block in the presence of isolated LAFB Acquired LAFB in the absence of AV block Persistent first-degree AV block in the presence of BBB that is old or age indeterminate

LV = left ventricular; AV = atrioventricular; PTCA = percutaneous transluminal coronary angioplasty; CABG = coronary artery bypass graft; BBB = bundle branch block; RBBB and LBBB = right and left bundle branch block; LAFB and LPFB = left anterior and posterior fascicular block. For definition of classes see p. 1253 . patients who develop hemodynamic compromise or intractable ischemia with this arrhythmia. Intravenous beta blockers are considered appropriate agents to slow a rapid ventricular response in the absence of contraindications. The guidelines do not recommend routine administration of antiarrhythmic therapy for nonsustained ventricular tachycardia or less severe ventricular arrhythmias, nor do they support prophylactic antiarrhythmic therapy for patients receiving thrombolytic agents. Intravenous amiodarone is considered an appropriate agent in patients with sustained monomorphic ventricular tachycardia. The ACC/AHA guidelines consider temporary pacemaker placement appropriate in patients with second-degree Mobitz type II or third-degree atrioventricular block, as well as various configurations of bifascicular and potentially trifascicular block. Permanent pacemaker placement is supported for symptomatic atrioventricular block at any level but not for uncomplicated unifascicular block.

Pharmacotherapy (Table 35-G-5) Intravenous heparin therapy is considered clearly appropriate (Class I) for patients undergoing revascularization and probably appropriate (Class IIa) for patients receiving intravenous alteplase therapy or with non-ST segment elevation MI (Table 35-G-5) . Intravenous heparin is also recommended for patients at high risk for embolic events, such as those with large or anterior MIs. The ACC/AHA guidelines support a low threshold for initiation of beta-adrenoceptor blocker therapy within 12 hours of the onset of MI in patients without contraindications. Early administration of angiotensin-converting enzyme inhibitors is recommended for patients with ST segment elevation in anterior leads. Initiation of this therapy is considered clearly (Class I) or probably indicated (Class IIa) in broad classes of patients without contraindications. In contrast, the use of calcium channel blockers is discouraged. Exceptions include the use of verapamil or diltiazem for patients in whom beta blockers cannot be used or are ineffective for management of arrhythmia or ischemia. The ACC/AHA task force considered diltiazem only marginally appropriate (Class IIb) in the first 24 hours for patients with non-ST segment elevation infarction without left ventricular dysfunction, pulmonary congestion, or congestive heart failure. The role of intravenous magnesium therapy was considered unestablished, although evidence supported its use in patients with documented magnesium deficits or episodes of torsades de pointes type ventricular tachycardia.

Discharge from Hospital (Table 35-G-6) The ACC/AHA guidelines strongly support performance of noninvasive risk stratification using exercise or pharmacological stress testing. The guidelines indicate that the lowest cost alternative--exercise electrocardiography--is an appropriate first-line test. Imaging and pharmacological stress testing are recommended when clinical or electrocardiographic findings compromise the reliability of exercise electrocardiography. The ACC/AHA task force concluded that there was not strong evidence to support routine use of ambulatory (Holter) monitoring or analyses of heart rate variability (Class IIb). Routine use of coronary angiography and revascularization in patients without evidence of ongoing ischemia was also considered inappropriate (Class III) or weakly supported by evidence (Class IIb). However, invasive evaluation and treatment was recommended (Class I or IIa) when patients had spontaneous or induced evidence

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TABLE 35--G-5 -- ACC/AHA GUIDELINES FOR PHARMACOTHERAPY IN ACUTE MYOCARDIAL INFARCTION (AMI) Indication Class I Class IIa Class IIb Class III Heparin

Patients undergoing percutaneous or surgical revascularization

Intravenously in patients undergoing reperfusion therapy with alteplase Intravenous UFH or LMWH subcutaneously for patients with non-ST segment elevation MI. Subcutaneous UFH (e.g., 7500 U b.i.d.) or LMWH (e.g., enoxaparin 1 mg/kg b.i.d.) in all patients not treated with thrombolytic therapy who do not have a contraindication to heparin. In patients who are at high risk for systemic emboli (large or anterior MI, AF, previous embolus, or known LV thrombus), intravenous heparin is preferred. Intravenously in patients treated with nonselective thrombolytic

Patients treated with nonselective thrombolytic agents, not at high risk, subcutaneous heparin, 7500 U to 12,500 U twice a day until completely ambulatory

Routine intravenous heparin within 6 hours to patients receiving a nonselective fibrinolytic agent (streptokinase, anistreplase, urokinase) who are not at high risk for systemic embolism

heparin is preferred. Intravenously in patients treated with nonselective thrombolytic agents (streptokinase, anistreplase, urokinase) who are at high risk for systemic emboli (large or anterior MI, AF, previous embolus, or known LV thrombus) Beta-adrenoceptor blocking agents: early therapy

Patients without a contraindication to beta-adrenoceptor blocker therapy who can be treated < 12 hours of onset of AMI, irrespective of administration of concomitant thrombolytic therapy or performance of primary angioplasty Patients with continuing or recurrent ischemic pain Patients with tachyarrhythmias, such as AF with a rapid ventricular response Non-ST segment elevation MI

Patients with Patients with moderate LV severe LV failure (the failure presence of bibasilar rales without evidence of low cardiac output) or other relative contraindications to beta-adrenoceptor blocker therapy, provided patients can be monitored closely

Angiotensin-converting Patients within the enzyme (ACE) first 24 hours of a inhibitors suspected AMI with ST segment elevation in > 2 anterior precordial leads or with clinical heart failure in the absence of hypotension (systolic BP < 100 mm Hg) or known contraindications to use of ACE inhibitors Patients with MI and LV ejection fraction < 40% or patients with clinical heart failure on the basis of systolic pump dysfunction during and after convalescence from AMI

All other patients within the first 24 hours of a suspected or established AMI, provided significant hypotension or other clear-cut contraindications are absent Asymptomatic patients with mildly impaired LV function (ejection fraction 40% to 50%) and a history of old MI

Patients who have recently recovered from MI but have normal or mildly abnormal global LV function

Calcium channel blockers

Verapamil or diltiazem in patients in whom beta-adrenoceptor blockers are ineffective or contraindicated (i.e., bronchospastic disease) for relief of ongoing ischemia or control of a rapid ventricular response with AF after AMI in the absence of CHF, LV dysfunction, or AV block

In non-ST segment elevation infarction, diltiazem may be given to patients without LV dysfunction, pulmonary congestion, or CHF. It may be added to standard therapy after the first 24 hours and continued for 1 year.

Nifedipine (short acting) is generally contraindicated in routine treatment of AMI because of its negative inotropic effects and the reflex sympathetic activation, tachycardia, and hypotension associated with its use. Diltiazem and verapamil are contraindicated in patients with AMI and associated LV dysfunction or CHF.

Magnesium

Correction of documented magnesium (and/or potassium) deficits, especially in patients receiving diuretics before onset of infarction

Magnesium bolus and infusion in high-risk patients such as the elderly and/or those for whom reperfusion therapy is not suitable

Episodes of torsades de pointes-type VT associated with a prolonged QT interval should be treated with 1 to 2 gm of magnesium administered as a bolus over 5 minutes. UFH = unfractionated heparin; LMWH = low molecular weight heparin; AF = atrial fibrillation; LV = left ventricular; BP = blood pressure; VT = ventricular tachycardia; AV = atrioventricular; CHF = congestive heart failure. For definition of classes see p. 1253 .

TABLE 35--G-6 -- ACC/AHA GUIDELINES FOR PREPARATION FOR DISCHARGE FROM HOSPITAL AFTER ACUTE MYOCARDIAL INFARCTION (AMI) Indication Class I Class IIa Class IIb Class III

Noninvasive evaluation of low-risk patients

Stress ECG

Dipyridamole or adenosine stress perfusion nuclear Before discharge for scintigraphy or dobutamine prognostic echocardiography assessment before discharge or functional for prognostic capacity (submaximal assessment in at 4 to 6 days patients judged to be unable to or symptom exercise limited at 10 to 14 days) Exercise two-dimensional Early after discharge for echocardiography or nuclear prognostic scintigraphy assessment and functional (before or early after discharge capacity (14 for prognostic to 21 days) assessment) Late after discharge (3 to 6 weeks) for functional capacity and prognosis if early stress was submaximal

Exercise, vasodilator stress nuclear scintigraphy, or exercise stress echocardiography when baseline abnormalities of the ECG compromise interpretation

Stress testing within 2 to 3 days of AMI Either exercise or pharmacological stress testing at any time to evaluate patients with unstable postinfarction angina pectoris At any time to evaluate patients with AMI who have uncompensated CHF, cardiac arrhythmia, or noncardiac conditions that severely limit their ability to exercise. Before discharge to evaluate patients who have already been selected for cardiac catheterization

Assessment of ventricular arrhythmia--routine testing

Coronary angiography and possible PTCA

Ambulatory (Holter) monitoring, signal-averaged ECG, heart rate variability, baroreflex sensitivity monitoring, alone or in combination for risk assessment after MI, especially in patients at higher perceived risk, when findings might influence management issues, or for clinical research purposes Patients with spontaneous episodes of myocardial ischemia or episodes of myocardial ischemia provoked by minimal exertion during recovery from AMI

When MI is suspected to have occurred by a mechanism other than thrombotic occlusion at an atherosclerotic plaque. This would include coronary embolism, certain metabolic or hematological diseases, or coronary artery spasm

Before definitive therapy of a mechanical complication of infarction such as acute MR, VSD, Survivors of AMI pseudoaneurysm, with depressed or LV aneurysm LV systolic function (LV Patients with ejection fraction persistent less than or equal hemodynamic to 40%), CHF, instability prior revascularization,

Coronary angiography performed in all patients after infarction to find persistently occluded infarct-related arteries in an attempt to revascularize the artery or to identify patients with three-vessel disease

Routine use of coronary angiography and subsequent PTCA of the infarct-related artery within days after receiving thrombolytic therapy

Survivors of MI who are thought not to be candidates for coronary All patients after revascularization a non-Q-wave MI Recurrent VT or VF or both, despite antiarrhythmic therapy in patients without

or LV aneurysm Patients with persistent hemodynamic instability

LV systolic function (LV ejection fraction less than or equal to 40%), CHF, prior revascularization, or malignant ventricular arrhythmias

Recurrent VT or VF or both, despite antiarrhythmic therapy in patients without evidence of ongoing myocardial ischemia

Survivors of AMI who had clinical heart failure during the acute episode but subsequently demonstrated well-preserved LV function Routine coronary angiography and PTCA after successful thrombolytic therapy

Routine PTCA of the stenotic infarct-related artery immediately after thrombolytic therapy PTCA of the stenotic infarct-related artery within 48 hours of receiving a thrombolytic agent in asymptomatic patients without evidence of ischemia

ECG = electrocardiogram; CHF = congestive heart failure; MR = mitral regurgitation; VSD = ventricular septal defect; LV = left ventricular; VT = ventricular tachycardia; VF= ventricular fibrillation; PTCA = percutaneous transluminal coronary angioplasty. For definition of classes see p. 1253 .

Indication

TABLE 35--G-7 -- SECONDARY PREVENTION Class I Class IIa Class IIb

Class III

Management of lipids

The AHA step II diet, which is low in saturated fat and cholesterol in all patients after recovery from AMI Patients with LDLC > 125 mg/dl despite the AHA step II diet should be placed on drug therapy, with the goal of reducing LDLC to < 100 mg/dl Patients with normal plasma cholesterol levels with HDLC < 35 mg/dl should receive nonpharmacological therapy (e.g., exercise) designed to raise it

Drug therapy added to diet in patients with LDLC levels < 130 mg/dl but > 100 mg/dl after an appropriate trial of the AHA step II diet

Drug therapy with either niacin or gemfibrozil added to diet regardless of LDLC and HDLC when triglyceride levels are > 200 mg/dl.

Patients with normal total cholesterol levels but HDLC < 35 mg/dl despite diet and other nonpharmacological therapy may be started on drugs such as niacin to raise HDL levels.

Long-term beta-adrenoceptor blocker therapy in survivors of myocardial infarction

All but low-risk patients without a clear contraindication to beta-adrenoceptor blocker therapy. Treatment should begin within a few days of the event (if not initiated acutely) and continue indefinitely.

Low-risk patients without a clear contraindication to beta-adrenoceptor blocker therapy.

Patients with moderate or severe LV failure or other relative contraindications to Survivors of non-ST beta-adrenoceptor segment elevation blocker therapy, MI. provided patients can be monitored closely

Long-term anticoagulation

Post-MI patients Post-MI patients unable to take daily with extensive wall aspirin motion abnormalities Post-MI patients in persistent AF Patients with paroxysmal AF. Patients with LV thrombus

Post-MI patients with severe LV systolic dysfunction with or without CHF

Estrogen replacement therapy and myocardial infarction

HRT with estrogen plus progestin for secondary prevention of coronary events should not be given de novo to postmenopausal women after AMI. Postmenopausal women who are already taking HRT with estrogen plus progestin at the time of AMI can continue this therapy.

LDLC and HDLC = low- and high-density lipoprotein cholesterol; LV = left ventricular; CHF = congestive heart failure; AF = atrial fibrillation. For definition of classes see p. 1253 . of myocardial ischemia or other complications of ischemic heart disease.

Secondary Prevention (Table 35-G-7) The ACC/AHA guidelines strongly endorse pharmacological and aggressive dietary interventions to reduce low-density lipoprotein (LDL) cholesterol after acute myocardial infarction. An AHA Step II diet is considered appropriate for all patients after recovery from AMI, and initiation for drug therapy is considered clearly appropriate (Class I) if LDL cholesterol is greater than 125 mg/dl despite this diet. The use of a lower LDL cholesterol threshold (100-125 mg/dl) for initiation of drug therapy was considered to be less clearly established (Class IIa). Exercise and other efforts to raise high-density lipoprotein cholesterol are also recommended. The guidelines reflect enthusiasm for the benefits of beta blockers for all but low-risk patients if there are no contraindications to these agents. Anticoagulation with warfarin is considered appropriate for patients unable to take daily aspirin or for patients who have atrial fibrillation or left ventricular thrombus. The guidelines are somewhat supportive (Class IIa) of anticoagulation in patients with extensive wall motion abnormalities or paroxysmal atrial fibrillation but not for all patients with severe left ventricular dysfunction. The guidelines do not support initiation of hormone replacement therapy in postmenopausal patients with the goal of preventing coronary events after AMI but did not oppose their continuation.

References American College of Emergency Physicians: Clinical policy for the initial approach to adults presenting with a chief complaint of chest pain, with no history of trauma. Ann Emerg Med 25:274-299, 1995. 1.

Ryan TJ, Antman EM, Brooks NH, et al: 1999 update: ACC/AHA guidelines for the management of patients with acute myocardial infarction: Executive summary and recommendations: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol 34:890-911, 1999. 2.

National Heart Attack Alert Program Coordinating Committee 60 Minutes to Treatment Working Group: Emergency Department: Rapid Identification and Treatment of Patients with Acute Myocardial Infarction. NIH publication No. 93-3278. National Heart, Lung, and Blood Institute, Public Health Service, US Department of Health and Human Services, September 1993. 3.

Braunwald E, Mark DB, Jones RH, et al: Unstable Angina: Diagnosis and Management. Clinical Practice Guideline Number 10 (amended). AHCPR publication No. 94-0602. Rockville, MD, Agency for Health Care Policy and Research and the National Heart, Lung, and Blood Institute, Public Health Service, US Department of Health and Human Services, May 1994. 4.

Braunwald E, Antman EM, Beasley JW, et al: ACC/AHA guidelines for the management of patients with unstable angina: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol 36:970-1062, 2000. 5.

Nichol G, Walls R, Goldman L, et al: A critical pathway for management of patients with acute chest pain at low risk for myocardial ischemia: Recommendations and potential impact. Ann Intern Med 127:996-1005, 1997. 6.




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Chapter 36 - Unstable Angina Christopher P. Cannon Eugene Braunwald

Unstable angina lies in the center of the spectrum of clinical conditions caused by myocardial ischemia. These range from chronic stable angina pectoris (see Chap. 37) to the acute coronary syndromes. The latter, in turn, consist of acute myocardial infarction (MI) associated with electrocardiographic ST segment elevation (STEMI) (see Chap. 35) and unstable angina/non-ST segment elevation MI (UA/NSTEMI). The former is most commonly caused by acute total coronary occlusion, [1] [2] and urgent reperfusion is the mainstay of therapy, whereas UA/NSTEMI is usually associated with severe coronary obstruction but not total occlusion of the culprit coronary artery.[3] [4] If the myocardial ischemia that results from the coronary obstruction is long in duration and/or great in severity, myocardial necrosis occurs,[5] and the patient is classified as having a non-Q-wave MI or, now more aptly termed, NSTEMI (see Fig. 35-2) . Although, with the advent of thrombolysis and other emergency reperfusion therapies, a great deal of attention has focused on acute MI with ST segment elevation, UA/NSTEMI (the focus of this chapter) occurs with much greater frequency. Every year in the United States, approximately 1.3 million patients are admitted to the hospital with unstable

angina or NSTEMI compared with approximately 350,000 patients with acute STEMI.[6] DEFINITION AND CLASSIFICATION DEFINITION.

This is largely based on the clinical presentation[7] (see p. 1235 ). Stable angina pectoris is characterized by a deep, poorly localized chest or arm discomfort (rarely described as pain) that is reproducibly associated with physical exertion or emotional stress and relieved within 5 to 15 minutes by rest and/or sublingual nitroglycerin. Unstable angina is defined as angina pectoris (or equivalent type of ischemic discomfort) with at least one of three features: (1) it occurs at rest (or with minimal exertion) usually lasting more than 20 minutes (if not interrupted by nitroglycerin); (2) it is severe and described as frank pain and of new onset (i.e., within 1 month); and (3) it occurs with a crescendo pattern (i.e., more severe, prolonged, or frequent than previously). Some patients with this pattern of ischemic discomfort, especially those with prolonged rest pain, [5] develop evidence of myocardial necrosis on the basis of the release of cardiac markers and thus have a diagnosis of NSTEMI. Traditionally, this diagnosis has been based on elevation of serum creatine kinase (CK)-MB, but recently troponin T and I assays have been used to define ischemic myocardial damage based on their higher sensitivity for myocardial necrosis and powerful prognostic ability (see pp. 1236 , 1237 , and 1240 ). CLASSIFICATION.

Because unstable angina comprises such a heterogeneous group of patients, classification schemes based on clinical features have been proposed.[7] [8] [9] [10] A clinical classification of unstable angina, presented by one of the authors (Table 36-1) ,[8] has been found to be a useful means of stratifying risk.[11] [12] [13] [14] [15] Patients are divided into three groups according to the clinical circumstances of the acute ischemic episode: primary unstable angina, secondary unstable angina (i.e., with unstable angina related to obvious precipitating noncoronary factors such as anemia, infection, or cardiac arrhythmias), and post-MI angina. Patients are also classified according to the severity of the ischemia (acute rest pain, subacute rest pain, or new-onset severe angina)[8] (see Table 36-1) . This classification has been shown to be predictive of plaques with thrombus at angiography[11] [16] [17] or in atherectomy specimens[18] and in risk stratification (see p. 1234 ).[12] [13] [14] Because unstable angina is a clinical syndrome rather than a specific disease (much like hypertension rather than pneumococcal pneumonia), and because it has many potential causes, an etiological approach has been proposed.[10] Five pathophysiological processes that may contribute to the development of unstable angina have been identified (Fig. 36-1) : 1. Plaque rupture with superimposed nonocclusive thrombus 2. Dynamic obstruction (i.e., coronary spasm of an epicardial artery, as in Prinzmetal angina [see Chap. 37 ] or constriction of the small muscular coronary arteries) 3. Progressive mechanical obstruction

4. Inflammation and/or infection 5. Secondary unstable angina, precipitated by increased myocardial oxygen demand or decreased supply (e.g., thyrotoxicosis or anemia) Individual patients may have several of these processes coexisting as the cause of their episode of unstable angina. Use of this etiological approach will refine the diagnostic approach and help target therapeutic strategies to treat the underlying disease that precipitated the episode of unstable angina. 1233

TABLE 36-1 -- BRAUNWALD CLINICAL CLASSIFICATION OF UNSTABLE ANGINA CLASS DEFINITION DEATH OR MYOCARDIAL INFARCTION TO 1 YEAR* Severity Class I

New onset of severe angina or accelerated 7.3% angina; no rest pain

Class II

Angina at rest within past month but not within preceding 48 hr (angina at rest, subacute)

10.3%

Class III

Angina at rest within 48 hr (angina at rest, subacute)

10.8%

Clinical Circumstances A (secondary angina) Develops in the presence of extracardiac condition that intensifies myocardial ischemia

14.1%

B (primary angina)

Develops in the absence of extracardiac condition

8.5%

C (postinfarction angina)

Develops within 2 weeks after acute myocardial infarction

18.5% p 60 percent luminal diameter stenosis) of three vessels, 30 percent with two-vessel disease, 40 percent with single-vessel disease, and 20 percent with no significant coronary stenosis.[101] Five to 10 percent of patients had left main stem stenosis greater than 50 percent.[100] [101] [118] Similar findings have been reported from registries of unselected UA/NSTEMI patients. [100] [118] Women and nonwhites with UA/NSTEMI have less extensive coronary disease than their counterparts,[96] [97] [98] [118] [119] whereas patients with NSTEMI have more extensive disease than those who present with unstable angina.[97] Fifteen to 30 percent of patients who present with symptoms of unstable angina will have no significant coronary stenosis on coronary angiography.[96] [97] [100] [101] [118] [119] [120] Women and nonwhites comprise a larger proportion of such patients without epicardial coronary disease,[96] [97] [118] [119] [120] suggesting a difficulty in making a firm diagnosis of unstable angina in these groups and/or a different pathophysiological mechanism for their clinical presentation. Approximately one third of patients with unstable angina without a critical epicardial obstruction will have impaired coronary flow, suggesting a pathophysiological role for coronary microvascular dysfunction.[120] The short-term prognosis is excellent in this group of patients. The culprit lesion in unstable angina typically exhibits an eccentric stenosis with scalloped or overhanging edges and a narrow neck.[4] [22] [65] These angiographic findings may represent disrupted atherosclerotic plaque, thrombus, or a combination. [121] Features suggesting thrombus include globular intraluminal masses with a rounded or polypoid shape[4] (see Fig. 36-2) . "Haziness" of a lesion has been used as an

angiographic marker of possible thrombus, but this finding is less specific. Patients with angiographically visualized thrombus have impaired coronary flow and worse clinical outcomes, compared with those without thrombus. [122] [123] Of interest, however, is that angiographically documented thrombus is present in only 20 to 40 percent of patients using a rigorous definition.[4] [123] [124] It is likely that the frequency is much greater and that angiography simply is not sensitive enough to detect all but the largest thrombi. ANGIOSCOPY AND INTRAVASCULAR ULTRASOUND.

Greater definition of the culprit lesion has been possible using angioscopy, where "white" (platelet-rich) thrombi are frequently observed as opposed to "red" thrombi, which are more often seen in patients with acute STEMI.[55] [56] [62] [64] Intravascular ultrasound examination identified more soft "echolucent" plaques and fewer calcified lesions among patients with unstable versus stable angina.[17] OTHER LABORATORY TESTS.

A chest roentgenogram may be useful in identifying pulmonary congestion or edema, which would be more likely in patients with NSTEMI involving a significant proportion of the left ventricle or in those with prior known left ventricular dysfunction.[7]

1237

The presence of congestion has been shown to confer an adverse prognosis.[125] [126] Obtaining a serum cholesterol level is useful in identifying an important, treatable cause of coronary atherosclerosis. Because serum cholesterol levels begin to fall 24 hours after acute MI or unstable angina, it should be measured at the time of hospital admission. If only a later sample is obtained, but the value falls into a range that warrants long-term treatment (see Chap. 39) appropriate therapy can be initiated,[127] [128] [129] although the optimal timing of initiation of cholesterol-lowering therapy is being studied. Other circulating markers of increased risk are discussed later (see p. 1240 ). Evaluation for other secondary causes of unstable angina[8] may also be appropriate in selected patients (e.g., checking thyroid function in a patient who presents with unstable angina and a persistent tachycardia). DIAGNOSIS OF UA/NSTEMI The diagnosis of unstable angina is a clinical one, based on the patient's description of symptoms, as described earlier. A diagnosis of NSTEMI is made on the basis of a clinical history consistent with UA/NSTEMI and positive circulating cardiac markers[7] (see p. 1240 and Chap. 35) . However, in the United States 6 to 7 million persons per year present to an emergency department (ED) with a complaint of chest pain or other symptoms suggestive of possible acute coronary syndrome, of whom only 20 to 25

percent have a final diagnosis of unstable angina or MI.[130] [131] ASSESSING LIKELIHOOD OF CORONARY ARTERY DISEASE.

Thus, the key first step in evaluation of patients with possible UA/NSTEMI is to determine the likelihood that coronary artery disease is the cause of the presenting symptoms.[7] From several large studies of patients presenting with chest pain to an ED,[100] [112] [130] [132] [133] [134] [135] [136] [137] [138] [139] [140] [141] [142] [143] [144] [145] certain features portend a higher likelihood that the patient actually has unstable angina (Table 36-2) . High likelihood exists among patients with prior coronary disease and/or with symptoms TABLE 36-2 -- FEATURES ASSOCIATED WITH HIGHER LIKELIHOOD OF CORONARY ARTERY DISEASE AMONG PATIENTS PRESENTING WITH SYMPTOMS SUGGESTIVE OF UNSTABLE ANGINA History Chest pain as chief complaint similar to prior ACS symptoms Known history of coronary artery disease, myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft History of angina Age>60 Male gender More than two major cardiac risk factors Diabetes Extracardiac vascular disease (carotid or peripheral) Physical Examination Pulmonary rales, hypotension Transient mitral regurgitation Diaphoresis Electrocardiogram New/presumably new ST deviation >0.05 mV T wave inversion 0.1 mV Q waves, left bundle branch block Cardiac Markers Elevated CK-MB, troponin I or T Data supporting these factors come from references [100] [130] [132] [133] [134] [135] [136] [137] [138] [139] [140] [141] [142] [143] [144] [145] and [412] . that are similar to a prior episode of MI or unstable angina.[130] [132] [133] [134] [136] [137] Elevation of cardiac markers or evidence of congestive heart failure or hemodynamic compromise also increase the likelihood of UA/NSTEMI.

CLINICAL AND ECG PREDICTOR RULES.

Several groups have developed predictor rules to enhance clinical assessment of patients presenting with chest pain to the ED.[132] [133] [134] [135] [136] [137] [138] [139] These "predictor rules" use clinical variables as well as ECG findings to define either MI,[132] [133] [135] any acute coronary syndrome (UA, NSTEMI, or STEMI),[134] [137] [138] [139] or subsequent cardiac complications regardless of initial diagnosis.[136] In general, all of these prediction rules can assist the clinician in assessing the likelihood of unstable angina or MI, but because of the numerous questions that are part of the assessment they are not often used in clinical practice. One algorithm, the Acute Cardiac Ischemia--Time Insensitive Prediction Instrument (ACI-TIPI) has been integrated into ECG devices and provides a likelihood of the patient having unstable angina or MI.[137] [139] This device evaluates the ECG for the presence of ST segment deviation, Q waves, and T wave inversion; and the operator enters into the computer the patient's age and gender and whether the patient's primary symptom was chest/left arm pain. The ACI-TIPI algorithm then computes a probability that the patient has an acute coronary syndrome, which is printed with the computer's standard interpretation of the ECG. This device was shown in a randomized trial to reduce unnecessary hospital and coronary care unit admissions and thus provide more cost-effective triage of patients. [139] CARDIAC-SPECIFIC TROPONINS.

The troponins can be used in two ways in the ED to evaluate patients with possible UA/NSTEMI: (1) to diagnose NSTEMI and (2) to define prognosis (i.e., the risk of developing recurrent cardiac ischemic events, including death, recurrent infarction, and recurrent severe ischemia requiring rehospitalization or urgent revascularization). In numerous studies, in patients admitted to the hospital with unstable angina[115] [141] [142] [143] [144] [145] [146] [147] [148] [149] [150] [151] [152] [153] [154] [155] (see p. 1240 ) as well as in the broad group of patients presenting to the ED with chest pain,[141] [143] [144] elevations of either troponin T or I have been shown to be very strong predictors of subsequent cardiac events. However, "false-positive" troponin tests have been noted among series of patients presenting to the ED with chest pain.[156] [157] [158] In patients presenting to the ED with a complaint of chest pain, the clinical suspicion (and prevalence) of coronary artery disease is lower than it is in patients who are admitted to the hospital with unstable angina.[141] [143] Thus, the use of cardiac markers in the ED setting should be integrated with the clinical history and the ECG to arrive at an overall assessment of the likelihood of the patient having unstable angina.[141] [143] [159] The timing of when blood samples should be obtained during initial evaluation of UA/NSTEMI has been examined in several studies. Most have included a "baseline" sample,[115] [146] [148] [149] which in studies conducted within clinical trials of unstable angina was at the time of randomization (i.e., at least several hours after the patient had presented to the ED). Recent large studies, in which the first blood sample is taken at the time of the patient's initial evaluation in the ED, have shown elevations of troponin T or I to be strongly predictive of subsequent cardiac complications. [141] [144] However,

several recent studies have found incremental benefit by adding an additional one or two samples (generally 4, 8, or 16 hours later), with the second or third sample identifying a progressively greater number of patients who are positive and who are found to be high risk.[141] [143] [146] [151] [153] Serial measurements are definitely needed among patients who present to the hospital within 6 hours from the onset of pain (which comprise the majority of patients [133] [141] ) because of the release kinetics of troponins and CK-MB (see Chap. 35) . In this early time window, myoglobin or CK-MB isoforms may be useful markers.[112] [160] [161] However,

1238

owing to low specificity of myoglobin for myocardial tissue, it should not be used in isolation but rather confirmed with a later sample analyzed for a more cardiac-specific marker (e.g., troponin or CK-MB).[7] Emergency Department Chest Pain Pathways

The current approach to evaluating patients with chest pain (or related symptoms suggestive of UA/NSTEMI) incorporates four major diagnostic tools--clinical history, ECG, cardiac markers and provocative stress testing. They have three major objectives: (1) to diagnose infarction (using cardiac markers), (2) to evaluate for evidence of ischemia at rest (using symptoms, ECG, and/or continuous ECG monitoring), and (3) to evaluate for significant coronary artery disease (provocative stress testing). Most pathways, including that shown in Figure 36-5 , begin with a clinical assessment of the likelihood of the presenting symptoms being angina.[7] Patients with intermediate or high likelihood of ischemia (i.e., those with any feature shown in Table 36-2) are admitted to the hospital and treated with appropriate therapy for UA/NSTEMI (see p. 1241 ). On the other hand, patients, with atypical pain, not suggestive of ischemia, are discharged home with follow-up to their primary physicians. The remaining patients with a low likelihood of ischemia (i.e., without any of the factors shown in Table 36-2) are observed in the ED (or chest pain unit or related facility) [162] [163] with a standardized protocol.[164] [165] These patients are monitored for recurrent rest pain and have a panel of markers (currently CK-MB, troponin I, and myoglobin) at arrival and 6 hours later. If the onset of pain was more than 6 hours before arrival, the baseline sample is frequently considered sufficient to "rule out" MI. If cardiac markers are positive or if the patient develops recurrent pain with ECG changes, the patient is admitted to the hospital and treated for UA/NSTEMI. If the patient remains pain free and the markers are negative, the patient goes on to exercise stress testing. For most patients, ECG stress testing is used, but for patients with fixed ECG abnormalities (e.g., left bundle branch block [LBBB]) perfusion imaging is employed and for those who cannot walk, pharmacological stress testing is used. If the clinical history suggests a very low likelihood of acute ischemia, patients are discharged home with subsequent outpatient stress testing. The goal is to carry out the

testing and discharge (or admit) patients within 6 to 9 hours from ED arrival with follow-up to their primary physicians. The safety of early exercise stress testing in patients presenting to the ED with chest pain was initially questioned, but several recent studies have demonstrated no adverse outcomes when applied to appropriately selected patients (as described earlier).[166] [167] [168]

CARDIAC IMAGING: SESTAMIBI PERFUSION IMAGING AND ECHOCARDIOGRAPHY.

The use of additional imaging techniques is taking on increasing importance in the early diagnosis of patients presenting with suspected unstable angina and MI, especially when the ECG findings are obscured by LBBB or a paced rhythm. Sestamibi (see Chap. 9) has been useful for patients presenting with chest pain in the ED without diagnostic ECG, to discriminate patients with coronary artery disease (in whom perfusion defects are observed) from those with noncardiac chest pain (with normal perfusion scans).[169] [170] Sestamibi scanning (and echocardiography) also can provide information about left ventricular ejection fraction and wall motion that may be useful in triage decisions of the patients. Some centers have utilized stress echocardiography in evaluating chest pain patients.[171] [172] [173] However, in two studies, little additional information was obtained in the routine use of echocardiography in all chest pain patients.[162] [174] Echocardiography performed while the patient is at rest in the ED has been used to evaluate whether a wall motion

Figure 36-5 Brigham and Women's Hospital Emergency Department "Rule Out Myocardial Infarction (MI)" critical pathway. The approach to patients presenting with acute chest pain or other symptoms suggestive of possible UA/NSTEMI is first to assess the likelihood of coronary artery disease (CAD). Patients with high or intermediate likelihood are admitted to the hospital and treated according to the UA/NSTEMI pathway. Those with clearly atypical chest pain are discharged home. Patients with a low likelihood enter the pathway and are observed in a monitored bed in the emergency department (ED) observation unit over a period of 6 hours, and 12-lead electrocardiograms (ECGs) are performed if the patient has recurrent chest discomfort. A panel of cardiac markers (e.g., troponin I, CK-MB, and myoglobin) are drawn at baseline and 6 hours later. If the patient develops recurrent pain, has ST segment or T wave changes, or has positive cardiac markers, he or she is admitted to the hospital and treated for UA/NSTEMI. If the patient has negative markers and no recurrence of pain, he or she is sent for exercise treadmill testing (ETT), with imaging reserved for patients with abnormal baseline ECGs (e.g., left bundle branch block or left ventricular hypertrophy with ST-T wave abnormalities). If the test is positive in a patient presenting with acute chest pain, the patient is admitted; if the test is negative, the patient is discharged home with follow-up to his or her primary physician.

1239

abnormality is present, to help in establishing (or excluding) the diagnosis of ischemic heart disease,[175] and in determining prognosis.[176] However, cost issues have

precluded widespread routine use of echocardiography, but most centers use echocardiography selectively (i.e., in patients with LBBB or paced rhythms or in patients with suspected valvular disease and/or aortic dissection, especially transesophageal echocardiography for the latter).[177] [178] [179] One study found improved sensitivity of perfusion imaging compared with stress echocardiography or ECG stress testing,[180] whereas another study found similar overall diagnostic capabilities of the two imaging modalities[181] (see also Chap. 13) . Both of these modalities can assess global left ventricular function, a powerful determinant of subsequent prognosis after MI[182] [183] (and presumably after unstable angina as well), and this may be important in triaging medical therapy among patients with confirmed MI or unstable angina (e.g., angiotensin-converting enzyme [ACE] inhibitors).[184] However, because most patients presenting to EDs do not have coronary artery disease,[130] [131] such widespread assessment of left ventricular function would likely not be cost effective. CHEST PAIN CENTERS.

Many hospitals have developed "chest pain centers" within or closely related to the ED in which patients with suspected acute coronary syndromes can be triaged. Standardized protocols for acute STEMI can be implemented, thereby reducing door-to-needle time[185] (see Chap. 35) , and rapid "rule out MI" protocols for low-risk patients with chest pain can be carried out.[165] [186] Use of such chest pain centers or specialized ED units can reduce by 20 to 30 percent the number of patients who require admission to the hospitals[162] [163] [170] [174] [187] and randomized trials.[163] [174] One multicenter study found that the implementation of a chest pain unit significantly decreased the rate of hospital admission and overall costs, despite an overall increase in the number of patients who underwent "rule-out MI" evaluation instead of being discharged home directly.[187] Thus, there is emerging evidence that chest pain centers or specific protocols/critical pathways in the ED can improve the efficiency of health care for this large population of patients. Natural History

The outcome of patients with UA/NSTEMI is generally favorable when compared with acute STEMI,[96] [97] [99] although there are several subgroups of patients who can have higher mortality (see later). In the TIMI III Registry of patients with UA/NSTEMI, 21 percent "ruled in" for an NSTEMI at the time of admission; 62 percent underwent cardiac catheterization, 22 percent angioplasty, and 13 percent coronary bypass surgery. By 42 days, mortality was 2.4 percent and a new or recurrent MI occurred in 2.9 percent of patients. Within clinical trials, in which inclusion criteria select higher risk patients (see later), rates of death by 30 days ranged from 3.5 to 4.5 percent and rates of new or recurrent MI ranged from 6 to 12 percent.[80] [81] [83] RISK STRATIFICATION As already noted, unstable angina is a heterogeneous condition that ranges from one

with an excellent outcome with modest adjustments in therapeutic regimen to one in which the risk of death or MI is high and intensive (and expensive) treatment is needed. Evidence is available from recent large clinical trials for important subgroups of patients who are at higher risk of adverse outcomes (Table 36-3) . [7] Furthermore, these groups appear to derive greater benefit from more aggressive antithrombotic therapy (see p. 1246 ). Clinical predictors can be also used to assist in triage of unstable angina patients to the coronary care unit versus a monitored TABLE 36-3 -- INDICATORS OF INCREASED RISK IN UNSTABLE ANGINA History Advanced age (>65 years) Diabetes mellitus Post-myocardial infarction angina Prior peripheral vascular disease Prior cerebrovascular disease Clinical Presentation Braunwald Class II or III (acute or subacute rest pain) Braunwald Class B (secondary unstable angina) Heart failure/hypotension Electrocardiogram New/ST segment deviation 0.05 mV New T wave inversion 0.3 mV Left bundle branch block Cardiac Markers Increased troponin T or I or CK-MB Increased C-reactive protein (CRP) Angiogram Thrombus bed.[5] [7] [104] Patients determined to be at high risk should be admitted to the coronary care unit, whereas those with intermediate or lower risk could be admitted to a monitored bed on a cardiac step-down unit. CLINICAL VARIABLES.

The Braunwald classification of unstable angina [8] (see Table 36-1) has been shown in several studies to be useful in identifying high-risk patients.[12] [13] [14] In the multicenter TIMI III Registry, which included 3318 consecutive patients with UA/NSTEMI, this classification was an important predictor of rate of death or MI to 1 year--both by the severity of the unstable angina and by the clinical circumstances in which it occurred (see Table 36-1) . High-risk groups of patients with unstable angina are those with acute

rest pain, those with post-MI unstable angina, and those with secondary unstable angina.[14] HIGH-RISK SUBGROUPS.

Increasing age has been shown to be associated with a significant increase in adverse outcomes in patients with UA/NSTEMI.[100] [188] Diabetic patients with UA/NSTEMI are at approximately 50 percent higher risk than nondiabetics (see Chap. 63) .[189] [190] Patients with extracardiac vascular disease (i.e., those with either cerebrovascular disease or peripheral arterial vascular disease) also appear to have approximately 50 percent higher rates of death or recurrent ischemic events compared with patients without previous peripheral or cerebrovascular disease, even after controlling for other differences in baseline characteristics.[191] Patients who present with evidence of congestive heart failure (Killip Class > II) have increased risk of death in the setting of unstable angina.[126] [192] In addition, patients who develop recurrent ischemia after initial presentation have also been found to be at increased risk.[83] [193] PRIOR ASPIRIN THERAPY.

Another group of patients with UA/NSTEMI that has been identified as high risk are those who present with acute ischemia despite chronic aspirin therapy. These patients are sometimes termed "aspirin failures," and a subset of these patients may actually represent "aspirin resistance"[194] ; however, the pathophysiology of this observation is not fully defined and is actively being studied.[195] This group represents an increasing proportion of patients (from 60 to 80 percent of patients in recent trials) and, among patients not randomized to a glycoprotein IIb/IIIa inhibitor, their subsequent rate of death or MI was 50 percent higher than those not previously taking aspirin.[196] [197] Treatment with a glycoprotein IIb/IIIa inhibitor

1240

appeared to decrease this risk (see p. 1246). In the OPUS-TIMI 16 trial, higher event rates were again observed in prior aspirin users, but this was not an independent predictor of mortality or recurrent cardiac events.[198] Thus, the development of UA/NSTEMI despite aspirin therapy is a useful clinical marker of high risk. RISK ASSESSMENT BY ECG.

The admission ECG is very useful in predicting long-term adverse outcomes. In the TIMI III Registry of patients with UA/NSTEMI, independent predictors of 1-year death or MI included LBBB (risk ratio 2.8) and ST segment deviation of 0.05 mV or greater (risk ratio 2.45) (both p125 mg/dl, including after revascularization Diet for LDL >100 mg/dl

C

Angiotensin-converting enzyme inhibitors, especially if LV dysfunction, 125 mg/dl A

Postdischarge follow-up

I

Discharge instructions should include a follow-up appointment. Low-risk medically treated patients and revascularized patients should return in 2-6 wk and higher-risk patients in 1-2 wk

C

Patients managed initially with a conservative strategy who experience recurrent UA or severe (Canadian class III) chronic stable angina despite medical management should be considered for coronary arteriography if they are suitable for revascularization

B

Patients who have tolerable stable angina or no C anginal symptoms at follow-up visits should be managed with long-term medical therapy for stable CAD Use of medication

I

Prior to hospital discharge, patients and/or designated responsible caregivers should be provided with instruction with respect to medication type, purpose, dose, frequency, and pertinent side effects that are well understood Anginal discomfort lasting more than 2 or 3 min should prompt the patient to discontinue the activity or remove himself/herself from the stressful event. If pain does not subside immediately, the patient should be instructed to take NTG. If the first tablet or spray does not provide relief within 5 min, a second and third dose, at 5-min intervals, should be taken. Pain lasting longer than 15-20 min and persistent pain despite 3 NTG doses should prompt the patient to seek immediate medical attention by going to the nearest hospital ED, preferably by ambulance or the quickest available alternative If the pattern of anginal symptoms changes (e.g., pain more frequent or severe, precipitated by less effort, or now occurring at rest), the patient should contact his/her physician to determine the need for additional treatment or testing

All C

Risk factor modification

I

Specific instructions should be given on Smoking cessation, achievement or maintenance of optimal weight, daily exercise, and diet

B

Cholesterol-lowering medications for LDL >125 mg/dl

A

Diet for LDL >100 mg/dl

C

Hypertension control

B

Tight control of hyperglycemia in diabetics

B

Consider referral of patients who are smokers to a B smoking cessation program or clinic and/or an outpatient cardiac rehabilitation program Life style issues

I

Health care providers should discuss the safety and timing of resumption of sexual activity (e.g., 1-2 wk for low-risk patients, 4 wk for post-CABG surgery patients)

C

Beyond the instructions for daily exercise, patients C require specific instructions on activities (e.g., heavy lifting, climbing stairs, yard work, household activities) that are permissible and those that should be avoided. Specific mention should be made about when they can resume driving and return to work ASA=acetylsalicylic acid; CAD=coronary artery disease; CHF=congestive heart failure; ED=emergency department; EF=ejection fraction; HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A; LDL=low-density lipoprotein; LV=left ventricular; MI=myocardial infarction; NTG=nitroglycerin; UA=unstable angina.

Issue

TABLE 36--G-5 -- MANAGEMENT OF SPECIAL POPULATIONS Class Recommendation Level of Evidence

Patients with I chest pain after cocaine use

IIa

NTG and calcium channel blockers for patients with ST segment elevation or depression

B

Immediate coronary arteriography, if possible, in C patients whose ST segments remain elevated after NTG and calcium channel blockers. Thrombolysis (with or without PCI) if thrombus is detected IV calcium channel blockers for patients with ST segment elevation or depression

B

Beta blockers for hypertensive patients (systolic B: >150 mm Hg) or those with sinus tachycardia (pulse >100/min)

C

Thrombolytic therapy if ST segments remain elevated despite NTG and calcium blockers and if coronary angiography is not possible

C

Coronary arteriography, if available, for patients C with ST depression or isolated T wave changes not known to be old and who are unresponsive to NTG and calcium channel blockers

Variant (Prinzmetal) angina

III

Coronary arteriography in patients with chest pain without ST-T wave changes

C

I

Coronary arteriography in patients with episodic chest pain and ST segment elevation that resolves with NTG and/or calcium channel blockers

B

Treatment with nitrates and calcium channel blockers in patients whose coronary arteriogram is normal or shows only nonobstructive lesions

B

IIa

In the absence of significant CAD on coronary B arteriography, provocative testing with methylergonovine, acetylcholine, or methacholine when coronary spasm is suspected but there is no ECG evidence of transient ST segment elevation

IIb

Provocative testing in patients with a nonobstructive lesion on coronary arteriography, a clinical picture of coronary spasm, and evidence of transient ST segment elevation

B

Provocative testing in patients with B nonobstructive lesions on coronary arteriography and a clinical picture of coronary spasm and transient ST segment depression III

Provocative testing carried out without coronary arteriography

C

III

Syndrome X

I

IIb

Provocative testing carried out without coronary arteriography

C

Provocative testing in patients with high-grade obstructive lesions on coronary arteriography

B

Reassurance and medical therapy with nitrates, beta blockers, and calcium channel blockers alone or in combination

B

Risk factor reduction

C

Intracoronary ultrasound to rule out missed obstructive lesions

B

If no ECGs are available during chest pain and coronary spasm cannot be ruled out, coronary arteriography and provocative testing using methylergonovine, acetylcholine, or methacholine should be carried out

C

Hormone replacement in postmenopausal women unless contraindicated

C

Imipramine for continued pain despite Class I measures

C

BP=blood pressure; CAD=coronary artery disease; ECG=electrocardiogram; NTG=nitroglycerin; PCI=percutaneous coronary intervention.

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References Braunwald E, Antman EM, Beasley JW, et al: ACC/AHA guidelines for the management of patients with unstable angina: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol 2000, 36:970-1062, 2000. 1.

Braunwald E, Mark DB, Jones RH, et al: Unstable Angina: Diagnosis and Management. Clinical Practice Guideline Number 10 (amended). AHCPR Publication No 94-0602. Rockville, MD, Agency for Health Care Policy and Research and the National Heart, Lung and Blood Institute, Public Health Service, US Department of Health and Human Services, May 1994. 2.

Gibbons RJ, Chatterjee K, Daley J, et al: ACC/AHA/ACP guidelines for the management of patients with chronic stable angina. J Am Coll Cardiol 33:2092-2197, 1999. 3.




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Chapter 37 - Chronic Coronary Artery Disease BERNARD J. GERSH EUGENE BRAUNWALD ROBERT O. BONOW

Chronic coronary artery disease (CAD) is most commonly due to obstruction of the coronary arteries by atheromatous plaque[1] (the pathogenesis of atherosclerosis is described in Chapter 30) . Factors that predispose to this condition are discussed in Chapter 31 , the control of coronary blood flow in Chapter 34 , acute myocardial infarction in Chapter 35 , and unstable angina in Chapter 36 ; sudden cardiac death, another significant consequence of CAD, is presented in Chapter 26 . No uniform syndrome of signs and symptoms is initially seen in patients with CAD. Chest discomfort is usually the predominant symptom in chronic (stable) angina (see p. 1273 ), unstable angina (see Chap. 36) , Prinzmetal (variant) angina ( p. 1324 ), microvascular angina ( p. 1329 ), and acute myocardial infarction (Chap. 35) . However, syndromes of CAD also occur in which ischemic chest discomfort is absent or not prominent, such as asymptomatic (silent) myocardial ischemia (see p. 1330 ), congestive heart failure, cardiac arrhythmias, and sudden death (Chap. 26) . Obstructive CAD also has many nonatherosclerotic causes, including congenital abnormalities of the coronary arteries, myocardial bridging, coronary arteritis in

association with the systemic vasculitides, and radiation-induced coronary disease.[2] [3] Whether coronary ectasia is a cause of angina pectoris in the absence of coronary artery obstruction remains to be clarified.[4] Myocardial ischemia and angina pectoris may also occur in the absence of obstructive CAD, as in the case of aortic valve disease (see Chap. 46) , hypertrophic cardiomyopathy (Chap. 48) , and idiopathic dilated cardiomyopathy (Chap. 48) . Moreover, CAD may coexist with these other forms of heart disease. THE MAGNITUDE OF THE PROBLEM The importance of CAD in contemporary society is attested to by the almost epidemic number of persons afflicted--especially when this number is compared with the anecdotal reports of its occurrence in the medical literature before this century. Moreover, as the challenges posed by infectious, parasitic, and nutritional disorders and perinatal mortality are overcome, particularly in the developing world, a global epidemic of CAD looms large on the horizon (see Chap. 1) . It is estimated that 12,200,000 Americans have CAD, 6,300,000 of whom have angina pectoris and 7,200,000 have had myocardial infarction.[5] [6] The economic cost of CAD and stroke in the United States in 2000 is estimated at $326.6 billion ($118.2 billion for CAD).[5] Given the current magnitude of the problem and the increasing prevalence of CAD that is anticipated because of aging of the population, recognition, management, and prevention of CAD are of major public health importance.[5] [6] CAD mortality rates vary widely among countries and even within a country. Recent 10-year data from the World Health Organization Monitoring of Trials and Determinants in Cardiovascular Disease (MONICA) Project in 37 different populations demonstrated a reduction in CAD events and mortality rates in most countries, but with contradictory results for a few countries, mostly in central and eastern Europe and Asia.[7] Within the United States, death rates from cardiovascular disease among black males and females are substantially higher than those among whites.[5] Among American Indians, not only do rates of CAD exceed those reported for other U.S. populations, but the disease is more often fatal.[8] However, there is encouraging evidence that in the last three decades the age-adjusted death rate from CAD, which had reached pandemic proportions in industrial countries during the middle years of the 20th century, has decreased.[9] For example, between 1961 and 1991, the age-adjusted death rate for CAD declined by 52 percent, more so in men than women.[5] Similar trends have been observed in many industrialized nations with different health care systems. Multiple causes may have contributed to this favorable trend, including a reduction in risk factors (see Chap. 31) , improvements in socioeconomic circumstances such as enhanced access to care, and new methods of diagnosis and treatment. In the United States, it has been estimated that approximately 50 percent of the decrease in CAD mortality during the last decade has resulted from reductions in primary and secondary risk factors, but the contributions from new methods of treatment are also considered substantial.[10]

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Stable Angina Pectoris CLINICAL MANIFESTATIONS CHARACTERISTICS OF ANGINA (see also Chap. 3) .

Angina pectoris is a discomfort in the chest or adjacent areas caused by myocardial ischemia. It is usually brought on by exertion and associated with a disturbance in myocardial function, but without myocardial necrosis.[11] Heberden's initial description of the chest discomfort as conveying a sense of "strangling and anxiety" is still remarkably pertinent, although adjectives frequently used to describe this distress include "viselike," "constricting," "suffocating," "crushing," "heavy," and "squeezing." In other patients, the quality of the sensation is more vague and described as a mild pressure-like discomfort, an uncomfortable numb sensation, or a burning sensation. The site of the discomfort is usually retrosternal, but radiation is common and usually occurs down the ulnar surface of the left arm; the right arm and the outer surfaces of both arms may also be involved [11] (see Fig. 3-2) . Epigastric discomfort alone or in association with chest pressure is not uncommon. Anginal discomfort above the mandible, below the epigastrium, or confined to the ear is rare. Anginal "equivalents" (i.e., symptoms of myocardial ischemia other than angina), such as dyspnea, faintness, fatigue, and eructations, are common, particularly in the elderly. A history of abnormal exertional dyspnea may be an early indicator of CAD even when angina is absent or no electrocardiographic (ECG) evidence of ischemic heart disease can be found.[12] Dyspnea at rest or with exertion may be a manifestation of severe ischemia and lead to increases in left ventricular filling pressure. Nocturnal angina should raise the suspicion of sleep apnea.[13] A careful clinical history is key to making the correct diagnosis and is particularly important in this era of cost-conscious practice of medicine because it may obviate more expensive testing. If the quality of the pain and its duration, precipitating factors, and associated symptoms are taken into consideration, it is usually possible to arrive at a correct diagnosis (see Table 3-4) . The typical episode of angina pectoris usually begins gradually and reaches its maximum intensity over a period of minutes before dissipating. It is unusual for angina pectoris to reach its maximum severity within seconds, and it is characteristic that patients with angina usually prefer to rest, sit, or stop walking during episodes.[11] Chest discomfort while walking in the cold, uphill, or after a meal is suggestive of angina. Features suggesting the absence of angina pectoris include pleuritic pain, pain localized to the tip of one finger, pain reproduced by movement or palpation of the chest wall or arms, and constant pain lasting many hours or, alternatively, very brief episodes of pain lasting seconds. Pain radiating into the lower extremities is also a highly unusual manifestation of angina pectoris. Typical angina pectoris is relieved within minutes by rest or by the use of nitroglycerin. The response to the latter is often a useful diagnostic tool, although it should be remembered that esophageal pain and other syndromes may also respond to nitroglycerin. A delay of more than 5 to 10 minutes before relief is obtained by rest and nitroglycerin suggests that the symptoms are either not due to ischemia or, alternatively, are due to severe ischemia, i.e., acute myocardial infarction or unstable angina. The

phenomenon of "first effort" or "warm-up" angina is used to describe the ability of some patients in whom angina develops with exertion to subsequently continue at the same level of exertion without symptoms after an intervening period of rest. This attenuation of myocardial ischemia observed with repeated exertion has been postulated to be due to ischemic preconditioning.[14] An important component of the history is to assess the degree of cardiovascular disability caused by angina pectoris. Such assessment is a crucial part of the evaluation for coronary revascularization. Although several classifications for assessing cardiovascular disability are available,[15] the Canadian Cardiovascular Society Functional Classification System (see Table 3-11) is most widely used.[16] MECHANISMS.

The mechanisms of cardiac pain and the neural pathways involved are poorly understood.[1] It is presumed that angina pectoris results from ischemic episodes that excite chemosensitive and mechanoreceptive receptors in the heart. Stimulation of these receptors results in the release of adenosine, bradykinin, and other substances that excite the sensory ends of the sympathetic and vagal afferent fibers. The afferent fibers traverse the nerves that connect to the upper five thoracic sympathetic ganglia and upper five distal thoracic roots of the spinal cord. Impulses are transmitted by the spinal cord to the thalamus and hence to the neocortex. Within the spinal cord, cardiac sympathetic afferent impulses may converge with impulses from somatic thoracic structures, which may be the basis for referred cardiac pain, for example, to the chest. In comparison, cardiac vagal afferent fibers synapse in the nucleus tractus solitarius of the medulla and then descend to excite the upper cervical spinothalamic tract cells, which may contribute to the anginal pain experienced in the neck and jaw.[17] On the basis of positron-emission tomographic (PET) findings on changes in regional cerebral blood flow associated with angina pectoris, it has been proposed that cortical activation is necessary for pain sensation and the thalamus acts as a gate for afferent pain signals.[18] Differential Diagnosis of Chest Pain (see Fig. 3-3 (Figure Not Available) and Table 3-4)

Differentiation of various disorders from CAD is challenging because the severity of the chest pain and the seriousness of the underlying disorder are not necessarily related. Compounding the difficulty in differential diagnosis is the common myth that pain in the left arm or left side of the chest is an ominous sign signifying the presence of CAD. However, a host of other disorders can also cause discomfort in these locations. ESOPHAGEAL DISORDERS.

The common esophageal disorders that may simulate or coexist with angina pectoris are gastroesophageal reflux and disorders of esophageal motility, including diffuse spasm as well as "nutcracker" esophagus, which is characterized by high-amplitude peristaltic contractions and vigorous achalasia.[19] Symptomatic esophageal reflux is common and estimated to occur in 7 to 14 percent of an otherwise "healthy" U.S.

population. In a comparative study of patients with chest pain and normal coronary angiograms and controls with confirmed CAD, esophageal function testing (including manometry, provocation tests, and 24-hour ambulatory pH monitoring) commonly implicated the esophagus as a cause of pain in patients with normal coronary angiograms. Nonetheless, a similar high frequency of esophageal abnormalities among patients with angina pectoris suggests that the esophagus may be an unrecognized source of pain in both groups of patients.[19] Further evidence of a relationship between esophageal abnormalities and angina pectoris was provided by a prospective study demonstrating that esophageal acid stimulation can cause anginal attacks in association with a significant reduction in coronary blood flow in patients with CAD.[20] A lack of any significant effect in this study in heart transplant recipients with cardiac denervation suggests a neural origin. The classic manifestation of esophageal pain is "heartburn," particularly in connection with changes in posture and meals and in association with dysphagia. Esophageal spasm may also cause constant retrosternal discomfort of uniform intensity or severe spasmodic pain during or after

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swallowing. To further compound the difficulty in distinguishing between angina and esophageal pain, both may be relieved by nitroglycerin. However, esophageal pain is often relieved by milk, antacids, foods, or, occasionally, warm liquids. GASTROESOPHAGEAL REFLUX.

The esophageal acid perfusion, or Bernstein, test may be helpful in its use of alternate infusions of dilute acid and normal saline by a nasal gastric catheter with the tip placed at the level of the midesophagus.[19] Infusion of acid produces pain in over 90 percent of patients with subjective and objective evidence of gastroesophageal acid reflux, but it is particularly useful if the patient's symptoms are reproduced. Acid reflux into the esophagus can also be recognized by recording the pH from an electrode at the tip of a catheter inserted into the distal portion of the esophagus. ESOPHAGEAL MOTILITY DISORDERS.

Esophageal motility disorders are not uncommon in patients with retrosternal chest pain of unclear cause and should be specifically excluded or confirmed, if possible.[21] In addition to chest pain, the majority of such patients have dysphagia. Although barium studies may reveal motility problems, esophageal manometry may show diffuse esophageal spasm, increased pressure at the lower esophageal sphincter, and other motility disorders. Provocative pharmacological agents such as methacholine may provoke esophageal pain and manometric signs of spasm. A more complex problem is determining whether part or all of the symptoms in patients with known CAD are due to esophageal disease. Both CAD and esophageal disease

are common clinical entities that may coexist. Diagnostic evaluation for an esophageal disorder may be indicated in patients with CAD who have a poor symptomatic response to antianginal therapy in the absence of documentation of severe ischemia or in patients with persistent symptoms despite adequate coronary revascularization. BILIARY COLIC.

Although visceral symptoms are a common association of myocardial ischemia (particularly acute inferior myocardial infarction [see Chap. 35 ]), cholecystitis and related hepatobiliary disorders may also mimic ischemia and should always be considered in patients with atypical chest discomfort, particularly those with diabetes.[22] The pain is steady, usually lasts 2 to 4 hours, and subsides spontaneously without any symptoms between attacks. It is generally most intense in the right upper abdominal area but may also be felt in the epigastrium or precordium. This discomfort is often referred to the scapula, may radiate around the costal margin to the back, or may in rare cases be felt in the shoulder and suggest diaphragmatic irritation. Ultrasonography is accurate in diagnosing gallstones and allows determination of gallbladder size and thickness and whether the bile ducts are dilated. COSTOSTERNAL SYNDROME.

In 1921, Tietze first described a syndrome of local pain and tenderness, usually limited to the anterior chest wall and associated with swelling of costal cartilage. This condition causes pain that can resemble angina pectoris. The full-blown Tietze syndrome, i.e., pain associated with tender swelling of the costochondral junctions, is uncommon, whereas costochondritis causing tenderness of the costochondral junctions (without swelling) is relatively common.[23] Pain on palpation of these joints is a useful clinical sign. Local pressure should be applied routinely to the anterior chest wall during examination of a patient with suspected angina pectoris. In addition, costochondritis is usually well localized. Although palpation of the chest wall often reproduces pain in patients with various musculoskeletal conditions, it should be appreciated that chest wall tenderness may also be associated with and does not exclude symptomatic CAD.[24] OTHER MUSCULOSKELETAL DISORDERS.

Cervical radiculitis may be confused with angina. This condition may occur as a constant ache, sometimes resulting in a sensory deficit. The pain may be related to motion of the neck, just as motion of the shoulder triggers attacks of pain from bursitis. A hyperalgesic area noted by running the finger down the back and exerting pressure may lead to a suspicion of thoracic root pain. Occasionally, pain mimicking angina can be due to compression of the brachial plexus by the cervical ribs, and tendinitis or bursitis involving the left shoulder may also cause angina-like pain. Physical examination may also detect pain brought about by movement of an arthritic shoulder or a calcified shoulder tendon. OTHER CAUSES OF ANGINA-LIKE PAIN.

Acute myocardial infarction is usually associated with prolonged (>30 minutes), severe pain occurring at rest that apart from duration and intensity, may be similar to angina pectoris. It is associated with characteristic ECG changes and the release of cardiac markers (see Chap. 35) . Unstable angina is a severe form of angina that may also occur at rest and may not be relieved by nitroglycerin (see Chap. 36) . The classic symptom of dissecting aortic aneurysm is a severe, often sharp pain that radiates to the back (see Chap. 40) . Although aortic dissection is generally part of the differential diagnosis of acute myocardial infarction, the syndrome may be chronic in some patients. The pain is often described as sharp, but its pleuropericarditic quality is usually helpful in the differential diagnosis. Severe pulmonary hypertension may be associated with exertional chest pain with the characteristics of angina pectoris, and indeed, this pain is thought to be due to right ventricular ischemia that develops during exertion (see Chap. 53) . Other associated symptoms include exertional dyspnea, dizziness, and syncope. Associated findings on physical examination, such as parasternal lift, a palpable and loud pulmonary component of the second sound, and right ventricular hypertrophy on the ECG, are usually readily recognized. Pulmonary embolism is initially characterized by dyspnea as the cardinal symptom, but chest pain may also be present (see Chap. 52) . Pleuritic pain suggests pulmonary infarction, and a history of exacerbation of the pain with inspiration, along with a pleural friction rub, usually helps distinguish it from angina pectoris. The pain of acute pericarditis (see Chap. 50) may at times be difficult to distinguish from angina pectoris. However, pericarditis tends to occur in younger patients than does angina, and the diagnosis depends on the combination of chest pain not relieved by rest or nitroglycerin, a pericardial friction rub, and ECG changes. Chronic CAD can and frequently does coexist with any of the other disorders mentioned above, and noncardiac disease can trigger a true angina attack in a patient with CAD. An additional component of the history is an evaluation of risk factors for CAD because such risk factors in turn have an effect on both the probability of significant obstructive CAD and the overall prognosis.[25] Physical Examination GENERAL EXAMINATION.

Inspection of the eyes may reveal a corneal arcus, and examination of the skin may show xanthomas (see Fig. 4-2) . Among patients with heterozygous familial hypercholesterolemia (in whom CAD is common), the presence of a corneal arcus increases with age and, in some studies, correlates positively with levels of cholesterol and low-density lipoprotein (LDL) and also with the prognosis.[26] [27] Xanthelasma, in which lipid deposits are intracellular, appears to be promoted by increased levels of

triglycerides and a relative deficiency of high-density lipoprotein (HDL). The presence of xanthelasma is a strong marker of dyslipidemia and, often, a family history of cardiovascular disease, and should provide a strong impetus for performing a comprehensive lipid profile.[28] Retinal arteriolar changes are common in patients with CAD and diabetes mellitus or hypertension. Moreover, diabetes-associated visual impairments, including retinopathy, are independent predictors of increased mortality from all causes, including CAD.[29] Some correlation has been noted between CAD and a diagonal earlobe crease (except in American Indians and Asians). A unilateral diagonal earlobe crease is often present in younger persons with CAD and becomes bilateral with advancing age.[30] A hospital-based, case-control study of men admitted with a first nonfatal myocardial infarction demonstrated that the presence of a diagonal earlobe crease was associated with a relative risk of 1.37 for myocardial infarction; the risk is similarly increased in the presence of baldness and thoracic hairiness.[31] Blood pressure may be chronically elevated or may rise acutely (along with the heart rate) during an angina attack. Changes in blood pressure may precede (and precipitate) or follow (and be caused by) angina. Other important features of the general physical examination are abnormalities in arterial pulses and the venous system. A rapid pulse may be a clue to cardiac decompensation

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or to a systemic condition such as thyrotoxicosis or anemia, which can exacerbate angina pectoris. The association between peripheral vascular disease and CAD is strong and well documented.[32] [33] This association is not confined to patients with symptomatic or clinically overt peripheral vascular disease or CAD but is also seen in asymptomatic subjects with a reduced ankle-brachial blood pressure index or evidence of early carotid disease on ultrasonography.[34] The presence of carotid and peripheral arterial disease on palpation and auscultation increases the likelihood that chest discomfort of unclear origin is caused by CAD. Evaluation of the patient's venous system, particularly in the legs, may have an important bearing on the type of grafting procedure used in subsequent coronary bypass surgery. CARDIAC EXAMINATION.

The physical findings of hypertrophic cardiomyopathy (see Chap. 48) or aortic valve disease (Chap. 46) suggest that angina may be due to conditions other than (or in addition to) CAD. It is often helpful to examine the heart during an episode of pain because ischemia may produce transient left ventricular dysfunction with a third heart sound and pulmonary rales detectable on physical examination.[35] If massage of the carotid sinus produces pain relief in a patient without a carotid bruit, the pain is probably anginal. Softening of the mitral component of the first heart sound as a result of

ischemic left ventricular dysfunction may also be demonstrated during angina. Paradoxical splitting of the second heart sound (see Chap. 4) may occur transiently during angina and appears to be related to asynergy and prolongation of left ventricular contraction, which results in delayed closure of the aortic valve. If other obvious cardiac diseases are absent, a third or loud fourth heart sound suggests ischemia as the basis for the chest pain. These sounds are common in patients with angina at rest, and their frequency is increased during handgrip exercise,[36] even if the latter does not precipitate angina pectoris. A sustained apical cardiac impulse is common in patients with moderate or severe left ventricular dysfunction. A displaced ventricular impulse, particularly if dyskinetic, is a sign of significant left ventricular systolic dysfunction, especially in a patient who previously had a myocardial infarction. Transient apical systolic murmurs are quite common in CAD and have been attributed to reversible papillary muscle dysfunction secondary to transient myocardial ischemia. When persistent, such murmurs may be due to papillary muscle fibrosis, which is often a manifestation of subendocardial infarction or a regional wall motion abnormality altering the alignment of the papillary muscles in relation to other components of the mitral valve apparatus. These murmurs are more prevalent in patients with extensive CAD, especially those with prior myocardial infarction and left ventricular dysfunction, and may indicate an adverse prognosis.[37] Systolic murmurs may assume a variety of configurations (early, late, or holosystolic) and may be accentuated by exertion or during angina. A midsystolic click, often followed by a late systolic murmur produced by mitral valve prolapse (see Chap. 46) , also occurs in patients with CAD. A diastolic murmur or a continuous murmur is a rare finding in CAD and has been attributed to turbulent flow across a proximal coronary artery stenosis.[38] PATHOPHYSIOLOGY Angina pectoris results from myocardial ischemia, which is caused by an imbalance between myocardial O2 requirements and myocardial O2 supply.[1] The former may be elevated by increases in heart rate, left ventricular wall stress, and contractility (see Chap. 34) ; the latter is determined by coronary blood flow and coronary arterial O 2 content (Fig. 37-1) . ANGINA CAUSED BY INCREASED MYOCARDIAL O2 REQUIREMENTS.

In this condition, sometimes termed "demand angina," the myocardial O2 requirement increases in the face of a constant and usually restricted O 2 supply. The increased requirement commonly stems from norepinephrine release by adrenergic nerve endings in the heart and vascular bed, a physiological response to exertion, emotion, or mental stress. Of great importance to the myocardial O2 requirement is the rate at which any task is carried out. Hurrying is particularly likely to precipitate angina, as are efforts involving motion of the hands over the head. Mental stress may also precipitate angina, presumably by increased hemodynamic and catecholamine responses to stress, increased adrenergic tone, and reduced vagal activity.[39] [40]

Figure 37-1 Factors influencing the balance between myocardial O 2 requirements (left) and supply (right). Arrows indicate effects of nitrates. In relieving angina pectoris, nitrates exert favorable effects by reducing O2 requirements and increasing supply. Although a reflex increase in heart rate would tend to reduce the time for coronary flow, dilation of collaterals and enhancement of the pressure gradient for flow to occur as the left ventricular end-diastolic pressure (LVEDP) falls tend to increase coronary flow. A o P=aortic pressure; NC=no change. (From Frishman WH: Pharmacology of the nitrates in angina pectoris. Am J Cardiol 56:8I, 1985. By permission of Excerpta Medica.)

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The combination of physical exertion and emotion in association with sexual activity commonly precipitates angina pectoris, but sexual activity seldom triggers myocardial infarction.[41] Anger may produce constriction of coronary arteries with preexisting narrowing without necessarily affecting O2 demand. Other factors causing angina secondary to an increase in myocardial O2 requirement in patients with obstructive CAD include physical exertion after a heavy meal and the excessive metabolic demands imposed by chills, fever, thyrotoxicosis, tachycardia from any cause, and hypoglycemia. Among patients with stable, fixed obstructive CAD, several studies using ambulatory ECG monitoring have documented the importance of increases in myocardial O 2 requirement and, in particular, tachycardia as a precipitant of ischemia. [42] In all these conditions, underlying coronary artery obstruction is usually present, and the other factors (e.g., exertion, emotion, or fever) precipitate ischemia and chest discomfort by stimulating myocardial O2 need in the presence of a relatively fixed and limited myocardial O2 supply. ANGINA CAUSED BY TRANSIENTLY DECREASED O2 SUPPLY.

Increasing evidence suggests that not only unstable angina but also chronic stable angina may be caused by transient reductions in O2 supply as a consequence of coronary vasoconstriction, [1] [43] a condition that is sometimes termed "supply angina" and due to the entity of "dynamic stenosis." [44] The coronary arterial bed is well innervated, and a variety of stimuli alter coronary tone (see Chap. 34) . Two main explanations have been offered for the association between coronary vasoconstriction and spasm in the presence of organic stenoses. First, platelet thrombi and leukocytes may elaborate vasoconstrictor substances such as serotonin and thromboxane A2 . Second, endothelial damage in atherosclerotic coronary arteries may result in decreased production of vasodilator substances and an abnormal vasoconstrictor response to exercise and other stimuli. A variable threshold of myocardial ischemia in patients with chronic stable angina may be due to dynamic changes in peristenotic smooth muscle tone and also to constriction of arteries distal to the stenosis. [45] In this setting, calcium antagonists and nitrates are less effective than in patients with variant angina, perhaps because of the nature of the constricting stimuli and the site of

constriction.[45] Patients with angina precipitated by a transient reduction in myocardial O2 supply may have a spectrum of signs and symptoms that depend on the severity of the underlying fixed defect and the degree of the dynamic change in coronary arterial tone. In a typical patient with chronic stable angina, the degree of fixed obstruction is sufficient to result in an inadequate coronary flow rate to cope with the increased O2 demands of exercise. However, episodes of transient coronary vasoconstriction may be superimposed on this inadequate flow rate and cause additional limitations to coronary flow reserve in many patients. In rare patients without organic obstructing lesions, severe dynamic obstruction occurring at rest alone can cause myocardial ischemia and result in angina (see Prinzmetal [Variant] Angina, p. 1324 ). On the other hand, in patients with severe fixed obstruction to coronary blood flow, only a minor increase in dynamic obstruction is necessary for blood flow to fall below a critical level and cause myocardial ischemia. FIXED COMPARED WITH VARIABLE-THRESHOLD ANGINA.

The threshold for angina differs widely among patients with chronic angina. In patients with fixed-threshold angina precipitated by increased O2 demands with few if any dynamic (vasoconstrictor) components, the level of physical activity required to precipitate angina is relatively constant. Characteristically, these patients can predict the amount of physical activity that will precipitate angina, e.g., walking up exactly two flights of stairs at a customary pace. When these patients are tested on a treadmill or bicycle, the pressure-rate product (the so-called double product, a correlate of the myocardial O2 requirement) that elicits angina and/or ECG evidence of ischemia is relatively constant. In patients with fixed-threshold, demand angina, the specific threshold at which ischemia develops (as reflected in angina and/or ST segment depression) is a function of the myocardial O2 requirement. As the activity of the left ventricle (and therefore its O 2 requirement) increases, a point is reached at which perfusion distal to a critical coronary arterial obstruction cannot supply sufficient O 2 to myocardium perfused by the obstructed artery; ischemia and angina ensue. This relationship is, however, modified by the effects of coronary vasomotor tone on myocardial O 2 supply.[46] Coronary vascular reserve (or coronary vasodilator or flow reserve) is impaired in patients with significant obstructive CAD and also in those with microvascular disease or endothelial damage from conditions such as hypertension.[47] The majority of patients with variable-threshold angina have atherosclerotic coronary arterial narrowing, but dynamic obstruction caused by vasoconstriction plays an important role in causing myocardial ischemia. These patients typically have "good days," when they are capable of substantial physical activity, as well as "bad days," when even minimal activity can cause clinical and/or ECG evidence of myocardial ischemia or angina at rest. Often, even in the course of a single day, they may be

capable of substantial physical activity at one time while minimal activity results in angina at another. Patients with variable-threshold angina often complain of a circadian variation in angina that is more common in the morning. Angina on exertion and sometimes even at rest may be precipitated by cold temperature,[48] emotion, and mental stress.[49] A cold environment has been shown to increase peripheral resistance, both at rest and during exercise.[50] The rise in arterial pressure, by augmenting myocardial O2 requirements, lowers the threshold for the development of angina. An alternative or additional explanation is the development of cold-induced coronary vasoconstriction via activation of peripheral and reflex mechanisms.[50] The entity of postprandial angina has been recognized for about two centuries and may be a marker of severe multivessel CAD.[51] The mechanism has not been explained, but it may be due to redistribution of coronary blood flow away from the territory supplied by severely stenosed vessels.[52] Some evidence indicates that this phenomenon is more prominent after high-carbohydrate than high-fat meals. [51] MIXED ANGINA.

The term mixed angina has been proposed by Maseri and colleagues to describe the many patients who fall between the two extremes of fixed-threshold and variable-threshold angina.[53] The pathophysiological and clinical correlations of ischemia in patients with stable CAD may have important implications for the selection of antiischemic agents, as well as for their timing. The greater the contribution from increased myocardial O2 requirements to the imbalance between supply and demand, the greater the likelihood that beta-blocking agents will be effective, whereas nitrates and calcium channel blocking agents, at least on theoretical grounds, are likely to be especially effective in episodes caused primarily by coronary vasoconstriction. The finding that in most patients with chronic stable angina an increase in myocardial O2 requirement precedes episodes of ischemia, i.e., that they have demand angina, argues in favor of beta blockers as essential therapeutic agents. [54] GRADING OF ANGINA PECTORIS.

A system of grading the severity of angina pectoris proposed by the Canadian Cardiovascular Society has gained widespread acceptance[16] (see Table 3-11) . The system is a modification of the New York Heart Association functional classification but allows patients to be categorized in more specific terms. Other grading systems include a specific activity scale developed by Goldman and associates[15] and an anginal "score" developed by Califf and colleagues.[55] The Goldman scale is based on the metabolic cost of specific activities and appears to be valid when used by both physicians and nonphysicians. The anginal score of Califf and coworkers integrates the clinical features and "tempo" of angina together with ECG ST and T wave changes and offers independent prognostic information above that provided by age, gender, left ventricular function, and coronary angiographic anatomy. A limitation of all these grading systems is their dependence on accurate patient observation and patients' widely varying tolerance for symptoms. Prospective evaluation of the reproducibility of the New York Heart Association estimates of functional class made by two physicians demonstrated a

reproducibility of only 56 percent, and only 51 percent of the estimates agreed with treadmill exercise performance. Functional estimates based on the Canadian Cardiovascular Society criteria were more reproducible (73 percent) but still did not correlate well with objective measures of exercise performance.[15]

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TABLE 37-1 -- PRETEST LIKELIHOOD OF CORONARY ARTERY DISEASE IN SYMPTOMATIC PATIENTS ACCORDING TO AGE AND SEX* AGE (yr) NONANGINAL ATYPICAL TYPICAL CHEST PAIN ANGINA ANGINA Men

Women Men Women Men Women

30-39

4

2

34

12

76

26

40-49

13

3

51

22

87

55

50-59

20

7

65

31

93

73

60-69

27

14

72

51

94

86

From Gibbons RJ, Chatterjee K, Daley J, et al: ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Chronic Stable Angina). J Am Coll Cardiol 33:2092, 1999. By permission of The American College of Cardiology and The American Heart Association. *Each value represents the percentage with significant coronary artery disease on catheterization (combined data from Diamond and Forrester [ 56] and Chaitman et al. [ 59] ).

CORRELATION BETWEEN HISTORICAL FEATURES AND CORONARY ANGIOGRAPHY.

An important objective of the history and physical examination is to acquire information that can be used to estimate the probability of the presence of obstructive CAD. The importance of this point is emphasized by the impact of the pretest likelihood of CAD on the performance of a standard exercise test.[35] The ability to predict the probability of CAD with reasonable accuracy from the history and physical examination was demonstrated originally by Diamond and Forrester and expanded on by other studies in both men and women referred for cardiac catheterization or stress testing.[56] [57] [58] The inclusion of such risk factors as cigarette smoking, hyperlipidemia, and diabetes mellitus strengthens the predictability of these models, as do certain changes on the ECG.[57] Subsequently, the Diamond and Forrester model was shown to be in strong agreement with the findings of the Coronary Artery Surgery Study (CASS).[59] The joint American College of Cardiology and American Heart Association (ACC/AHA) Guidelines

Committee[35] combined data from both studies to illustrate the pretest likelihood of CAD in men and women stratified by age and nature of the chest pain (Table 37-1) . Although the clinical manifestations of CAD, including rest angina and nocturnal and postprandial angina, tend to be more severe in patients with multivessel than single-vessel disease, neither the severity, duration, or nature of the pain nor its precipitating factors correlate with the extent of disease at angiography. Perhaps the most striking example of the lack of historical-arteriographic correlation is in two subgroups of patients--those with advanced obstructive CAD who are asymptomatic with "silent ischemia" (see p. 1330 and those with Prinzmetal, or variant, angina, who may have episodes of very severe anginal discomfort, yet have minimal or no underlying coronary atherosclerosis (see p. 1324 ). NONINVASIVE TESTING Biochemical Tests

In patients with chronic stable angina, metabolic abnormalities that are risk factors for the development of CAD are frequently detected. These abnormalities include hypercholesterolemia and other dyslipidemias (see Chap. 31) , carbohydrate intolerance, and insulin resistance.[60] [61] All patients with established or suspected CAD warrant biochemical evaluation of total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and fasting blood glucose.[62] New biochemical markers, such as C-reactive protein, lipoprotein Lp(a), and homocysteine, have been shown to increase the likelihood of future cardiovascular events,[63] [64] [65] especially in patients with hypercholesterolemia, but no consensus has been reached regarding routine measurement of these markers, and measuring them is not generally recommended. [66] Serum levels of cardiac markers are normal in patients with chronic stable angina, which serves to differentiate them from patients with acute myocardial infarction. Resting Electrocardiogram (see also Chap. 5)

The resting ECG is normal in approximately half of patients with chronic stable angina pectoris, and even patients with severe CAD may have a normal tracing at rest. A normal resting ECG suggests the presence of normal resting left ventricular function [67] and is an unusual finding in a patient with an extensive previous infarction. The most common ECG abnormalities in patients with chronic CAD are nonspecific ST-T wave changes with or without abnormal Q waves. Numerous pitfalls must be avoided when using the resting ECG for the diagnosis of myocardial ischemia. In addition to myocardial ischemia, other conditions that can produce ST-T wave abnormalities include left ventricular hypertrophy and dilatation, electrolyte abnormalities, neurogenic effects, and antiarrhythmic drugs. [68] In patients with known CAD, however, the occurrence of ST-T wave abnormalities on the resting ECG may correlate with the severity of the underlying heart disease, including the number of vessels involved and the presence of left ventricular dysfunction.[69] This association may explain the adverse impact of ST-T wave changes on prognosis in these patients. In contrast, a normal

resting ECG is a more favorable long-term prognostic sign in patients with suspected or definite CAD.[35] [70] Interval ECGs may reveal the development of Q wave infarctions that have gone unrecognized clinically. Various conduction disturbances, most frequently left bundle branch block and left anterior fascicular block, may occur in patients with chronic stable angina, and they are often associated with impairment of left ventricular function[71] and reflect multivessel disease and previous myocardial damage. Hence, such conduction disturbances are an indicator of a relatively poor prognosis.[35] In patients with chronic stable angina, abnormal Q waves are relatively specific, but insensitive indicators of previous myocardial infarction. Various arrhythmias, especially ventricular premature beats, may be present on the ECG, but they too have low sensitivity and specificity for CAD. Ambulatory ECG monitoring has shown that many patients with symptomatic myocardial ischemia also have episodes of silent ischemia that would otherwise go unrecognized during normal daily activities (see p. 1330 ). Although this form of ECG testing provides a quantitative estimate of the frequency and duration of ischemic episodes during routine activities, its sensitivity for detecting CAD is less than that of exercise ECG. Left ventricular hypertrophy on the ECG is a poor prognostic factor in patients with chronic stable angina. This finding should suggest the presence of underlying hypertension, aortic stenosis, or hypertrophic cardiomyopathy and warrants further evaluation, such as echocardiography to assess left ventricular size, wall thickness, and function. During an episode of angina pectoris, the ECG becomes abnormal in 50 percent or more of patients with normal resting ECGs. The most common finding is ST segment depression, although ST segment elevation and normalization of previous resting ST-T wave depression or inversion ("pseudonormalization") may develop.

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Noninvasive Stress Testing (see also Chap. 13)

Noninvasive stress testing can provide useful and often indispensable information to establish the diagnosis and estimate the prognosis in patients with chronic stable angina.[35] [72] However, several studies have emphasized that the indiscriminate use of such tests may provide limited incremental information over and above that provided by the physician's detailed and thoughtful clinical assessment.[35] [57] [73] [74] [75] [76] Appropriate application of noninvasive tests requires consideration of Bayesian principles (see Chap. 6) . These principles state that the reliability and predictive accuracy of any test is defined not only by its sensitivity and specificity but also by the prevalence of disease (or pretest probability) in the population under study. In an era of emphasis on cost-effectiveness, optimal utilization of testing requires an

assessment of the incremental amount of information provided by a test, over and above what can be obtained from standard clinical variables alone. Noninvasive testing should be performed only if the test result will alter the planned management strategy. The value of noninvasive stress testing is greatest when the pretest likelihood is intermediate because the test result will have the greatest effect on the posttest probability of CAD and, hence, on clinical decision-making in this group of patients. Exercise Electrocardiography (see also Chap. 6)

DIAGNOSIS OF CORONARY ARTERY DISEASE.

As a screening test for CAD, the exercise ECG is useful in that it is relatively simple and inexpensive. It is particularly helpful in patients with chest pain syndromes who are considered to have a moderate probability of CAD and in whom the resting ECG is normal, provided that they are capable of achieving an adequate workload.[77] Although the incremental diagnostic value of exercise testing is limited in patients in whom the estimated prevalence of CAD is either high or low, the test provides useful, additional information about the degree of functional limitation in both groups of patients and about the severity of ischemia and prognosis in patients with a high pretest probability of CAD.[35] [78] [79] The exercise ECG variable most useful for the detection of CAD and, in particular, multivessel disease is the ST segment shift during exercise and recovery.[78] [80] The sensitivity of the ST segment response increases with age, with the severity of CAD, and with the magnitude of the ST segment change itself (see Fig. 6-7) .[35] The predictive value for the detection of CAD is 90 percent if typical chest discomfort occurs during exercise along with horizontal or downward-sloping ST segment depression of 1 mm or more. ST segment depression of 2 mm or more accompanied by typical chest discomfort is virtually diagnostic of significant CAD.[80] In the absence of typical angina pectoris, downsloping or horizontal ST segment depression of 1 mm or more has a predictive value of 70 percent for the detection of significant coronary stenosis, but the predictive value increases to 90 percent with ST segment depression of 2 mm or more. The early onset of ST segment depression during exercise, its long persistence following discontinuation of exercise, a downsloping or horizontal depression, and a low work capacity or exercise duration are all strongly associated with multivessel disease. Exercise-induced QRS prolongation also appears to be a function of exercise-induced ischemia[81] and is related to the extent of exercise-induced segmental contraction abnormalities. A meta-analysis of 147 published studies involving more than 24,000 patients was performed in the process of establishing the ACC/AHA Guidelines on Exercise Testing.[78] Wide variability in sensitivity and specificity was reported, with a mean sensitivity of 68 percent and mean specificity of 77. The results of stress testing often influence the subsequent decision for angiography and create a posttest referral bias that tends to inflate sensitivity and decrease specificity.[82] When meta-analyses are restricted to studies designed to avoid such work-up bias, the sensitivity is only 45 to 50 percent but the specificity is 85 to 90 percent.[78]

A major factor contributing to the low sensitivity of exercise ECG is that many patients are incapable of reaching the level of exercise required for near-maximal effort (85 percent or more of the maximal predicted heart rate), particularly those receiving beta-adrenergic blockers, those in whom fatigue, leg cramps, or dyspnea develops, and those with musculoskeletal symptoms. ST segment changes have low specificity in patients taking digitalis and those with left ventricular hypertrophy and repolarization abnormalities. ST segment changes cannot be interpreted when patients have left bundle branch block, Wolff-Parkinson-White syndrome, or an artificial pacemaker. In these subsets of patients, noninvasive imaging with exercise or pharmacological stress testing or diagnostic coronary angiography may be indicated. INFLUENCE OF ANTIANGINAL THERAPY.

Antianginal pharmacological therapy reduces the sensitivity of exercise testing as a screening tool. Beta blockade increases the exercise duration and suppresses, diminishes, or delays the appearance of ST segment depression and thus obscures the diagnostic interpretation of exercise testing.[78] [83] Because beta blockade reduces the sensitivity of the test, a negative exercise test in patients receiving antianginal drugs does not exclude significant and possibly life-threatening myocardial ischemia. Therefore, if the purpose of the exercise test is to diagnose ischemia, it should be performed, if possible, in the absence of antianginal medications. However, the advisability of withholding medications in an individual patient before exercise testing is a matter of judgment. Two or 3 days are required for patients receiving long-acting beta blockers. Unless the patient has severe angina, sublingual nitroglycerin for 1 or 2 days is likely to be sufficient to control symptoms if other therapy is withdrawn. For long-acting nitrates, calcium antagonists, and short-acting beta blockers, discontinuing use of the medications the day before testing usually suffices. If the purpose of the exercise test is to identify safe levels of daily activity or the extent of functional disability, the test should be performed while the patient is taking the usual medications. Nuclear Cardiology Techniques (see Chap. 9)

STRESS MYOCARDIAL PERFUSION IMAGING.

Exercise perfusion imaging incorporates all the components of the exercise ECG with images of myocardial blood flow by using either thallium-201 or a technetium-99m (99m Tc)-based perfusion tracer. [84] The radionuclide is injected intravenously at peak exercise or at a symptom-limited endpoint, such as angina pectoris or dyspnea; the patient is encouraged to exercise for another 30 to 45 seconds to ensure that initial myocardial uptake of the tracer reflects the perfusion pattern at peak stress. Acquisition of the stress images is performed several minutes later when the patient is at rest. A separate image acquisition is obtained at rest to compare the stress images with images of resting perfusion. Reversible perfusion defects between stress and rest indicate exercise-induced ischemia, whereas irreversible defects usually represent regions of myocardial fibrosis (see Fig. 9-12) . In the case of thallium-201, a stress-redistribution

protocol is usually followed, in which rest images are obtained 3 to 4 hours after the stress test without a second injection of tracer. More rapid washout rates of thallium from normal versus ischemic myocardium produce apparent filling in of perfusion defects caused by reversible ischemia, a process termed "redistribution." With 99m Tc perfusion tracers, which do not redistribute appreciably, two separate injections are required, one during stress and the other at rest. This technique can be accomplished by using either 1-day or 2-day imaging protocols.[84] [85] A hybrid dual-isotope protocol has evolved in which both thallium and a 99m Tc tracer are used. [86] [87] The lower-energy thallium is injected at rest and imaged, followed immediately by stress imaging with the higher-energy, 99m Tc-labeled compound. This latter procedure can be accomplished within 90 minutes and has the advantage of requiring a much shorter time for completing the study than with standard thallium stress-redistribution or 99m Tc stress-rest imaging protocols. Exercise perfusion imaging with simultaneous ECG is

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superior to exercise ECG alone in detecting CAD, in identifying multivessel disease, in localizing diseased vessels, and in determining the magnitude of ischemic and infarcted myocardium (see also Chap. 13) . The published results of exercise single-proton emission computed tomographic (SPECT) imaging involving more than 5200 patients with angiographic documentation of the presence or absence of CAD yield an average sensitivity and specificity of 89 and 76 percent, respectively (range, 71 to 98 percent and 43 to 92 percent, respectively). [35] Referral bias may account, in part, for the low specificity of many studies, and the few studies that adjusted for referral bias report a specificity higher than 90 percent.[35] The results with thallium-201 are comparable to those obtained with 99m Tc-sestamibi or 99m Tc-tetrofosmin, so these agents can in general be used interchangeably for the diagnosis of CAD. Perfusion imaging is valuable for detecting myocardial viability in patients with regional or global left ventricular dysfunction, with or without Q waves[88] [89] (see Chap. 13) . Stress perfusion imaging also provides important information in regard to prognosis.[74] [75] [90] [91]

Stress myocardial scintigraphy is particularly helpful in the diagnosis of CAD in patients with abnormal resting ECGs and those in whom ST segment responses cannot be interpreted accurately, such as patients with left ventricular hypertrophy and repolarization abnormalities, those with left bundle branch block, and those receiving digitalis. Because stress myocardial perfusion imaging is a relatively expensive test (three to four times the cost of an exercise ECG), certain issues should be considered: (1) a regular exercise ECG should always be considered first in patients with chest pain and a normal resting ECG for screening and detection of CAD[35] [78] ; (2) stress myocardial perfusion scintigraphy should not be used as a screening test in patients in whom the prevalence of CAD is low because the majority of abnormal tests will be

false-positive results; (3) stress perfusion imaging is more sensitive in detecting CAD, especially in patients with single-vessel CAD, than exercise ECG[35] [84] ; (4) perfusion imaging is more accurate in patients with resting ECG abnormalities and those receiving digitalis; and (5) perfusion imaging is more accurate in localizing and quantifying regions of myocardial ischemia, which is of particular importance in patients who previously had revascularization, and in determining the extent of viable myocardium in patients with left ventricular dysfunction. PHARMACOLOGICAL NUCLEAR STRESS TESTING.

For patients unable to exercise adequately, especially the elderly and patients with peripheral vascular disease, pulmonary disease, arthritis, or a previous stroke, pharmacological vasodilator stress with dipyridamole or adenosine may be used.[84] [92] [93] In most nuclear cardiology laboratories, such patients account for approximately 40 percent of those referred for perfusion imaging. A comparison of 2000 patients undergoing adenosine and dipyridamole pharmacological stress testing demonstrated that adverse effects occurred less often with dipyridamole than with adenosine.[94] However, the effects of adenosine are very brief, whereas those associated with dipyridamole are more difficult to manage and necessitate longer monitoring time, as well as fairly frequent intravenous administration of aminophylline for reversal. In patients with asthma, dobutamine stress perfusion imaging is a useful and safe alternative to vasodilator stress imaging,[95] but adenosine and dipyridamole are more sensitive for detecting CAD because they produce a greater increase in coronary blood flow.[96] Although the diagnostic accuracy of pharmacological vasodilator stress perfusion imaging is comparable to that achieved with exercise perfusion imaging,[97] treadmill testing is preferred for patients who are capable of exercising because the exercise component of the test provides additional diagnostic information about ST segment changes, effort tolerance and symptomatic response, and heart rate and blood pressure response. EXERCISE RADIONUCLIDE ANGIOGRAPHY.

The use of radionuclide angiography for detecting and estimating prognosis in CAD has been supplanted largely by exercise echocardiography. Although radionuclide angiography is more accurate than echocardiography in measuring the ejection fraction, failure to augment the ejection fraction with exercise is a nonspecific finding that is influenced by age, gender, and the presence of hypertension. The addition of radionuclide ventriculography in patients with a normal ECG at rest adds little to the diagnostic information provided by clinical and other exercise variables.[84] Echocardiography provides a more accurate assessment of exercise-induced changes in regional wall motion and systolic wall thickening, which are more specific markers of reversible ischemia than are changes in ejection fraction. Stress Echocardiography (see also Chap. 7)

EXERCISE ECHOCARDIOGRAPHY.

Two-dimensional echocardiography is useful in the evaluation of patients with chronic CAD because it can assess global and regional left ventricular function in the absence and presence of ischemia, as well as detect left ventricular hypertrophy and associated valve disease. Echocardiography is relatively inexpensive and safe. Stress echocardiography, in which imaging is performed at rest and immediately after exercise, allows the detection of regional ischemia by identifying new areas of wall motion disorders. Adequate images can be obtained in more than 85 percent of patients, and the test is highly reproducible. The inability to image at peak exercise is only a minor disadvantage because most wall motion abnormalities do not normalize immediately upon cessation of exercise. Detection of ischemic myocardium has been enhanced with the development of systems that allow simultaneous side-by-side display of rest and postexercise images. Numerous studies have shown that exercise echocardiography can detect the presence of CAD with an accuracy that is similar to that of stress myocardial perfusion imaging and superior to exercise ECG alone.[35] [98] [99] Stress echocardiography is also valuable in localizing and quantifying ischemic myocardium. Published results in more than 3200 patients with angiographic confirmation of the presence or absence of CAD yield an average sensitivity of 85 percent and specificity of 86 percent. [35] As with perfusion imaging, stress echocardiography also provides important prognostic information in patients with known or suspected CAD.[35] Indications for stress echocardiography are similar to those discussed above for stress myocardial perfusion imaging. Stress echocardiography is an excellent alternative to nuclear cardiology procedures. Although less expensive than nuclear perfusion imaging, stress echocardiography is more expensive and less available than exercise ECG, and a regular exercise ECG should always be considered first for screening and detection of CAD in patients with a normal resting ECG who are capable of performing treadmill exercise.[35] [78] PHARMACOLOGICAL STRESS ECHOCARDIOGRAPHY.

In patients unable to exercise, those unable to achieve adequate heart rates with exercise, and those in whom the quality of the echocardiographic images during or immediately after exercise is poor, alternative approaches are available. The most well studied and clinically available method is dobutamine stress echocardiography,[35] [100] [101] in which constant echocardiographic imaging is performed during the infusion of dobutamine beginning at 5 to 10 mug/kg/min with graded increases to a maximum of 40 to 45 mug/kg/min. Dobutamine increases both the heart rate and contractility and produces diagnostic changes in regional wall motion and systolic wall thickening as ischemia develops. Low-dose dobutamine infusion (5 to 10 mug/kg/min) is also valuable for assessing contractile reserve in regions with hypokinetic or akinetic wall motion at rest, as a means of identifying viable myocardium that may improve in function after revascularization[89] [102] [103] (see Chap. 13) . Atropine increases the accuracy of dobutamine stress echocardiography in patients with inadequate heart rate responses,[104] especially

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those taking beta blockers and those in whom second-degree heart block develops at higher atrial rates. Dobutamine stress imaging achieves diagnostic accuracy comparable to that of exercise echocardiography,[35] [100] [101] but as with myocardial perfusion imaging, exercise stress imaging is preferable in patients capable of performing adequate exercise. An exception to this general policy is a patient with left ventricular dysfunction who is undergoing dobutamine echocardiography to assess myocardial viability. Dobutamine stimulation is safe, especially if the test is terminated at the onset of the first ischemic regional wall motion abnormalities. An alternative form of pharmacological stress echocardiography is the use of high-dose dipyridamole infusion[105] or adenosine infusion, but exercise and dobutamine stress appear to have greater sensitivity than vasodilator stress in detecting CAD[100] [101] and are superior in assessing the extent of CAD.[100] All forms of stress echocardiography have similar high specificity because a new wall motion abnormality in a patient with normal resting left ventricular function is a highly specific finding for reversible ischemia. Transesophageal dobutamine stress echocardiography has been shown to be feasible, safe, and accurate for the detection of myocardial ischemia. Although not a readily available technique for large numbers of patients, it may allow extension of dobutamine stress testing to patients with inadequate transthoracic echocardiographic imaging.[106] STRESS ECHOCARDIOGRAPHY VERSUS STRESS NUCLEAR PERFUSION IMAGING (see also Chap. 13) .

The two stress imaging methods in general provide similar accuracy in detecting CAD. In studies in which the same patients were studied with both techniques and with coronary angiography, nuclear myocardial perfusion imaging had slightly greater sensitivity and stress echocardiography had greater specificity.[107] The potential advantage of stress echocardiography in terms of enhanced specificity has also been demonstrated in meta-analyses (which did not account for possible posttest referral bias).[99] Stress echocardiography is also associated with lower cost and easier implementation in the physician's office. The choice of diagnostic test to perform, however, depends on several additional factors, including local expertise and available facilities. CONTRAST ECHOCARDIOGRAPHY (see also Chap. 7) .

Contrast echocardiography is a rapidly evolving field in noninvasive testing for the diagnosis and assessment of CAD.[108] A major objective is the development of intravenous ultrasonic contrast agents for noninvasive myocardial perfusion imaging. With greater spatial resolution than nuclear perfusion imaging, echocardiography has the potential for evaluating transmural distribution of flow heterogeneity and detecting changes in subendocardial perfusion. Although this goal has not been fully realized with the intravenous administration of ultrasonic contrast agents, early work is promising. [109] An outgrowth of this research is two developments that have improved wall motion

assessment during standard stress echocardiography. The first is blood pool opacification with intravenous injection of a contrast agent, which has improved delineation of the left ventricular endocardial surface.[110] The second is the use of harmonic imaging, which can be used even without administration of a contrast agent and, in addition, enhances definition of the endocardial border.[111] Poor visualization of endocardial borders in a sizable subset of patients has been a limitation of stress echocardiography for many years, and these two new developments have significantly improved endocardial border definition, with the potential for enhanced detection of ischemic myocardium. Clinical Application of Noninvasive Testing

GENDER DIFFERENCES IN THE DIAGNOSIS OF CAD (see also Chap. 58) .

On the basis of earlier studies that indicated a much higher frequency of false-positive stress test results in women than in men, it is generally accepted that ECG stress testing is not as reliable in women. However, the prevalence of CAD among women in the patient populations under study was low, and the lower positive predictive value of exercise ECG in women can be accounted for, in large part, on the basis of Bayesian principles (Table 37-1) .[112] Once men and women are stratified appropriately according to the pretest prevalence of disease, the results of stress testing are similar. [78] [113] Exercise imaging modalities have greater diagnostic accuracy than exercise ECG in both men and women.[35] [78] Although soft tissue attenuation artifacts, especially those caused by breast tissue, may reduce the specificity of myocardial perfusion imaging in women, these artifacts can usually be identified by experienced observers without a substantial reduction in diagnostic accuracy, and risk assessment by nuclear perfusion imaging is not diminished in women compared with men.[114] In addition, the use of gated SPECT imaging has greatly improved identification of these artifacts by demonstrating that regions with apparently irreversible perfusion defects have normal wall motion, thereby enhancing diagnostic accuracy.[115] Among women without a history of myocardial infarction, exercise echocardiography was superior to exercise ECG in the detection of CAD.[116] [117] IDENTIFICATION OF PATIENTS AT HIGH RISK.

When applying noninvasive tests to the diagnosis and management of CAD, it is useful to grade the results as "negative"; "indeterminate"; "positive, not high risk"; and "positive, high risk." The criteria for high-risk findings on stress ECG, myocardial perfusion imaging, and stress echocardiography are listed in Table 37-2 . Regardless of the severity of symptoms, patients with high-risk noninvasive test results have a very high likelihood of CAD and, if they have no obvious contraindications to revascularization, should undergo coronary arteriography. Such patients, even if asymptomatic, are at risk for left main or three-vessel CAD, and many will have impaired left ventricular function. Hence, they are at high risk for experiencing coronary events. The prognosis in these patients may often be improved by coronary bypass surgery. In contrast, patients with clearly negative exercise tests, regardless of

symptoms, have an excellent prognosis that cannot usually be improved by revascularization. If they do not have serious symptoms, they generally do not require coronary arteriography. ASYMPTOMATIC PERSONS.

In asymptomatic persons or in those with chest pain not likely to be angina, the pretest likelihood of CAD is low (10 yr)

Effective in relieving symptoms

Limited to specific anatomical subsets

CORONARYARTERY BYPASS GRAFTSURGERY Effective in relieving symptoms

Cost

Improved survival in certain subsets

Increased risk of a repeat procedure because of late graft closure

Ability to achieve complete revascularization

Morbidity

Wider applicability Modified from Faxon DP: Coronary angioplasty for stable angina pectoris. In Beller G (ed): Chronic Ischemic Heart Disease. In Braunwald E (ed): Atlas of Heart Disease. Vol 5. Philadelphia, Current Medicine, 1995. by both techniques. Most patients with chronically occluded coronary arteries were excluded, and of those who were clinically eligible, approximately two-thirds were excluded for angiographic reasons. The lack of any difference in late mortality and myocardial infarction between the two groups in such patients indicates that PCI is a reasonable initial strategy, provided that the patient accepts the distinct possibility of symptom recurrence and need for repeat revascularization. Patients with a single localized lesion in each affected vessel and preserved left ventricular function fare best with PCI. NEED FOR COMPLETE REVASCULARIZATION.

Complete revascularization is an important goal in patients with left ventricular dysfunction and/or multivessel disease. The major advantage of CABG surgery over PCI is its greater ability to achieve complete revascularization, particularly in patients with three-vessel disease. In the majority of such patients, particularly those with chronic total coronary occlusion, left ventricular dysfunction, or left main CAD, CABG is the procedure of choice.[348] [475] Among patients with borderline left ventricular function (ejection fraction between 40 and 50 percent) and milder degrees of ischemia, PCI may provide adequate revascularization, even if it is not complete anatomically. In many patients, either method of revascularization is suitable. Other factors that come into consideration include (1) access to a high-quality team and operator with an excellent record of success; (2) patient preference--some patients are made anxious by the idea that after PCI they remain at risk for symptom recurrence and may require reintervention (such patients are better candidates for surgical treatment); (3) advanced patient age and comorbidity--frail, very elderly patients and those with comorbid conditions, such as cancer or serious liver disease with a limited life expectancy, but who have disabling angina--are often better candidates for PCI; and (4) younger patient age--PCI is also often preferable in younger patients (50 percent) of the left main coronary artery 2. Left main equivalent: significant (>70 percent) stenosis of the proximal left anterior descending coronary artery and proximal left circumflex artery

3. Three-vessel disease, especially if left ventricular function is reduced

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TABLE 37--G-2 -- APPROPRIATENESS OF CABG FOR SPECIFIC PATIENT SUBSETS Clinical Subset Class I Class IIa Class IIb Class III Asymptomatic or mild angina

Significant left main coronary artery stenosis Left main equivalent: significant ( 70%) stenosis of the proximal LAD and proximal left circumflex artery Three-vessel disease

Proximal LAD One- or 2-vessel Other stenosis with 1- or disease not 2-vessel disease* involving the proximal LAD

Stable angina

Same as for Proximal LAD None patients with stenosis with asymptomatic or 1-vessel disease* mild angina, plus One- or 2-vessel coronary artery Two-vessel disease with disease without significant significant proximal LAD proximal LAD stenosis and stenosis but with a either an EF moderate area of viable 100 mg/dl

3-Hydroxy-3-methylglutaryl/coenzyme A reductase inhibitors preferred if elevated low-density lipoprotein is major aberration

Smoking cessation

I

Smoking cessation education and possibly counseling and pharmacotherapy

From Gibbons RJ, Chatterjee K, Daley J, et al: ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Chronic Stable Angina). J Am Coll Cardiol 33:2092-2197, 1999. Reprinted with permission from the American College of Cardiology. explicitly call for all patients to undergo such screening, they note that many centers screen all those 65 years or older. Other patients who should undergo carotid artery ultrasound screening include those with a prior history of cerebrovascular disease. Aspirin for the first year after CABG is considered the drug of choice for prophylaxis against early saphenous graft closure from thrombus; most patients continue this therapy indefinitely to reduce the risk for myocardial infarction. Patients with LDL cholesterol levels above 100 mg/dl warrant dietary and nondietary interventions to improve their lipid profile. Smoking cessation counseling should also be a routine part of care. The guidelines also indicate that cardiac rehabilitation should be offered to all eligible patients.

ORGANIZATIONAL CONSIDERATIONS. The ACC/AHA guidelines noted studies suggesting that survival after CABG is worse when performed at institutions or by operators performing a low volume of procedures annually. The guidelines commented that data support close monitoring of institutions or individuals performing fewer than 100 cases annually.

References Gibbons RJ, Chatterjee K, Daley J, et al: ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). J Am Coll Cardiol 33:2092-2197, 1999. 1.

Ryan TJ, Bauman WB, Kennedy JW, et al: Guidelines for percutaneous transluminal coronary angioplasty. A report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Subcommittee on Percutaneous Transluminal Coronary Angioplasty). J Am Coll Cardiol 22:2033-2054, 1993. 2.

Eagle KA, Guyton RA, Davidoff R, et al: ACC/AHA guidelines for coronary artery bypass graft surgery. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery). J Am Coll Cardiol 34:1262-1347, 1999. 3.

Braunwald E, Antman EM, Beasley JW, et al: ACC/AHA guidelines for the management of patients with unstable angina: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol, 36:970-1062, 2000. 4.

The Society for Cardiac Angiography: Guidelines for credentialing and facilities for performance of coronary angioplasty. Cathet Cardiovasc Diagn 15:136-138, 1988. 5.

Ryan TJ, Klocke FJ, Reynolds WA: Clinical competence in percutaneous transluminal coronary angioplasty: A statement for physicians from the ACP/ACC/AHA Task Force on Clinical Privileges in Cardiology. J Am Coll Cardiol 15:1469-1474, 1990. 6.

Hirshfeld JW, Ellis SG, Faxon DP, et al: Recommendations for the assessment and maintenance of proficiency in coronary intervention procedures. Statement of the American College of Cardiology. J Am Coll Cardiol 31:722-743, 1998. 7.

Kirklin JW, Akins CW, Blackstone EH, et al: Guidelines and indications for coronary artery bypass graft surgery. A report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Subcommittee on Coronary Artery Bypass Graft Surgery). J Am Coll Cardiol 17:543, 1991. 8.

Afridi I, Grayburn PA, Panza JA, et al: Myocardial viability during dobutamine echocardiography predicts survival in patients with coronary artery disease and severe left ventricular dysfunction. J Am Coll Cardiol 32:921, 1998. 9.

Meluzin J, Cerny J, Frelich M, et al: Prognostic value of the amount of dysfunctional but viable myocardium in revascularized patients with coronary artery disease and left ventricular dysfunction. J Am Coll Cardiol 32:912, 1998. 10.




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Chapter 38 - Percutaneous Coronary and Valvular Intervention JEFFREY J. POPMA RICHARD E. KUNTZ

The use of percutaneous coronary intervention (PCI) in patients with ischemic coronary artery disease (CAD) has expanded dramatically over the past two decades. More than 650,000 patients underwent PCI in 1999 in the United States, far exceeding the number of patients undergoing coronary artery bypass graft surgery (CABG). Continual technological improvements (e.g., stents, atherectomy and thrombectomy devices), refinements in periprocedural adjunctive pharmacology (e.g., glycoprotein IIb-IIIa [GP IIb-IIIa] inhibitors), and a better understanding of early and late outcomes in patients with comorbidities have fostered the expanded use of PCI as definitive therapy for ischemic CAD. This chapter will review (1) the current methods used for PCI, including conventional balloon angioplasty and new coronary devices; (2) the procedural outcomes and complication rates obtained with contemporary PCI methods; (3) the periprocedural pharmacological strategies to reduce acute complications and restenosis after PCI; and (4) recommendations for coronary revascularization in patients with ischemic CAD, with consideration of the alternatives of medical therapy, PCI, and CABG. A discussion of

the current issues in patient selection, technical performance, and outcomes associated with percutaneous mitral and aortic valvuloplasty is also included. HISTORICAL PERSPECTIVE

Balloon angioplasty, or percutaneous transluminal coronary angioplasty (PTCA), was first performed by Andreas Gruentzig in 1977 with the use of a prototype, fixed-wire balloon catheter.[1] The procedure was initially limited to patients with symptomatic CAD who had focal lesions in proximal coronary vessels and was used as an alternative to CABG.[1] Because of an objective reduction in stenosis severity and consistent improvement in clinical ischemia with this novel method,[2] the number of patients treated with balloon PTCA expanded dramatically over the next decade.[3] Operator experience and equipment design also evolved rapidly, with a transition from poorly steerable, fixed-wire balloon dilatation catheters to highly steerable, over-the-wire, and rapid-exchange balloon dilatation systems. These catheter designs resulted in more flexible, trackable, and lower-profile balloon dilatation systems and allowed the expansion of PCI to a broader spectrum of patients, such as those with multivessel disease, "high-risk" anatomy, reduced left ventricular function, and other serious comorbid medical conditions.[3] It soon became apparent that two major issues limited the widespread use of balloon PTCA in patients with symptomatic CAD. Abrupt vessel closure resulting from angioplasty-induced dissection and thrombus formation occurred in 6.8 to 8.3 percent of cases,[4] [5] [6] [50A] largely unpredictable in individual patients despite the description of several predisposing factors in a number of series.[7] [8] [9] [10] Although in-laboratory abrupt vessel closure was reversible in most patients, emergency CABG was occasionally (3 to 5 percent of cases) required to relieve ongoing transmural ischemia resulting from catheter-based complications. In some cases, the urgency of surgical revascularization mandated that saphenous vein grafts (SVGs) be used instead of the preferred arterial conduits. The second major limitation of balloon PTCA was the development of restenosis, either clinically manifested by symptom recurrence or identified as recurrent arterial narrowing by routine repeat angiography. The pathology of restenosis has remained poorly understood, and pharmacological agents have not consistently reduced its occurrence. A number of new coronary devices were developed in the early 1990s to improve upon the early and late procedural outcomes achieved with balloon PTCA. These novel methods were designed to remove (e.g., directional, rotational, or extraction atherectomy), ablate (e.g., excimer laser angioplasty), or scaffold (e.g., stents) atherosclerotic plaque. Randomized clinical trials have shown that some devices (e.g., stents) resulted in better early and late clinical outcome while others (e.g., excimer laser angioplasty) imparted no incremental clinical benefit and were potentially detrimental in comparison to balloon PTCA. Given these devices' diverse mechanisms of benefit and their niche application in selected patients, it became apparent that a "lesion-specific" approach to coronary angioplasty was required, with the specific type of revascularization tailored to the precise characteristics of the vessel wall pathology. Coronary angioplasty then

encompassed the use of both balloons and new devices, and the generic term percutaneous coronary intervention was introduced. BALLOON PTCA Balloon PTCA expands the coronary lumen by stretching and tearing the atherosclerotic plaque and vessel wall and, to a lesser extent, by redistributing atherosclerotic plaque along its longitudinal axis.[11] [12] There is no evidence that balloon PTCA compresses atherosclerotic plaque. TECHNICAL ASPECTS.

Balloon PTCA is performed by over-the-wire, rapid-exchange, or fixed-wire balloon dilatation systems. A 1.0 to 1.1:1.0 balloon-to-artery ratio is optimal for balloon size selection; higher ratios are associated with complications, and lower ones predispose to restenosis.[13] Although "stand-alone" balloon PTCA is usually (>80 percent) effective in improving ischemic symptoms, it is limited by substantial early elastic recoil, which results in an average 30 to 35 percent residual stenosis. On occasion, propagation of a coronary dissection and superimposed platelet thrombus formation after balloon PTCA result in early complications, including abrupt vessel closure. An "optimal" angiographic result (140 mm Hg systolic or 90 mm Hg diastolic Add blood pressure medication, individualized to other patient requirements and characteristics (i.e., age, race, need for drugs with specific benefits) if blood pressure is not 160 mm Hg systolic or >100 mm Hg diastolic

Lipid management

Start AHA step II diet in all patients: 30% fat, 200 meters

IIb

Pain free, claudication walking 20 kg)

1.0-2.0 mg IV, TDD

0.125-0.250 mg IV

over 48 hr

qd

TDD=Total digitalizing dose. *PO=Oral dose approximately 20 percent greater than IV dose except in "older children." In older children, IV=oral dose.

dosage regimen of drugs administered to young patients must be adjusted to take into account the age and size of the patient and the maturity-dependent pharmacological properties of cardioactive drugs. Because this is especially true in early infancy, Table 43-6 provides the dosages of digoxin and diuretics commonly used for infants. Digitalis and Diuretics.

Digoxin is the glycoside used exclusively to treat pediatric patients in most cardiac centers because it is readily absorbed, available in convenient dosage form, and excreted rapidly from the body. The efficacy and safety of digitalis remain topics of debate, although on balance, continued use is warranted. Premature infants are more sensitive to digitalis than are full-term newborns, who, in turn, are more sensitive than older infants. Infants absorb and excrete digoxin as well as adults do, and their relative distribution of the glycoside to different body tissues is also similar. The prevailing dose schedules for digoxin produce higher serum concentrations in infants than would be considered optimal for adults.[83] The basis for the higher digitalis requirement in infancy is unclear, although it may relate to an age-dependent alteration in the sensitivity of the myocardium per se to the glycosides. In this regard, infants tolerate higher serum digoxin concentrations than adults without developing signs of toxicity. In adults, the usual therapeutic concentrations of digoxin are less than 2 ng/ml blood, and toxicity commonly occurs above that level. In contrast, in infants, therapeutic levels of digoxin range from 1 to 5 ng/ml (mean = 3.5), and toxicity is associated with concentrations in excess of 3 ng/ml. Older children have therapeutic and toxic levels similar to those of adults.[84] A restricted fluid intake (65 ml/kg/day) and a low-sodium diet (1 to 2 mEq/kg/day) should accompany diuretic therapy in the most seriously ill infants with heart failure. Furosemide is the agent of choice when the rapid elimination of excess salt and water is needed. Hydrochlorothiazide, occasionally in conjunction with spironolactone or triamterene to reduce potassium loss and sodium retention, is convenient for long-term therapy.

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TABLE 43-7 -- DOSAGE REGIMENS: INOTROPIC AGENTS DRUG DOSE COMMENTS Epinephrine (Adrenalin)

0.05-1.0 mug/kg/min IV

May cause hypertension and cardiac arrhythmias; inactivated in alkaline solution

Isoproterenol (Isuprel)


May decrease coronary blood flow; results in peripheral and pulmonary vasodilation

Norepinephrine (Levophed)


Causes significant vasoconstriction

Dobutamine (Dobutrex)

2-10 mug/kg/min IV (max 40 mug/kg/min)

No direct effect on renal perfusion, little or no peripheral vasodilatation or tachycardia

Dopamine (Intropin)

2-20 mug/kg/min IV (max 50 mug/kg/min)

Significant renal vasodilatation

2-5 mug/kg/min

Inotropic±heart rate acceleration

5-8 mug/kg/min

Significant heart rate acceleration

>8 mug/kg/min

±Vasoconstriction

>10 mug/kg/min

Significant vasoconstriction

15-20 mug/kg/min Levodopa

40-80 mg/kg/d PO; maximum Administer with pyridoxine 0.7 single dose 1 gm q6h mg/kg/d (maximum 25 mg) and metoclopramide 0.1 mg/kg/dose, 1 hr before levodopa dose (Above dose/effect relations speculative in neonates)

Amrinone

Dose schedule not well established for infants and children

May cause thrombocytopenia, hepatic and gastrointestinal disturbance, fever, and arrhythmias

40-75 mug/kg/min IV for 2-3 min, then maintenance at 3-10 mug/kg/min; Dose not to exceed 10 mg/kg/24 hr Milrinone

Dose schedule not established for infants and children

See Amrinone

Adults: bolus 50 mug/kg maintenance 0.375-0.75 mug/kg/min Modified from Friedman WF, George BL: New concepts and drugs in the treatment of congestive heart failure. Pediatr Clin North Am 31:1197, 1984.

Other Pharmacological Approaches.

These may prove to be of significant benefit in selected instances in which digitalis and diuretics are relatively ineffective. In situations in which cardiac decompensation is not the result of an obstructive lesion, catecholamines may be used temporarily to alleviate cardiac failure while the patient is awaiting more definitive operative treatment (Table 43-7) .[81] In infants with the coarctation of the aorta syndrome, in whom ductal constriction unmasks the aortic branch point, producing aortic narrowing, or with aortic arch interruption, heart failure may be reversed dramatically by intravenous infusion of prostaglandin E1 (0.03 to 0.1 mg/kg/min), which results in dilatation of the ductus arteriosus and relief of the obstruction.[85] Conversely, in preterm infants in whom patent ductus arteriosus is responsible for profound cardiopulmonary deterioration, constriction of the ductus arteriosus may be accomplished by inhibition of prostaglandin synthesis with the nonsteroidal anti-inflammatory agent indomethacin (0.2 mg/kg intravenously).[86] [87]

Vasodilator therapy also is used in infants or children with heart disease in whom preload or afterload alterations may be expected to improve cardiac performance (Table 43-8) .[81] [88] Moreover, treatment of severe cardiac failure often requires combining inotropic and afterload-reducing agents (see Chap. 18 ). Combinations of dopamine, dobutamine, and nitroprusside have been used extensively and effectively in the pediatric population, primarily in the setting of low cardiac output after open-heart surgery.[89] [90] Use of oral afterload-reducing agents, e.g., hydralazine or captopril, in association with digoxin is worthwhile in the long-term therapy of outpatients with congestive cardiomyopathy and/or significant mitral or aortic regurgitation.[88] Rapid developments in molecular biology have begun to revolutionize our understanding of cardiovascular regulation, both before and after birth and at all ages. As knowledge is gained about the mechanisms responsible for the variability of gene expression in the heart, it is apparent that the future holds the opportunity for clinicians to modify TABLE 43-8 -- DOSAGE REGIMENS: VASODILATORS IN INFANTS AND CHILDREN DRUG DOSE AND ROUTE OF COMMENTS ADMINISTRATION Nitroglycerin

0.5-20 mug/kg/min IV (max 60 mug/kg/min IV)

Dosage schedule for IV and other routes of administration not well established for children

Hydralazine (Apresoline)

0.5 mg/kg/d PO q6-8hr (max 200 mg/d or 7 mg/kg/d)

May cause tachycardia, gastrointestinal symptoms, neutropenia, lupus-like syndrome

1.5 mug/kg/min IV or 0.1-0.5 mg/kg/dose IV q6hr (max 2 mg/kg q6hr)

Captopril (Capoten)

0.1-0.4 mg/kg/dose PO given q6-24hr as needed

May cause neutropenia/proteinuria

Enalopril (Vasotec)

0.1 mg/kg/24 hr PO; increase as needed over 2 wk (max 0.5 mg/kg/24 hr IV: 0.01 mg/kg/dose q8-24 hr)

Nitroprusside (Nipride)

0.5-8 mug/kg/min IV

Prazosin (Minipress)

1st dose: 5 mug/kg PO (max 25 Initial dose used to elevate mug/kg/dose q6hr) hypotensive effects; orthostatic hypotension, attenuation of hemodynamic effects may occur

May result in thiocyanate or cyanide toxicity if used in high doses or for prolonged periods; light sensitive

Modified from Friedman WF, George BL: New concepts and drugs in the treatment of congestive heart failure. Pediatr Clin North Am 31:1197, 1984.

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gene expression in ways that will importantly enhance the heart's ability to respond to both the heart failure state and those diseases that are responsible for the abnormalities leading to cardiac disease.[91] CYANOSIS (See also p. 1617 ) Cyanosis in infants often presents as a diagnostic emergency, necessitating prompt detection of the underlying cause. The schema in Figure 43-6 outlines a general approach to diagnosis. The cardiologist must distinguish between three types of cyanosis--peripheral, differential, and central--while recognizing that cyanosis may accompany diseases of the central nervous, hematological, respiratory, and cardiac systems. PERIPHERAL CYANOSIS.

Peripheral cyanosis (normal arterial oxygen saturation and widened arteriovenous oxygen differences) usually indicates stasis of blood flow in the periphery. The level of reduced hemoglobin in the capillaries of the skin usually exceeds 3 gm/100 dl. The most prominent causes of peripheral cyanosis in newborns are autonomically controlled alterations in the cutaneous distribution of capillary blood flow (acrocyanosis) and septicemia associated with evidence of a low cardiac output, i.e., hypotension, weak pulse, and cold extremities. In many instances, peripheral cyanosis is clearly the result of a cold environment or high hemoglobin content. When cyanosis is caused by the former, vasodilatation produced by immersing the extremity in warm water for several minutes reverses the cyanosis.

CENTRAL CYANOSIS.

Oxygen unsaturation in central cyanosis may result from inadequately oxygenated pulmonary venous blood, in which case inhalation of 100 percent oxygen may diminish or clear the discoloration (discussed later). Conversely, in instances in which cyanosis is due to an intracardiac or extracardiac right-to-left shunt, pulmonary venous blood is fully saturated, and inhalation of 100 percent oxygen usually does not improve the infant's color. It is necessary to qualify the latter statement because oxygen may act directly in infants with elevated pulmonary vascular resistance to dilate the pulmonary blood vessels and thus reduce the magnitude of the venoarterial shunt. Central cyanosis also may be due to the replacement of normal by abnormal hemoglobin, as in methemoglobinemia. Several factors influence the oxygen saturation produced at any given arterial PO2 . These include temperature, pH, ratio of fetal to adult hemoglobin, and erythrocyte concentration of 2,3-diphosphoglycerate. For example, fetal hemoglobin has a higher affinity for oxygen than does adult hemoglobin and therefore would be more highly saturated at any given PO2 . Thus, determination of the systemic arterial oxygen tension may provide a more accurate picture of the underlying pathophysiology than simply measuring the oxygen saturation.[46] [92] DIFFERENTIAL CYANOSIS.

Differential cyanosis virtually always indicates the presence of congenital heart disease, often with patency of the ductus arteriosus and coarctation of the aorta as components of the abnormal anatomical complex. If the upper part of the body is pink and the lower part of the body blue, coarctation of the aorta or interruption of the aortic arch is probable, with oxygenated blood supplying the upper body and desaturated blood supplying the lower body by way of right-to-left flow through the ductus arteriosus. The latter also occurs in patients with patent ductus arteriosus and markedly elevated pulmonary vascular resistance. A patient with transposition of the great arteries and coarctation of the aorta with retrograde flow through a patent ductus arteriosus demonstrates the reverse situation, i.e., the lower part of the body is pink and the upper part blue. Simultaneous determinations of oxygen saturation in the temporal or right brachial artery and the femoral artery are helpful in confirming the presence of differential cyanosis. Differentiating Between Pulmonary and Cardiac Causes of Cyanosis

The distinction between respiratory signs and symptoms arising from cyanotic cardiac disease and those associated with a primary pulmonary disorder is an important challenge to the cardiologist.[41] Upper airway obstruction precipitates cyanosis by producing alveolar hypoventilation owing to reduced pulmonary ventilation. Mechanical obstruction may occur from the nares to the carina, and the important diagnostic possibilities among congenital abnormalities are choanal atresia, vascular ring, laryngeal web, and tracheomalacia. Acquired causes include vocal cord paresis,

obstetrical injury to the cricothyroid cartilage, and

Figure 43-6 Flow chart for the evaluation of cyanotic infants. Tests to be done are listed at the left. The response to each of these tests leads along the line to the proper diagnostic category. CHD = congenital heart disease; CHF = congestive heart failure; CNS = central nervous system; Hct = hematocrit; PDA = patent ductus arteriosus; T/GA = transposition of great arteries; Coarct=coarctation; Rm=room. (From Kirkpatrick SE, Friedman WF, Pitlick P, et al: Differential diagnosis of congenital heart disease in the newborn--University of California, San Diego, School of Medicine, and University Hospital, San Diego [Specialty Conference]. West J Med 128:127, 1978.)

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TABLE 43-9 -- ARTERIAL BLOOD GAS PATTERNS IN VARIOUS DISORDERS CAUSING CYANOSIS IN INFANTS PATTERN pH PO PCO RESPONSE VENOUS SUGGESTED CONDITION 2 TO O2 pH 2 1

Hyaline membrane or other pulmonary parenchymal disease

2

Hypoventilation

3

--

--

--

Venous admixture

4

--

--

Decreased or ineffective pulmonary blood flow

5

--

--

Systemic hypoperfusion

-- = no effect. For description of patterns, see pp. 1524 ff. foreign body. Structural abnormalities in the lungs resulting from intrapulmonary disease are more frequently a basis for cyanosis among newborns than is upper airway obstruction. Hyaline membrane disease, atelectasis, or pneumonitis causing inflammation, collapse, and fluid accumulation in the alveoli results in reduction of the oxygenation of blood reaching the systemic circulation.

Successfully distinguishing among these various causes of cyanosis depends on interpretation of the respiratory pattern, the cardiac physical examination, evaluation of arterial blood gases (Table 43-9) , and interpretation of the ECG, chest radiograph, and echocardiogram. RESPIRATORY PATTERNS.

The key to differential diagnosis at the bedside commonly is the proper evaluation of the pattern of respiration. Term infants normally exhibit a progressive reduction in respiratory rate during the first day of life from 60 to 70 breaths/min to 35 to 55 breaths/min. Moreover, mild intercostal retractions and minimal expiratory grunting disappear within several hours of birth. An increased depth of respiration in the presence of cyanosis but without other signs of respiratory distress often is associated with congenital cardiac disease in which inadequate pulmonary blood flow is the most important functional component. Apnea.

The most important variations from normal respiratory patterns are apnea, bradypnea, and tachypnea. Intermittent apneic episodes are common in premature infants with central nervous system immaturity or disease. In addition, higher centers may be depressed as a result of severe hypoxemia, acidemia, or administration of pharmacological agents to mother or baby. The association of apneic episodes, lethargy, hypotonicity, and a reduction of spontaneous movement most often points to intracranial disease as an underlying cause. Tachypnea.

Diverse conditions result in tachypnea in the newborn period. Tachypnea in the presence of intrinsic pulmonary disease with upper or lower airway obstruction usually is accompanied by flaring of the alae nasi, chest-wall retractions, and grunting. In contrast, tachypnea associated with intense cyanosis in the absence of obvious respiratory distress suggests the presence of cyanotic congenital heart disease. In general, highest respiratory rates (80 to 110 breaths/min) occur in association with primary lung disease, not heart disease. Initial chest radiography frequently is diagnostic, especially if the problem is aspiration, mucous plug, adenomatoid malformation, lobar emphysema, diaphragmatic hernia, pneumothorax, lung agenesis, pulmonary hemorrhage, or an abnormal thoracic cage configuration. Choanal atresia may be precluded by passing a feeding tube through the nares, and the more common types of esophageal atresia and tracheoesophageal fistula may be excluded by passing the tube farther into the stomach. CARDIAC EXAMINATION.

Specific findings on cardiovascular examination may direct attention to a cardiac cause of cyanosis. Peripheral perfusion is poor in the presence of severe primary myocardial

disease or the hypoplastic left heart syndrome. In contrast, peripheral pulses are bounding and the dorsalis pedis and palmar pulses are easily palpable in infants with patent ductus arteriosus, truncus arteriosus, or aorticopulmonary window. A marked discrepancy between upper and lower extremity blood pressures helps to identify infants with coarctation of the aorta. Inspection and palpation of the precordium allow an overall estimate of cardiac activity. A thrill in the suprasternal notch and/or over the precordium occasionally may be felt in infants with patent ductus arteriosus, critical aortic stenosis, or coarctation of the aorta. Characterization of the second heart sound may be of help because it often is single in infants with a hypoplastic left heart complex, pulmonary atresia with or without an intact ventricular septum, or truncus arteriosus. Wide splitting of the second heart sound may occur in infants with total anomalous pulmonary venous return. Ejection sounds often are detectable in infants with persistent truncus arteriosus and occasionally with critical aortic or pulmonic stenosis. The presence of a third heart sound is normal, but a gallop rhythm may provide a clue to myocardial failure. Wide splitting of the first and second heart sounds may produce the characteristically rhythmic auscultatory cadence of Ebstein's anomaly of the tricuspid valve (see Chaps. 25 and 44 ). The presence of a cardiac murmur may point clearly to underlying cardiac disease, but the absence of a murmur does not preclude a cardiac malformation. Moreover, cardiac murmurs of specific anomalies often are atypical in the newborn period. However, certain cardiac murmurs such as the decrescendo holosystolic murmur of tricuspid regurgitation in Ebstein's anomaly or the transient tricuspid regurgitation of infancy may point clearly to an accurate diagnosis. Auscultation of the head and abdomen may detect the murmur of an arteriovenous malformation at those sites in infants who present with findings of severe heart failure. BLOOD GAS AND pH PATTERNS.

Arterial blood gas analysis may be a reliable method of evaluating cyanosis, suggesting the type of altered physiology, and assessing responses to therapeutic maneuvers.[53] Specimens for blood gas analysis should be obtained in room air and in 100 percent oxygen. Stick capillary samples from the patient's warmed heel may be used, although determinations obtained by arterial puncture are preferable for evaluation of oxygenation because they are less susceptible to alterations in regional blood flow in critically ill infants. Sampling of right radial or temporal arterial blood is preferable because these sites are proximal to flow through a ductus arteriosus and do not reflect right-to-left ductal shunting, as would a sample from the descending aorta obtained by means of an umbilical artery catheter. A trial of continuous positive airway pressure may improve oxygenation in infants with either hyaline membrane disease or pulmonary edema. Arterial blood gas patterns in various pathophysiological conditions are listed in Table 43-9 . Pattern 1 typically is observed in infants with ventilation-perfusion abnormalities resulting from primary respiratory disease, often associated with elevated pulmonary vascular resistance and venoarterial shunting across a patent foramen ovale or patent ductus arteriosus. Pulmonary hypoventilation with carbon dioxide retention produces pattern 2. In the presence of a lesion causing obligatory venous admixture, such as total anomalous

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pulmonary venous connection (pattern 3), the response to oxygen may reflect an increase in pulmonary venous return secondary to a fall in pulmonary vascular resistance. Pattern 4 typically is seen in infants with a cardiac malformation that results in reduced pulmonary blood flow. Oxygen administration in these infants does not alter the arterial PO2 . The alterations of pattern 5 are observed when systemic hypoperfusion is the principal hemodynamic problem. In these babies, the arteriovenous oxygen difference is high, and the acidemia may be progressive and unrelenting. ELECTROCARDIOGRAM (see also Chap. 5 ).

ECG is less helpful in suggesting a diagnosis of heart disease in premature and newborn infants than in older children. Right ventricular hypertrophy is a normal finding in neonates, and the range of normal voltages is wide. However, specific observations can offer major clues to the presence of a cardiovascular anomaly. A counterclockwise, superiorly oriented frontal QRS loop with absent or reduced right ventricular forces suggests the diagnosis of tricuspid atresia. In contrast, when the QRS axis is normal but left ventricular forces predominate, the diagnosis of pulmonic atresia must be considered. The counterclockwise, superior QRS orientation also is observed in infants with an endocardiac cushion defect and in some with double-outlet right ventricle; right ventricular forces in these babies are increased. The initial septal vector should be assessed from the ECG. Q waves often are not clearly seen in the lateral precordial leads in the first 72 hours of life. A leftward, posteriorly directed septal vector giving rise to Q waves in the right precordial leads is abnormal and suggests the presence of marked right ventricular hypertrophy, single ventricle, or inversion of the ventricles. T wave alterations may be seen on a normal neonatal ECG and may be of no particular consequence. By 72 hours of age, however, the T waves should be inverted in V3 and V1 and upright in the lateral precordium; persistently upright T waves in the right precordial leads are a sign of right ventricular hypertrophy. Depressed or flattened T waves in the lateral precordium may suggest subendocardial ischemia and a left heart outflow tract obstructive lesion, electrolyte disturbance, acidosis, or hypoxemia. An ECG pattern of myocardial infarction suggests a diagnosis of anomalous pulmonary origin of the coronary artery. Finally, rhythm disturbances such as complete heart block or supraventricular tachycardia (see Chap. 25 ) can be detected readily by ECG. RADIOGRAPHIC EXAMINATION (see also Chap. 8 ).

Chest radiography often is useful in differentiating between respiratory and cardiac causes of cyanosis in the newborn period. Determination of a normal cardiac and abdominal situs aids in ruling out several kinds of complex cyanotic cardiac malformations associated with asplenia or polysplenia with abdominal heterotaxy and dextrocardia. The distinct appearance of pulmonary parenchymal disease, such as the classic reticulogranular pattern of hyaline membrane disease, may allow a specific

radiological diagnosis. In those premature infants with a large ductus arteriosus, the radiographic appearance often evolves from the typical findings of hyaline membrane disease to increased pulmonary vascular markings and finally to perihilar and generalized pulmonary edema. Most important, the pediatric cardiologist depends heavily on the evaluation of pulmonary vascular markings to categorize neonatal congenital cardiac malformations according to function. In the presence of cyanosis, diminished pulmonary vascular markings call attention to the group of anomalies that includes tetralogy of Fallot, pulmonic stenosis with intact ventricular septum, pulmonic atresia, tricuspid atresia, and Ebstein's malformation of the tricuspid valve. Reduced pulmonary blood flow is responsible for the systemic arterial desaturation in these babies. Increased pulmonary vascular markings in cyanotic infants are associated with lesions in which an obligatory admixture of systemic venous and pulmonary venous blood occurs. The more common anomalies in this category include transposition of the great arteries, hypoplastic left heart syndrome, truncus arteriosus, and total anomalous pulmonary venous drainage. As mentioned earlier, overall heart size in normal newborn infants is greater than in older children, and cardiothoracic ratios up to 0.60 are within normal limits. The thymus shadow occasionally obscures the cardiac silhouette and prohibits accurate estimation of heart size. An enlarged heart on x-ray examination suggests a cardiac disorder. However, in the presence of severe respiratory difficulties with an increase in carbon dioxide tension and a decrease in both pH and arterial oxygen tension, cardiomegaly may be only moderate. A right aortic arch suggests the presence of either tetralogy of Fallot or persistent truncus arteriosus. An ovoid heart with a narrow base associated with increased pulmonary vascular marking is typical of transposition of the great arteries. A boot-shaped heart with concavity of the pulmonary outflow tract suggests tetralogy of Fallot, pulmonic atresia, or tricuspid atresia. LABORATORY STUDIES IN CONGENITAL HEART DISEASE FETAL ECHOCARDIOGRAPHY (see also Chap. 7 ).

Ultrasound technology now allows examination of human fetal cardiac development and function in utero.[39] [93] [94] [95] Diagnostic-quality images of the fetal heart in utero can be obtained as early as 16 weeks of gestation. Cardiac structures are imaged primarily by cross-sectional echocardiography and augmented by a combination of range-gated pulsed Doppler ultrasonography, Doppler color flow imaging, and M-mode echocardiography. Analysis of the structure and function of the fetal heart during the second and third trimesters of pregnancy has allowed cardiologists to counsel prospective parents and, in a number of instances, to formulate management plans for pregnancy, delivery, and the immediate postnatal period. Using fetal echocardiography, major forms of congenital heart disease have been diagnosed in utero and cardiac rhythm abnormalities have been detected, permitting direct efforts at transplacental therapy. In particular, it has been established that a high incidence of cardiac pathology exists in the presence of nonimmune fetal hydrops. It appears clear that hydrops fetalis often represents end-stage fetal cardiac decompensation (Fig. 43-7) . AV

Figure 43-7 Fetal echocardiogram taken transabdominally through the uterus and the placenta shows a fetus lying with its head to the right hand side of the figure and demonstrates a pericardial (Peric) effusion (arrows). The right ventricle (RV), the aorta (AO), and the left atria (LA) are seen within the cardiac silhouette.

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valve insufficiency often causes fetal right ventricular volume overload and systemic venous hypertension, leading to hydrops fetalis. Pulsed Doppler and color flow mapping ultrasound examination of the fetus importantly supplement the echocardiographic findings in identifying the responsible defects, such as Ebstein's malformation of the tricuspid valve, atrial isomerism with AV septal defects, and the absent pulmonary valve and hypoplastic left heart syndromes. Fetal cardiac ultrasonography is of special importance in analyzing disturbances of fetal cardiac rhythm, which usually are first suspected on the basis of auscultatory findings. Transabdominal ECG cannot identify atrial depolarization and is of limited value in the analysis of cardiac arrhythmias in utero. However, M-mode recordings of cardiac motion versus time allow conclusions about electrical events in the fetal heart, as they are reflected by the mechanical responses that are recorded echocardiographically. Supraventricular tachyarrhythmias are a common cause of nonimmune fetal hydrops (Fig. 43-8) . Detection is of practical use in the treatment of these patients because the arrhythmia is treatable with the use of various antiarrhythmic drugs, such as digoxin, procainamide, propranolol, and flecainide, administered to the mother and reaching the fetus transplacentally or, rarely, under sonographic guidance, by injecting drugs, such as amiodarone, into the umbilical vein.[96] ECHOCARDIOGRAPHY IN THE NEONATE.

Echocardiography is of immense value in differentiating between heart disease and lung disease in newborns.[97] [97A] Indeed, it has become the standard for the diagnosis of virtually all cardiovascular malformations. A great many infants are now referred directly after ultrasound study for operative repair, without intervening cardiac catheterization. Echocardiographic diagnoses that often can be made with certainty include coarctation of the aorta, interruption of the aortic arch, patent ductus arteriosus, hypoplastic left heart syndrome, aortic valve stenosis, membranous and fibromuscular subvalvular aortic stenosis, aortic coarctation, hypertrophic cardiomyopathy, cor triatriatum, total anomalous

Figure 43-8 M-mode echocardiogram at 35 weeks' gestation, showing fetal supraventricular tachycardia

and pericardial effusion (PEff). The tracing, taken at the midventricular level, allows the heart rate to be calculated from atrioventricular valve (AVV) motion (250 beats/min). (Courtesy of Dr. Charles Kleinman.)

pulmonary venous connection, atrial septal defect, tricuspid atresia, Ebstein's anomaly of the tricuspid valve, valvular pulmonic stenosis, AV septal defect, single ventricle, double-outlet right ventricle, transposition of the great arteries, and patent ductus arteriosus. The echocardiogram provides suggestive and often conclusive evidence for tetralogy of Fallot, truncus arteriosus, and pulmonary atresia with an intact ventricular septum, as well as pulmonary atresia with a VSD and a patent ductus arteriosus. Doppler ultrasonography (see Chap. 7 ) supplements the two-dimensional echocardiographic examination by its ability to quantify valve gradients, cardiac output, blood flow patterns in the cardiac chambers and great arteries, and often shunt size.[98] [99] For example, the pulmonary-systemic blood flow ratio can be calculated by multiplying the square of the ratio of the great vessel diameters by the ratio of the peak systolic flow velocities, the pulmonary variable being the numerator in each ratio. The coupling of Doppler ultrasonographic techniques with the two-dimensional echocardiogram, and the representation in color of abnormalities in flow, volume, and direction (see Chap. 7 ), greatly improve diagnostic accuracy. Magnetic resonance imaging (see Chap. 10 ) can also be useful.[99A] DIAGNOSTIC CARDIAC CATHETERIZATION (see also Chap. 11 ).

If certain cardiac anomalies are identified by noninvasive studies or if a clear-cut differentiation cannot be made between cardiac and pulmonary disease, heart catheterization and angiocardiography may be necessary to define the underlying state precisely. However, fewer cardiac catheterizations have been performed in infants and children of all ages since the beginning of aggressive pursuit of preoperative diagnoses by noninvasive imaging modalities, particularly two-dimensional Doppler flow echocardiography.[99] [100] Hemodynamic study of newborn infants carries a small but distinct risk.[101] As a general rule, cardiac catheterization is not performed unless the information sought is central to treatment of the infant. Most infants with serious heart disease require therapeutic intervention, and thus catheterization should be performed only when surgical support is readily available. Cardiac catheterization is often performed in newborns who experience congestive heart failure in the first days after birth if the cause is an anatomical abnormality rather than an arrhythmia or a metabolic disturbance. Preferably, medical measures will have been instituted to stabilize the clinical state before a hemodynamic study is performed. Some newborns with cyanotic congenital heart disease require prompt cardiac catheterization because of the considerable risk of rapid deterioration. Under these circumstances, hemodynamic and angiographic studies may not only provide the anatomical diagnosis required before emergency operation but also allow the opportunity for therapeutic maneuvers such as balloon atrial septostomy to facilitate intercirculatory mixing in patients with complete transposition of the great arteries or to augment interatrial shunting in patients with a restrictive patent foramen ovale and either tricuspid, pulmonic, or mitral atresia or total anomalous pulmonary venous connection. Selective intravenous infusion of low doses of prostaglandin E1 (0.05 to 0.1 mug/kg/min)

has been used before and at cardiac catheterization for the emergency palliation of ductus-dependent cardiac lesions such as pulmonary atresia, aortic coarctation, and interruption of the aortic arch. Because a patent ductus arteriosus maintains pulmonary and systemic blood flow, respectively, in these infants, dilatation of the ductus with vasodilatory prostaglandins may retard their clinical deterioration. Thus, prostaglandin E1 infusion has been shown to be an effective short-term measure to correct hypoxemia and acidemia and to improve the preoperative and intraoperative status of infants who require surgical relief of the congenital cardiac lesion that is causing pulmonary or systemic hypoperfusion.

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THERAPEUTIC CATHETERIZATION (see also Chap. 38 ).

Balloon atrial septostomy was the first catheter intervention that proved useful in treating congenital heart disease, and it remains the standard initial palliation in infants with complete transposition of the great arteries unless the arterial switch operation is performed imminently.[102] Many additional transcatheter techniques are now used successfully to treat congenital heart disease. These include knife blade atrial septostomy; umbrella or coil closure of patent ductus arteriosus; self-expanding and centering Amplatzer occluding device, or buttoned or modified clamshell or umbrella device closure of atrial septal defect; balloon-expandable intravascular stents for peripheral pulmonary artery and selected postoperative stenoses; and balloon and coil embolization of large systemic pulmonary artery collateral vessels and arteriovenous fistulas.[103] [104] [105] Other procedures that have expanded the role of the cardiac catheter from a diagnostic tool to a therapeutic instrument include transvenous or transarterial pacemaker insertion and retrieval of foreign bodies from the cardiovascular system. Transluminal balloon angioplasty currently is used principally in pediatrics for dilation of pulmonic and aortic valve stenoses, native and recoarctation of the aorta, and peripheral pulmonary artery stenosis. Questions about transluminal angioplasty in native neonatal coarctation, tetralogy of Fallot, and congenital subaortic and mitral stenoses remain unresolved. Finally, electrode catheter radiofrequency ablative techniques for the treatment of tachycardias are now performed routinely in centers with pediatric electrophysiology programs.[106] ELECTROPHYSIOLOGICAL STUDIES (see also Chap. 23 ).

The cardiac catheterization laboratory also is being used with increasing frequency to define the anatomical and physiological diagnoses of arrhythmias, thus facilitating an accurate prognosis and providing a rational basis for pharmacological, catheter ablation, or surgical treatment.[107] [108] [109] Catheter ablation approaches to tachyarrhythmias are now standard pediatric procedures (see Chaps. 23 and 25 ). The invasive electrophysiological approach provides unique information that cannot be obtained noninvasively. This includes determination of conduction times of individual components of the conducting system and measurement of refractory periods for structures such as the AV node, His bundle, and bundle branches. In addition, one can determine the

origin or anatomical circuit, sustaining mechanisms, and possible perturbations that terminate the arrhythmia. This last maneuver is particularly important because it may enable the planning of effective drug treatment. It also may determine the advisability of catheter ablation, pacemaker control, or surgical treatment of the rhythm disturbance.




Specific Cardiac Defects Many classifications of congenital cardiovascular lesions have been proposed on the basis of hemodynamic, anatomical, and radiographic factors. Although the groups overlap, the following arrangement of cardiac anomalies is used in this chapter: (1) communications between the systemic and pulmonary circulations without cyanosis (left-to-right shunts), (2) obstructing valvular and vascular lesions with or without associated right-to-left shunt, (3) abnormalities in the origins of the great arteries and veins (the transposition complexes), (4) malpositions of the heart and cardiac apex, and (5) miscellaneous anomalies. LEFT-TO-RIGHT SHUNTS Atrial Septal Defect (See also p. 1593 ) MORPHOLOGY.

Atrial septal defect is one of the most commonly recognized congenital cardiac anomalies in adults but is very rarely diagnosed and even less commonly results in disability in infants.[110] The anatomical sites of interatrial defects are shown in Figure 43-9 . Defects of the sinus venosus type are high in the atrial septum near the entry of the superior vena cava and may be created by a deficiency in the wall that normally separates the pulmonary veins from the right lung and the superior vena cava and right atrium, thereby also resulting in partial anomalous pulmonary venous drainage.[111] The atrial septal defect most often involves the fossa ovalis, is midseptal in location, and is of the ostium secundum type. This type of defect is a true deficiency of the atrial septum and should not be confused with a patent foramen ovale. Embryologically, the left side of the atrial septum is derived from the septum primum, which possesses an

opening--the interatrial ostium secundum (see Fig. 43-1 ). The ostium secundum lies forward and superior to the position of the foramen ovale. The latter is formed by the septum secundum and occupies the right side of the atrial septum. Tissue of the septum primum lying to the left of the foramen ovale

Figure 43-9 Diagrammatic representation of open right atrium (RA) and right ventricle (RV) showing the position of the various types of interatrial communications. The superior vena cava (SVC), inferior vena cava (IVC), and right atrial appendage (RAA) define the areas of the right atrium. There are five potential spaces of interatrial communication. The classic ostium secundum (OS) atrial septal lies within the fossa ovalis. The second most frequent defect is an ostium primum (OP) atrial communication, followed by the superior vena caval type of sinus venosus (SV) defect lying posteriorly within the right atrium at the junction of the SVC and pulmonary veins. An IVC sinus venosus (SV) defect lies at the junction of the right atrium with the IVC. The last communication is through the coronary sinus (CS).

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serves as a flap valve that usually becomes fused postnatally with the side of the foramen ovale, yielding an anatomically closed or sealed foramen. "Probe patency," or an incomplete seal of the foramen ovale, occurs in about 25 percent of adults. A widely patent foramen ovale may be considered an acquired form of atrial septal defect that occurs especially when a disproportion exists between the size of the foramen ovale and the effective length of its valve. Enlargement of the foramen ovale per se is commonly associated with obstructive lesions on the right side of the heart, whereas a short valve relative to the size of the foramen often attends large-volume left-to-right shunts in which left atrial dilatation is prominent. Ostium primum atrial septal anomalies are a form of AV septal defect and are dealt with in the next section. Lutembacher's syndrome is a designation applied to the rare combination of atrial septal defect and mitral stenosis, which is almost invariably the result of acquired rheumatic valvulitis.[112] Ten to 20 percent of patients with ostium secundum atrial septal defect also have prolapse of the mitral valve as an associated anomaly.[113] HEMODYNAMICS.

The magnitude of the left-to-right shunt through an atrial septal defect depends on the size of the defect, the relative compliance of the ventricles, and the relative resistance in both the pulmonary and the systemic circulation.[114] In patients with a small atrial septal defect or patent foramen ovale, the left atrial pressure may exceed the right by several millimeters of mercury, whereas the mean pressures in both atria are nearly identical when the defect is large. Left-to-right shunting occurs predominantly in late ventricular systole and early diastole with some augmentation during atrial contraction. The shunt results in diastolic overloading of the right ventricle and increased pulmonary blood flow. During the first few days and weeks of life, pulmonary resistance falls and systemic resistance rises, facilitating right ventricular emptying and impeding left ventricular

emptying; the left-to-right shunt rises. Early in infancy, left-to-right flow through even a large interatrial communication commonly is limited by both the reduced chamber compliance of the thick neonatal right ventricle and the elevated pulmonary and reduced systemic vascular resistance of the neonate. The pulmonary vascular resistance commonly is normal or low in older infants or children with atrial septal defect, and the volume load usually is well tolerated, even though pulmonary blood flow may be two to five times greater than systemic. A transient and small right-to-left shunt occurring with the onset of left ventricular contraction and especially during respiratory periods of decreasing intrathoracic pressure is common in patients with ostium secundum defect, even in the absence of pulmonary hypertension. CLINICAL FINDINGS.

Patients with atrial septal defect usually are asymptomatic early in life, although occasional reports describe congestive heart failure and recurrent pneumonia in infancy.[110] Children with atrial septal defect may experience undue fatigue and exertional dyspnea. They tend to be somewhat underdeveloped physically and prone to respiratory infection. Atrial arrhythmias, pulmonary arterial hypertension, development of pulmonary vascular obstruction, and heart failure are exceedingly uncommon in the pediatric age range, in contrast to their common appearance in adults with atrial septal defect. In the former group, diagnosis often is entertained after detection of a heart murmur on routine physical examination prompts a more extensive cardiac evaluation. Small defects, less than 4 to 8 mm, have a modest probability of spontaneous closure.[115] Physical Examination.

Common findings include a prominent right ventricular cardiac impulse and palpable pulmonary artery pulsation. The first heart sound is normal or split, with accentuation of the tricuspid valve closure sound. Increased flow across the pulmonic valve is responsible for a midsystolic pulmonary ejection murmur. After the normal postnatal decline in pulmonary vascular resistance, the second heart sound is split widely and is relatively fixed in relation to respiration in patients with normal pulmonary pressures and low pulmonary vascular impedance because of a delay in pulmonic valve closure. With pulmonary hypertension, the splitting interval is a function of the electromechanical intervals of each ventricle; wide splitting occurs with shortening of the left and/or lengthening of the right ventricular electromechanical interval.[116] If the shunt is large, increased blood flow across the tricuspid valve is responsible for a mid-diastolic rumbling murmur at the lower left sternal border. In patients with associated prolapse of the mitral valve, an apical holosystolic or late systolic murmur radiating to the axilla often is heard, but a midsystolic click may be difficult to discern. Moreover, left ventricular precordial overactivity usually is absent because mitral regurgitation is mild in most patients. In teenage patients, the physical findings may be altered when an increase in pulmonary vascular resistance results in diminution of the left-to-right shunt. Both the pulmonary and the tricuspid murmurs decrease in intensity, whereas the pulmonic component of the second heart sound becomes accentuated and the two components

of the second heart sound may fuse; a diastolic murmur of pulmonic incompetence appears. Cyanosis and clubbing accompany development of a right-to-left shunt. Electrocardiogram.

In patients with an ostium secundum defect, the ECG usually shows right-axis deviation, right ventricular hypertrophy, and rSR or rsR pattern in the right precordial leads with a normal QRS duration ( Fig. 43-10 ; see also Fig. 44-1 ). It is not clear whether the delay in right ventricular activation is a manifestation of right ventricular volume overload or a true conduction delay in the right bundle branch and peripheral Purkinje system. An early notch (triphasic "crochetage") pattern on the R wave in inferior limb leads is as sensitive an indicator of atrial defect as incomplete right bundle branch block.[117] Left-axis

Figure 43-10 Typical electrocardiographic tracing in secundum atrial septal defect showing right-axis deviation, rSR in the right pericordial leads, and right ventricular hypertrophy. (Courtesy of Dr. Delores A. Danilowicz.)

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deviation of the P wave in the frontal plane (manifested by a negative P wave in lead III) suggests the presence of a sinus venosus rather than an ostium secundum type of atrial septal defect. Left-axis deviation and superior orientation and counterclockwise rotation of the QRS loop in the frontal plane suggest the presence of either an ostium primum defect or a secundum atrial septal defect in association with mitral valve prolapse. Prolongation of the PR interval may be seen with all types of atrial septal defects; the prolonged internodal conduction time may be related to both the increased size of the atrium and the increased distance for internodal conduction produced by the defect itself.[117] Chest Roentgenogram (see Fig. 44-2 ).

This usually reveals enlargement of the right atrium and ventricle, dilatation of the pulmonary artery and its branches, and increased pulmonary vascular markings. Dilatation of the proximal portion of the superior vena cava occasionally is noted in patients with a sinus venosus defect. Left atrial dilatation is extremely rare but may be observed when significant mitral regurgitation exists. Echocardiographic Features.

These include pulmonary arterial and right ventricular dilatation and anterior systolic (paradoxical) or "flat" interventricular septal motion if significant right ventricular volume overload is present.[98] The defect may be visualized directly by two-dimensional echo

imaging, particularly from a subcostal view of the interatrial septum ( Fig. 43-11 ; also see Chap. 7 ). Transesophageal color-coded Doppler echocardiography and color flow provides excellent visualization of defects of the atrial septum.[118] [119] Associated mitral valve prolapse also may be identified by echocardiographic examination (see Chap. 7 ). Findings on ultrafast computed tomographic (CT) scanning are discussed in Chapter 10 . Two-dimensional echocardiography, supplemented by conventional or color-coded Doppler flow and/or contrast echocardiography, has supplanted cardiac catheterization as the confirmatory test for atrial septal defect.[120] Cardiac catheterization is then used if inconsistencies exist in the clinical data or if significant pulmonary hypertension is suspected. Cardiac Catheterization.

Diagnosis may be readily confirmed by passage of the catheter across the atrial defect. The site at which the catheter crosses, if high in the cardiac silhouette, may suggest a sinus venosus defect; if midseptal, a patent foramen ovale or ostium secundum defect; or, if low, a primum defect.[121] Serial determinations of the oxygen saturation or indicator dilution curve techniques may

Figure 43-11 Subcostal coronal view showing a secundum atrial septal defect between the left atrium (LA) and the right atrium (RA). The right upper pulmonary vein (PV) is seen entering the left atrium. This view is posterior to the major portion of the ventricles; the left ventricle (LV) is seen, but only a small portion of the right ventricle (unlabeled) is apparent. I = inferior; L = left; R = right; S = superior.

be used to estimate the magnitude of the shunt. In the absence of pulmonary hypertension, pressures on the right side of the heart often are normal, despite a large shunt. When a high oxygen saturation is found in the superior vena cava or when the catheter enters pulmonary veins directly from the right atrium, a sinus venosus defect is likely, and indicator dilution curves and selective angiography aid in identifying the number and location of the anomalous veins. Partial anomalous pulmonary venous connection, although usually associated with sinus venosus defect, may accompany secundum defects. Selective left ventricular angiography identifies prolapse of the mitral valve and allows assessment of the magnitude of mitral regurgitation that may be present in such patients.[128] MANAGEMENT.

In contrast to adults, children with sinus venosus or secundum types of atrial septal defect seldom require treatment for heart failure or antiarrhythmic medications for atrial fibrillation or supraventricular tachycardia. Respiratory tract infections should be treated promptly. Although the risk of infective endocarditis is low, antibiotics should be administered prophylactically before dental procedures.

Operative or Transcatheter Repair.

This should be advised for all patients with uncomplicated atrial septal defects and evidence of significant left-to-right shunting, i.e., with pulmonary-systemic flow ratios exceeding about 1.5:1.0. Ideally, this should be carried out in those 2 to 4 years of age. Rarely, an atrial septal aneurysm is seen in association with a secundum-type atrial septal defect.[122] Such patients may experience spontaneous closure and may be monitored more conservatively until an older age before advising operation. Whether by median sternotomy or by minimally invasive transxiphoid techniques,[123] the defect is closed by suture or with a patch of prosthetic material with the patient on cardiopulmonary bypass. Earlier surgical repair is definitive treatment for the small number of infants and young children with significant symptoms or congestive failure. The surgical mortality rate is less than 1 percent, and results usually are excellent. Although the mitral valve may be examined directly at operation, it seldom is necessary in childhood to attempt plication or replacement of a ballooning or prolapsing mitral valve. Operation should not be carried out in patients with small defects and trivial left-to-right shunts (pulmonary-systemic flow ratio 1.5:1.0) or in those with severe pulmonary vascular disease (pulmonary-systemic resistance ratio 0.7:1.0) without a significant left-to-right shunt.[124] Although still investigational, considerable experience exists with transcatheter closure by a variety of occluding devices using fluoroscopic or transesophageal echocardiographic imaging guidance[125] [126] [127] (Fig. 43-12) . Limitations include difficulties in centering the device, the size of the sheath delivery system, the need to have more than a 4-mm separation between the edges of the defect and other important cardiac structures, and the inability to close defects whose stretched diameter exceeds 22 mm. Subtle evidence of left ventricular dysfunction may be observed preoperatively at cardiac catheterization in children with isolated large atrial septal defects but without overt left or right ventricular failure.[128] Thus, decreased left ventricular stroke volume and cardiac output have been observed in children with both low and normal left ventricular end-diastolic volumes. In routine catheterization studies carried out on patients whose atrial septal defects were closed during preadolescence or later, a residual reduced cardiac output response to intense upright exercise in the absence of residual shunts, arrhythmias, or pulmonary arterial hypertension has been observed. [129] Normal myocardial function is preserved in patients in whom the defects were closed in early childhood.[130] Electrophysiological Abnormalities.

Intracardiac electrophysiological studies reveal a high incidence of intrinsic

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Figure 43-12 Clamshell umbrella occlusion of an ostium secundum atrial septal defect. A long sheath is positioned in the left atrium (A). B, The distal umbrella arms are opened in the left atrium and the umbrella and sheath are pulled back together to the atrial septum. C, The proximal set of arms is then delivered on the right atrial side of the atrial septum. The correct position of the device is confirmed by fluoroscopy, angiography, and echocardiography before the device is released. (From Castaneda A, Jonas AR, Mayer JE Jr, et al: Cardiac Surgery of the Neonate and Infant. Philadelphia, WB Saunders, 1994, p 136.)

dysfunction of the sinoatrial and AV nodes, which persists after surgical repair. These intrinsic nodal abnormalities are more common in sinus venosus than in ostium secundum defects[131] but occur in both varieties. There also is evidence that the type of venous cannulation at the time of operative repair may contribute to the incidence and severity of arrhythmias observed at long-term follow-up. [132] Atrioventricular Septal Defect (See also p. 1596 )

AV septal defects account for 4 to 5 percent of congenital heart defects and comprise a range of malformations characterized by various degrees of incomplete development of the inferior portion of the atrial septum, the inflow portion of the ventricular septum, and the AV valves (see Figs. 43-1 and 44-3 ). These anomalies also have been called endocardial cushion defects and AV canal defects. The basic defect is a deficiency of the AV septum, which separates the left ventricular inlet from the right atrium; it causes anomalies that range in severity from a small ostium primum atrial defect to a complete AV septal malformation that also involves defects in the interventricular septum and the mitral and tricuspid valves. The latter often are abnormal to various degrees, with five or six leaflets of variable size present, and variability also in the completeness of their commissures. AV septal defects are often encountered in association with other congenital abnormalities, such as asplenia or polysplenia syndromes, trisomy 21 (Down syndrome), and Ellis-van Creveld syndrome of ectodermal dysplasia and polydactyly. Ostium Primum Defect (Partial AV Canal)

Ostium primum atrial septal defects lie immediately adjacent to the AV valves, either of which may be deformed and incompetent. Most often, only the anterior or septal leaflet of the mitral valve is displaced, and it commonly is cleft; the tricuspid valve usually is not involved. A cleft often is considered to be present in the mitral valve, although it is likely that the valve is in fact a trileaflet structure, with the cleft representing an abnormal commissure. The interatrial defect often is large, and the size of the left-to-right interatrial shunt in these patients is controlled by the same factors that exist in patients with ostium secundum atrial septal defect. Moreover, the clinical features are quite similar and principally consist of right ventricular precordial hyperactivity, a wide and persistently split second heart sound, a right ventricular outflow tract systolic ejection murmur, and a mid-diastolic tricuspid flow rumble. The murmurs of AV valve regurgitation may be audible if either valve is significantly abnormal; however, serious

AV valve regurgitation usually is absent. In the occasional patient, mitral regurgitation is substantial and creates prominent signs of left ventricular overload. Chest roentgenography usually reveals right atrial and ventricular cardiomegaly, prominence of the right ventricular outflow tract, and increased pulmonary vascular markings. The ECG findings (see Fig. 44-4 ) are characteristic and show a right ventricular conduction defect accompanied by left anterior division block, left-axis deviation, and superior orientation and counterclockwise rotation of the QRS loop in the frontal plane (see Chap. 5 ). Hemodynamic factors do not appear to be important in producing the characteristic ECG appearance. Rather, the superior QRS vector in patients with a shortened H-V interval appears to be related to early activation of the posterobasal left ventricular wall; in other patients with a normal conduction time between the bundle of His and the ventricles, the counterclockwise superior inscription of the frontal plane vector appears to be related to late activation of the anterolateral left ventricular wall.[133] A prolonged P-R interval is observed in many patients with an ostium primum atrial septal defect; prolonged internodal conduction may be related to displacement of the AV node in a posteroinferior direction in some patients and/or to the enlarged right atrium. ECHOCARDIOGRAPHY.

Two-dimensional echocardiography is considered the standard for the diagnosis of all forms of AV septal defect (see Chap. 7 ). Important features include enlargement of both the right ventricle and the pulmonary artery, systolic anterior ventricular septal motion, prolonged mitral-septal apposition in diastole, and various abnormalities in mitral valve motion.[134] The defect is clearly visualized from the precordial apical and subxiphoid positions, with the latter views best demonstrating the relation between the atrial defect, the AV valves, and the interventricular septum (Fig. 43-13) . Doppler color flow enhances these relations. Interatrial septal tissue is absent in the region of the crest of the interventricular septum; the trileaflet configuration of the mitral valve also may be identified. The subxiphoid long-axis view of the left ventricular outflow tract exhibits the gooseneck deformity in a manner similar to that with a right anterior oblique left ventricular angiogram. Echocardiography is particularly useful for detecting and characterizing double-orifice mitral valve, an association in about 3 percent of patients with ostium primum atrial defect. It also allows detection of

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Figure 43-13 Top panel, Transesophageal echocardiogram taken from a subcostal transgastric plane in a patient with tetralogy of Fallot and type C complete atrioventricular septal defect. A secundum atrial septal defect (upper smaller arrow) is also seen in the left panel, and the ostium primum component of the complete atrioventricular canal is seen below (larger lower arrow). The right frame shows the complete atrioventricular septal defect with the anterosuperior bridging leaflet (arrow) straddling between the left and right ventricles (LV, RV) without attaching to the interventricular septum. The left pulmonary artery (LP) is seen behind the ascending aorta (AO). Bottom panel, Four-chamber transesophageal plane demonstrates a communication above the anterior and bridging leaflets (ABL and PBL) in the right- and

left-hand frames, respectively. The small arrow indicates the typical position of an ostium primum atrial septal defect lying immediately below the rim of the atrial septum and above the valve tissue. LA = left atrium; RA = right atrium.

single left ventricular papillary muscle, hypoplasia of the left ventricle, and coarctation of the aorta, seen especially in symptomatic infants with an ostium primum atrial defect but without trisomy 21.[135] The angiographic features resemble those in the complete form of AV septal defect and are discussed later. Complete AV Septal Defect

MORPHOLOGY.

The complete form of the AV septal defect includes, in addition to the ostium primum atrial septal defect, a VSD in the posterior basal inlet portion of the ventricular septum and a common AV orifice.[136] The common AV valve usually has six leaflets: left superior and inferior, left and right lateral, and right superior and inferior. The left and right superior leaflets together often are referred to as the "anterior" bridging leaflet. No attachment exists between the left superior and inferior leaflets and the right superior and inferior leaflets. The left superior leaflet may cross the crest of the ventricular septum to reside partially on the right ventricular side. A classification of complete AV canal defect into types A, B, and C reflects the variability and the degree of anterior leaflet bridging of the ventricular septum (see Fig. 43-13 ). Thus, in type A, the anterior leaflet is almost entirely committed to the left ventricle and is attached by chordae tendineae to the crest of the ventricular septum. In type C there is marked rightward displacement of the anterior bridging leaflet, which floats freely over the crest of the ventricular septum and is not attached to it by chordae tendineae. In type B, chordal attachments extend medially to an anomalous papillary muscle adjacent to the septum in the right ventricle. A high incidence (about 35 percent) of additional cardiovascular lesions exists in patients with common AV canal. Principal among those associated with type C are tetralogy of Fallot, double-outlet right ventricle, transposition of the great arteries, and asplenia and polysplenia syndromes. Moreover, the type A complete AV septal anomaly commonly is seen in patients with Down syndrome. The designation unbalanced atrioventricular canal is applied to the condition in which one ventricle is hypoplastic and the other receives most of the common AV valve. Subaortic obstruction may be due to abnormal features of the left side of the common AV valve or to hypoplasia of the left ventricle. The left-sided (mitral) component may also be the site of a potential form of double-orifice mitral stenosis postoperatively.

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DIAGNOSIS.

Patients with common AV septal defects present clinically before age 1 year with a history of frequent respiratory infections and poor weight gain. Heart failure in infancy is extremely common. The physical findings are similar to those observed in patients with ostium primum atrial septal defect but may include as well the holosystolic, lower left sternal border murmur of an interventricular communication and/or the decrescendo, holosystolic apical murmur of mitral regurgitation. The ECG features of complete AV canal defects resemble those in the partial ostium primum variety of AV septal anomalies (see Fig. 43-10 ). Radiographically, the usual findings are generalized cardiomegaly and engorged pulmonary vessels. Two-dimensional echocardiography is diagnostic (see Chap. 7 ).[134] Apical and subcostal views are used to determine the size of the septal defects, the commitment of valve tissue and chordal attachments to the ventricles, ventricular size, the magnitude of AV valve insufficiency, and the anatomy of the left ventricular outflow tract. The subcostal oblique coronal view is often best to evaluate the commitment of AV valve tissue to each ventricle. Patterns of shunting and the number and magnitude of regurgitant jets are best evaluated by using pulsed, continuous-wave, and color flow Doppler imaging. On hemodynamic study, patients with persistent common AV canal invariably have elevated pulmonary arterial pressures; after age 2 years, a significant number of these patients have progressively severe pulmonary vascular obstructive disease. Diagnosis also is reliably established by selective left ventricular angiocardiography using rapid injection of relatively large quantities of contrast material.[137] The findings include an absence of the AV septum and a deficiency of the inlet portion of the ventricular septum, with elongation of the left ventricular outflow tract in relation to the inflow tract. The aortic valve is elevated and displaced anteriorly relative to the AV valves, changing the relation between the anterior components of the left AV valve and the aorta, which produces a pathognomonic gooseneck deformity seen angiographically in diastole. MANAGEMENT.

In patients with complete AV canal, cardiac decompensation should be controlled initially. Even with an adequate response to medical therapy early in life, operation should be considered before age 6 months because infants with a complete form of the AV septal defect are at high risk of obstructive pulmonary vascular disease. The level of major shunting should be determined by echocardiographic-Doppler data, or less often during initial hemodynamic and angiographic studies, because if it is mainly at the ventricular level, pulmonary artery banding occasionally may be advised for intractable heart failure and failure to thrive. Often, however, there is a significant left ventricular-right atrial shunt either directly or indirectly by way of mitral regurgitation and left-to-right interatrial shunting, which will be unaffected by pulmonary artery banding and requires complete surgical correction.

Surgical Repair.

Operative repair of uncomplicated primum defects is, for the most part, simple and yields good results. Left AV valve regurgitation and subaortic stenosis can be late complications amenable to reoperation. In most centers, primary repair in patients who have intractable heart failure, growth failure, or severe pulmonary hypertension is the preferred approach at any age.[138] Mild to moderate regurgitation often persists after surgical repair, particularly if significant AV valve incompetence existed preoperatively.[139] Rarely, if left AV leaflet tissue is remarkably deficient or deformed, mitral valve replacement may be required. Advances in the surgical approach to complex forms of AV septal defects have greatly improved the outlook for patients born with this malformation.[140] [141] These include better reconstruction of the mitral valve (Fig. 43-14) and more precise preoperative detection of such anatomical features as additional muscular VSDs, malalignment

Figure 43-14 A suture technique is illustrated for repair of a cleft mitral valve (A). Absolute alignment of the cleft in all its dimensions is of critical importance with placement of the sutures where the edges naturally coapt (B). C, The cleft repair is accompanied by annuloplasty. (From Castaneda A, Jonas RA, Mayer JE Jr, et al: Cardiac Surgery of the Neonate and Infant. Philadelphia, WB Saunders, 1994, p 174.)

of the complete AV septum, and left ventricular hypoplasia. Operative improvement is primarily related to a clearer understanding of the anatomy of this complex lesion and to the ability to reconstruct the left AV valve, often by splitting of papillary muscles and shortening of chordae tendineae, with or without annuloplasty. Many surgeons prefer to close the septal defects with a single patch rather than separating ventricular and atrial patches. Suture placement is avoided in the region of the AV node and the bundle of His. 1530

Figure 43-15 A, The four components of the ventricular septum viewed from the right ventricular side. I = inlet component, which extends from tricuspid annulus to attachments of the tricuspid valve; T = trabecular septum, which extends from the inlet out to the apex and up to the smooth-walled outlet; O = outlet septum or infundibular septum, which extends up to the pulmonary valve and membranous septum. B, The anatomical position of ventricular septal defects. a = outlet defect; b = papillary muscle of the conus; c = perimembranous defect; d = marginal muscular defects; e = central muscular defects; f = inlet defect; g = apical muscular defects. (From Graham TP Jr, Gutgesell HP: Ventricular septal defects. In Emmanouilides GC, Riemenschneider TA, Allen HD, et al [eds]: Moss and Adams' Heart Disease in Infants, Children, and Adolescents. 5th ed. Baltimore, © Williams & Wilkins, 1994, p 724.) Ventricular Septal Defect (See also p. 1595)

MORPHOLOGY.

Among the most prevalent of cardiac malformations, defects of the ventricular septum occur commonly, both as isolated anomalies and in combination with other anomalies. The ventricular septum is made up of four compartments: the membranous septum, the inlet septum, the trabecular septum, and the outlet, or infundibular, septum. Defects result from a deficiency of growth or a failure of alignment or fusion of component parts. Defects most commonly are classified as occurring in or adjacent to one or more of the septal components (Fig. 43-15) . [142] [143] The most common defects occur in the region of the membranous septum and are referred to as paramembranous or perimembranous defects because they are larger than the membranous septum itself and are associated with a muscular defect at a portion of their perimeter. They also are known as infracristal, subaortic, or conoventricular defects. These perimembranous defects also can be defined by their adjacent areas as inlet, trabecular, or outlet. A second type of defect is one with an entirely muscular rim. Such muscular defects also can be defined as inlet, trabecular, central, apical, marginal or Swiss cheese, or outlet and vary greatly in size, shape, and number. A third type of defect occurs when the outlet septum is deficient and commonly is referred to as supracristal, subpulmonary, outlet, infundibular, or conoseptal. Because the aortic and pulmonary valves are in fibrous continuity, this type of defect also may be referred to as doubly committed subarterial. A septal deficiency of the site of the AV septum characterizes defects called AV septal, AV canal, or inlet septal defects. The other feature of any defect may be a malalignment of the septal components. Either the inlet or the outlet septum can be malaligned. Malalignment of the inlet septum produces either mitral or tricuspid valve override and/or straddle. Malalignment of the outlet septum can be to the right or the left of the trabecular septum; when to the left of the trabecular septum, the VSD is characteristic of tetralogy of Fallot, double-outlet ventricle, truncus arteriosus, and, in some cases, transposition of the great arteries. ECHOCARDIOGRAPHY.

Two-dimensional and Doppler color flow mapping identify the type of defect in the ventricular septum (Fig. 43-16) .[144] [145] [146] Perimembranous VSDs are identified by septal dropout in the area adjacent to the septal leaflet of the tricuspid valve and below the right border of the aortic annulus. The subaortic or anterior malalignment type of VSD appears just below the posterior semilunar valve cusps, entirely superior to the tricuspid valve. The subpulmonary VSD appears as echo dropout within the outflow septum and extending to the pulmonary annulus. One or two of the aortic cusps may be seen to be protruding through the defect into the right ventricular outflow tract. The inlet AV septal-type of VSD extends from the fibrous annulus of the tricuspid valve into the muscular septum and often is entirely beneath the septal tricuspid leaflet. Muscular defects may appear anywhere throughout the ventricular septum and may be either large and single or small and multiple. Anatomical localization of all VSDs is facilitated by coupling two-dimensional ultrasound images (see Chap. 7 ) with a Doppler system and by superimposing a color-coded direction and velocity of blood flow on the real-time

images.

Figure 43-16 Four-chamber echocardiographic view in anatomical position demonstrates the ventricular septal defect (arrows within the left ventricular [LV] cavity). The tricuspid valve (TV) is adjacent to the ventricular septal defect and billows into the right ventricle (RV), a feature consistent with typical tricuspid tissue tags associated with perimembranous ventricular septal defect (formerly called ventricular septal aneurysm). LA = left atrium; RA = right atrium.

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Pulmonary and systemic blood flow can be calculated from arterial velocity profiles and cross-sectional areas of the great vessels.[147] Calculation of pulmonary/systemic flow ratios is reasonably accurate. Detection of jets within the right ventricle allows determination of right ventricular pressure by subtracting the product using the Bernoulli equation, which gives the pressure difference, from the systemic systolic blood pressure. Continuous-wave Doppler has been helpful in determining the right ventricular pressure from tricuspid regurgitation, which is found fairly often with VSDs. Many other techniques of Doppler measurement have been used with varying success in efforts to determine pulmonary arterial pressure accurately. PATHOPHYSIOLOGY.

The functional disturbance caused by a VSD depends primarily on its size and the status of the pulmonary vascular bed rather than on the location of the defect. A small VSD with high resistance to flow permits only a small left-to-right shunt. A large interventricular communication allows a large left-to-right shunt only if there is no pulmonic stenosis or high pulmonary vascular resistance because these factors also determine shunt flow. Resistance to left ventricular emptying also affects shunt flow because it is an important factor in determining left ventricular pressure. Large defects allow both ventricles to function hemodynamically as a single pumping chamber with two outlets, equalizing the pressure in the systemic and pulmonary circulations. In such patients, the magnitude of the left-to-right shunt varies inversely with pulmonary vascular resistance. The natural history of VSDs has a wide spectrum, ranging from spontaneous closure to congestive cardiac failure and death in early infancy. Within this spectrum are possible development of pulmonary vascular obstruction, right ventricular outflow tract obstruction, aortic regurgitation, and infective endocarditis.[148] [149] [150] [151] Infants

It is unusual for a VSD to cause difficulties in the immediate postnatal period, although congestive heart failure during the first 6 months of life is a frequent occurrence. Early diagnosis is helpful to ensure more careful observation of the affected infant. [148] The examining physician usually suspects the diagnosis because of a harsh systolic murmur at the lower left sternal border. The ECG and chest roentgenogram findings are within normal limits in the immediate neonatal period because appreciable left-to-right shunting

occurs only after the pulmonary vascular resistance decreases as the pulmonary vessels lose their fetal characteristics. It is desirable to monitor these infants closely. A VSD that either decreases in size or closes completely during the first year of life presents no problems to the practicing physician. Spontaneous closure occurs by age 3 years in about 45 percent of patients born with VSD; occasional patients, however, do not experience spontaneous closure until age 8 to 10 years or even later.[152] Closure is more common in patients born with a small VSD; nonetheless, about 7 percent of infants with a large defect and congestive heart failure early in life also may experience spontaneous closure. Partial rather than complete closure is common in patients with both large and small VSDs. Anatomically, reduction of the VSD often is based on adherence of the tricuspid valve to the defect, hypertrophy of septal muscle, or ingrowth of fibrous tissue. Rarely, closure of the VSD is the result of prolapse of an aortic cusp or infective endocarditis.[150] Some defects close when an aneurysm forms in the ventricular septum (see Fig. 43-16 ). On auscultation, a click may be heard in early systole as the aneurysm tenses toward the right; the septal aneurysm may be detected by echocardiography as an anterior systolic bulge in the right ventricular outflow tract. A persistent minute VSD is not life threatening unless infective endocarditis develops. With proper precautions (see Chap. 47 ), the incidence of this complication is less than 1 percent. If a moderate or large defect maintains its size after birth, the net left-to-right shunt increases during the first month of life as pulmonary vascular resistance falls. Physical examination during this time usually reveals a thrill along the lower left sternal border, and the holosystolic murmur of flow across the interventricular defect is accompanied by a low-pitched diastolic rumble at the apex, reflecting increased flow across the mitral valve. Chest roentgenograms reveal increased pulmonary vascular markings; evidence of left or biventricular hypertrophy may be observed on the ECG. Infants with a large left-to-right shunt tend to fare poorly, with recurrent upper and lower respiratory tract infections, failure to gain weight, and congestive heart failure. Congestive heart failure may be severe and intractable despite intensive medical management. MANAGEMENT.

We currently recommend primary intracardiac repair of the VSD at any age rather than surgical banding of the pulmonary artery[153] to reduce pulmonary blood flow and alleviate heart failure. An exception is made for the rare infant with multiple VSDs and a sievelike septum, who is at higher risk for complications after operative repair. Operation usually is deferred, along with debanding of the pulmonary artery, until the child reaches 3 to 5 years. Primary closure of the VSD, preferably through the right atrium, may be performed in infancy using cardiopulmonary bypass, profound hypothermia and cardiocirculatory arrest, or a combination of the two techniques. Mortality approaches zero in major centers if the defect is isolated and uncomplicated but approaches 10 percent if many anomalies are present.[154] Fortunately, medical treatment often is successful in controlling congestive heart failure. Nevertheless, these infants should be referred for cardiac catheterization to evaluate pulmonary vascular resistance and to detect associated defects that may require

operation, such as patent ductus arteriosus and coarctation of the aorta. Children

Beyond the first year of life, a variable clinical picture emerges in children with VSD.[148] [155] If a small defect is present, the child usually is asymptomatic, the ECG usually appears normal, and the chest roentgenogram shows normal or only a mild increase in pulmonary vascular markings. Effort intolerance and fatigue are associated with moderate left-to-right shunts. These children exhibit cardiomegaly with a forceful left ventricular impulse and a prominent systolic thrill along the lower left sternal border. The second heart sound normally is split, with moderate accentuation of the pulmonic component; a third heart sound and rumbling diastolic murmur that reflects increased flow across the mitral valve are audible at the cardiac apex. The characteristic murmur resulting from flow across the defect is harsh and holosystolic, is best heard along the third and fourth interspaces to the left of the sternum, and is widely transmitted over the precordium. A basal midsystolic ejection murmur due to increased flow across the pulmonic valve also may be heard. The ECG reveals left or combined ventricular hypertrophy, and the chest roentgenogram and CT scan (see Chap. 5 ) show cardiomegaly, left atrial enlargement, and vascular engorgement. PULMONARY HYPERTENSION.

It is of utmost importance to identify patients who may develop irreversible pulmonary vascular obstructive disease (Eisenmenger's reaction).[155] [156] [157] [158] Retrospective analyses of children who develop this complication indicate that infants with systemic or near systemic pressures in the pulmonary artery at the time of initial hemodynamic study are most at risk. If early primary closure is not recommended, recatheterization before age 18 months and a second determination of pulmonary vascular resistance should be performed in these patients to decide whether surgical intervention is obligatory to prevent development of fixed obliterative changes in the pulmonary vessels. Mechanisms.

It is likely that numerous factors are involved in the development of pulmonary vascular disease (see Chap. 53 ). The anatomically large VSD allows some or all of the systemic pressure to be transmitted to the pulmonary arteries, thereby retarding regression

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of their muscular media. Medial hypertrophy in the first months of life is responsible for higher pulmonary vascular resistance than would be anticipated for the amount of pulmonary blood flow. The shearing forces created by the high velocity of flow through narrowed pulmonary arterioles cause endothelial damage that is progressive.

Although an elevation in left atrial pressure may contribute to the rise in pulmonary vascular resistance, it is not an essential factor because pulmonary venous pressures can be low in patients who later develop pulmonary vascular disease. Nonetheless, pulmonary venous hypertension also may contribute to pulmonary arterial vasoconstriction and thus to increased shear forces. In this same regard, pulmonary vasoconstriction enhancing the risk of pulmonary vascular obstruction also may be caused by hypoxia due to either high altitude or lung disease. At high altitudes, large VSDs have higher pulmonary vascular resistances and smaller shunts than at low altitudes. Clinical Features.

If a child who previously had a loud murmur and thrill associated with poor growth suddenly has a growth spurt, fewer respiratory infections, and a diminution of the intensity of the cardiac murmur and disappearance of the thrill, he or she may be developing severe obliterative changes in the pulmonary vascular bed. An increase in intensity of the pulmonic component of the second heart sound, a reduction in heart size on the chest roentgenogram, and more pronounced right ventricular hypertrophy on the ECG also are noted. These changes occur because the increased pulmonary vascular resistance causes a decrease in the left-to-right shunt. If these changes are suspected, cardiac catheterization should be repeated; if they are confirmed, prompt surgical repair is indicated before an inoperable predominant right-to-left shunt ensues. If operation is performed before age 2 years, pulmonary vascular resistance may be expected to fall to normal levels.[158] In older patients, the degree to which pulmonary vascular resistance is elevated before operation is a critical factor determining prognosis. If the pulmonary vascular resistance is one-third or less of the systemic value, progressive pulmonary vascular disease after operation is unusual. However, if a moderate-to-severe increase in pulmonary vascular resistance exists preoperatively, either no change or progression of pulmonary vascular disease is common postoperatively. Moreover, the presence of increased pulmonary vascular resistance results in a higher immediate postoperative mortality rate for surgical closure of VSD. These observations make it clear that a large VSD should be approached surgically very early in life when pulmonary vascular disease is still reversible or has not yet developed (Fig. 43-17) . RIGHT VENTRICULAR OUTFLOW TRACT OBSTRUCTION.

With time, the clinical picture changes in 5 to 10 percent of patients with VSD and a moderate to large left-to-right shunt early in life. It begins to resemble more closely the tetralogy of Fallot (see Chap. 44 ); i.e., subvalvular right ventricular outflow tract obstruction develops owing to progressive hypertrophy of the crista supraventricularis. Depending on the severity of the latter process, it ultimately may result in reduced blood flow and a right-to-left shunt across the VSD. As right ventricular outflow tract obstruction develops, the holosystolic murmur is replaced by the crescendo-decrescendo ejection systolic murmur of pulmonic stenosis, and the pulmonary closure sound becomes softer. Right ventricular hypertrophy is evident on

the ECG, and the chest roentgenogram shows a reduction in pulmonary vascular markings and a smaller heart size with a right ventricular configuration. Infundibular

Figure 43-17 Early and late postoperative changes of pulmonary artery pressure after closure of ventricular septal defects in infants. (From Castaneda A, Jonas RA, Mayer JE Jr, et al: Cardiac Surgery of the Neonate and Infant. Philadelphia, WB Saunders, 1994, p 200.)

hypertrophy may progress quite rapidly within the first year of life, but the typical evolution to a clinical picture of cyanotic tetralogy of Fallot often takes 1 to 4 years. In those infants who develop right ventricular outflow obstruction, the incidence of spontaneous closure or reduction in size of a VSD is low. VENTRICULAR SEPTAL DEFECT WITH AORTIC REGURGITATION.

This well-described complication of VSD occurs in about 5 percent of patients.[159] It usually is noted after age 5 years when a physician detects the early diastolic blowing murmur and wide pulse pressure of aortic regurgitation while monitoring a patient with a VSD. The diagnosis is readily confirmed by Doppler echocardiography. In such patients, aortic regurgitation may become the predominant hemodynamic abnormality. It is of interest that VSD with aortic regurgitation is rare in Europe and the United States, with an incidence of about 4 percent of all cases of isolated VSD, whereas in Japan the incidence is substantially higher (about 10 percent). In the Japanese, in particular, aortic regurgitation is the result of herniation of an aortic leaflet (usually the right coronary) through a subpulmonic supracristal VSD. In these patients, closure of the VSD may be all that is required to relieve aortic regurgitation. In many patients, however, especially in the Western world, the VSD is below the infundibular septum (crista supraventricularis). Although aortic leaflet herniation, especially of the right or noncoronary cusp, may occur in some of these patients, aortic regurgitation often results from a primary abnormality of the valve, usually one defective commissure. In the latter situation, plication of the elongated leaflet may lessen but not abolish the aortic regurgitation; in some patients, prosthetic aortic valve replacement may be necessary to provide hemodynamic relief. In most patients with VSD and aortic regurgitation, the VSD is small to moderate in size, and mild right ventricular outflow tract obstruction exists. The latter is caused by either subpulmonic infundibular stenosis or projection of the herniated aortic cusp into the right ventricular outflow tract. The distinction between types of VSD with aortic regurgitation usually can be made by two-dimensional and Doppler echocardiography and by selective left ventricular angiocardiography to define the site of the interventricular communication in combination with retrograde aortography to assess the anatomy and competence of the aortic valve.[160] Management.

Treatment of patients with VSD and aortic regurgitation is controversial. In patients with a large, hemodynamically significant left-to-right shunt, repair of the VSD is indicated, but aortic regurgitation is repaired only if at least moderate aortic regurgitation exists. If

a supracristal VSD without aortic regurgitation is identified at cardiac catheterization in early childhood, a sensible argument for prophylactic closure of the VSD can be put forth to prevent the potential complication of aortic valve incompetence. In the presence of moderate or severe aortic regurgitation, valvuloplasty is preferred to valve replacement,[161] in recognition of the fact that the severity of aortic regurgitation may increase in subsequent years and that reoperation with valve replacement may be necessary. Operation should probably be deferred in asymptomatic patients with a subcristal VSD and an insignificant left-to-right shunt when aortic regurgitation is not severe. If the defect is supracristal in the same clinical setting, its closure may not alleviate the mild degree of aortic incompetence but may retard its progression. OTHER FORMS OF VENTRICULAR DEFECT.

Unusual forms of VSD include numerous muscular defects and left ventricular-right atrial communications. Defects in the muscular ventricular septum frequently are several small fenestrations that produce a large net left-to-right shunt.[151] Their recognition is a necessary preliminary to successful operation because incomplete repair may result in postoperative cardiac failure and death. A shunt from the left ventricle to right atrium may occur with a VSD in the most superior portion of the ventricular septum because the tricuspid valve is lower than the mitral valve. The clinical, ECG, and radiological findings in these patients do not differ appreciably from those in patients with a simple VSD, although right atrial enlargement may provide a clue to correct diagnosis of left ventricular-right atrial communication.[162] The pathophysiology of a single or common ventricle may resemble that of a large VSD, although these defects are dissimilar embryologically. The single chamber frequently is the morphological left ventricle; malposition of the great arteries is common. No cyanosis may be detectable if selective streaming and increased pulmonary blood flow rather than complete mixing occurs. Pulmonary hypertension invariably is present unless pulmonic stenosis exists. It is imperative to differentiate a single ventricle from a large VSD by echocardiography and angiography because the operative approaches to the former malformation require the atriopulmonary Fontan's connection. MANAGEMENT.

It is rarely necessary to restrict the activities of a child with an isolated VSD. Infective bacterial endocarditis is always a threat, and antibiotic prophylaxis for dental procedures and minor surgery is indicated (see Table 43-4 , p. 1516). [163] Respiratory infections require prompt evaluation and treatment. These children should be seen at least once or twice yearly to detect changes in the clinical picture that suggest the development of pulmonary vascular obliterative changes.

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SURGICAL TREATMENT.

When clinical findings suggest a moderate shunt but no pulmonary hypertension, elective hemodynamic evaluation should be undertaken before age 3 years. Of prime importance in the hemodynamic evaluation is determination of pressure and blood flow in the pulmonary artery.[164] Surgical treatment is not recommended for children who have normal pulmonary arterial pressures with small shunts (pulmonary-systemic flow ratios of less than 1.5 to 2.0:1).[165] In such patients, the remaining risk of infective endocarditis does not exceed the risk of operation. Moreover, although the inherent risk of operation is small, the possibility of postoperative heart block, infection, or other complications of operation and cardiopulmonary bypass dictates a conservative approach when the cardiac defect may be well tolerated for life. In some centers, the use of intraoperative transesophageal echocardiography has provided accurate assessment of patch integrity and the presence of additional muscular defects after termination of cardiopulmonary bypass.[166] [167] With larger shunts, elective operation may be advised before the child enters school, thus minimizing any subsequent distinction of these patients from their normal classmates. Total assessment of the psychosocial dynamics of the family and child is helpful in determining the proper age for elective operation in each patient. Under investigation is transcatheter closure by umbrella or clamshell occluder devices inserted by crossing the ventricular defect to guide a venous catheter through a long sheath and, ultimately, placing the device across the ventricular septum from the right ventricular side.[168] [169] [170] The use of such devices is limited to defects in the apical muscular septum, well distanced from the semilunar and AV valves. Complete heart block is the most significant surgically induced conduction system abnormality, occurring immediately after surgery in fewer than 1 percent of patients. Late-onset complete heart block occasionally is a problem, especially in the 10 to 25 percent of patients whose postoperative ECG findings show complete right bundle branch block with left anterior hemiblock. When the latter ECG pattern is observed in patients with transient complete heart block in the early postoperative period, electrophysiological studies should be conducted at postoperative cardiac catheterization. Patients presenting postoperatively with right bundle block and left anterior hemiblock appear to fall into two populations, defined by either peripheral damage to the conduction system or damage to the bundle of His or its proximal branches. The former has not been associated with transient postoperative complete heart block, and these patients usually have a benign course. Trifascicular damage may be demonstrated in the latter population by a prolonged H-V interval, which implies a higher risk of complete heart block later in life. Although prophylactic use of permanent pacemakers in asymptomatic patients with evidence of trifascicular damage is not currently recommended, this group certainly requires careful follow-up and continued study. Treadmill exercise studies of patients who preoperatively had normal or only moderately elevated pulmonary vascular resistance and essentially normal postoperative cardiac catheterization data may uncover late abnormalities in circulatory function.[171] Despite

normal cardiac output at rest, an impaired cardiac output response to exercise is noted in some. Moreover, despite normal pulmonary arterial pressure at rest, markedly abnormal increases in pulmonary arterial pressure may be noted during exercise. These findings may be related to abnormal left ventricular function after closure of the VSD and/or to persistent pathological changes in the pulmonary arterioles or to abnormal pulmonary vascular reactivity.[172] A direct relation exists between age at operation and the magnitude of the pulmonary arterial pressure response to intense exercise, suggesting that early operation may prevent permanent impairment of the functional capacity of the myocardium and pulmonary vascular bed. A child who has already developed pulmonary vascular obstruction and a net right-to-left shunt across the VSD may occasionally come to medical attention (see also p. 1614). Symptoms may consist of exertional dyspnea, chest pain, syncope, and hemoptysis; the right-to-left shunt leads to cyanosis, clubbing, and polycythemia. Little can currently be offered to this group of patients other than continuing support to the patient and family. Patent Ductus Arteriosus (See also Chap. 44 )

The ductus arteriosus normally exists in the fetus as a widely patent vessel connecting the pulmonary trunk and the descending aorta just distal to the left subclavian artery (see Fig. 43-4 , p. 1511). In a fetus, most of the output of the right ventricle bypasses the unexpanded lungs by way of the ductus arteriosus and enters the descending aorta, where it travels to the placenta, the fetal organ of oxygenation. It was earlier assumed that during fetal life the ductus arteriosus is a passively open channel that constricted postnatally by means of undefined molecular mechanisms in response to the abrupt rise in arterial PO2 accompanying the first breath of life.[173] Even in utero, the lumen of the ductus arteriosus may be influenced by vasoactive substances, particularly prostaglandins.[86] [87] [174] [175] [176] Thus, inhibition of prostaglandin synthesis causes profound constriction of the ductus arteriosus in the mammalian fetus that may be reversed by administration of vasodilatory E-type prostaglandins. Initial contraction and functional closure of the ductus arteriosus shortly after birth is related both to the sudden increase in the partial pressure of oxygen that accompanies ventilation and to changes in the synthesis and metabolism of vasoactive eicosanoids. Intimal proliferation and fibrosis proceed more gradually, so that anatomical closure may take as long as several weeks for completion.[177] The ductus arteriosus is a unique structure after birth because its patency may, on the one hand, result in cardiac decompensation but may, on the other hand, provide the only life-sustaining conduit to preserve systemic or pulmonary arterial blood flow in the presence of certain cardiac malformations.[178] Appreciable left-to-right shunting across the patent ductus arteriosus frequently complicates the clinical course of infants born prematurely.[179] The ductal shunt has been implicated specifically in the deterioration of pulmonary function in infants with the respiratory distress syndrome; in these infants severe congestive heart failure often is unresponsive to digitalis and diuretics.[87] A distinction should be made between patency of the ductus arteriosus in a preterm

infant, who lacks the normal mechanisms for postnatal ductal closure because of immaturity, and a full-term newborn, in whom patency of the ductus is a true congenital malformation, probably related to a primary anatomical defect of the elastic tissue within the wall of the ductus.[177] In the former circumstance, delayed spontaneous closure of the ductus may be anticipated if the infant does not succumb to the cardiopulmonary difficulties caused by the ductus itself or to some lethal complication of prematurity, such as hyaline membrane disease, intraventricular hemorrhage, or necrotizing enterocolitis. In a similar manner, some full-term newborns have persistent patency of the ductus arteriosus for weeks or months because their relative hypoxemia contributes to vasodilatation of the channel. In the latter category are infants born at high altitude; those born with congenital malformations causing hypoxemia, such as pulmonary atresia with or without VSD; or those born with malformations in which ductal flow supplies the systemic circulation, such as hypoplastic left heart syndrome, interruption of the aortic arch, or some examples of coarctation of the aorta syndrome. In the clinical settings in which the ductus preserves pulmonary blood flow, the essentially inevitable spontaneous closure of the vessel is associated with profound clinical deterioration. The latter may be reversed medically within the first 4 to 5 days of life by infusion of prostaglandin E1 intravenously. By dilating the constricted ductus arteriosus, a temporary increase occurs in arterial blood oxygen tension and oxygen saturation and correction of acidemia.[178] These infants can then undergo operative repair or a palliative systemic-pulmonary anastomosis, under more optimal circumstances. Pharmacological dilation of the ductus arteriosus also is effective in preoperative restoration of systemic blood flow and alleviation of heart failure, especially in infants with aortic coarctation or hypoplastic left heart syndrome, and in infants with complete transposition of the great arteries in whom intercirculatory mixing is augmented.

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PREMATURE INFANTS.

In most, if not all, preterm infants less than 1500-gm birth weight, persistence of a patent ductus arteriosus is prolonged, and in about one-third of these infants a large aorticopulmonary shunt is responsible for significant cardiopulmonary deterioration.[180] [181] Radiographic, echocardiographic, and Doppler ultrasound signs of significant left-to-right shunting usually precede the appearance of physical findings suggesting ductal patency. A significant increase in the cardiothoracic ratio is seen on sequential roentgenograms, as well as increased pulmonary arterial markings progressing to perihilar and generalized pulmonary edema. Serial echocardiographic evaluations that demonstrate increases in left ventricular end-diastolic and left atrial dimensions, especially when correlated with the aforementioned radiographic signs, are highly suggestive of a large shunt. Two-dimensional and Doppler echocardiography directly visualize and define the flow characteristics of the ductus arteriosus with great accuracy.[182]

Clinical Findings.

These include bounding peripheral pulses, an infraclavicular and interscapular systolic murmur (occasionally a continuous murmur), precordial hyperactivity, hepatomegaly, and either multiple episodes of apnea and bradycardia or respiratory dependence. Cardiac catheterization carries a high risk in preterm infants and seldom is indicated unless the diagnosis is obscure. Treatment.

Treatment of preterm infants with a patent ductus arteriosus varies with the magnitude of shunting and the severity of hyaline membrane disease because the ductus may contribute importantly to mortality in the respiratory distress syndrome. Intervention in an asymptomatic infant with a small left-to-right shunt is unnecessary because the patent ductus arteriosus almost invariably undergoes spontaneous closure and does not require late surgical ligation and division. Those infants who demonstrate unmistakable signs of a significant ductal left-to-right shunt during the course of the respiratory distress syndrome often are unresponsive to medical measures to control congestive heart failure and require closure of the patent ductus arteriosus to survive. These infants are best treated within the first 2 to 7 days of life by pharmacological inhibition of prostaglandin synthesis with indomethacin to constrict and close the ductus[179] [183] [184] [185] ; surgical ligation is required in the estimated 10 percent of infants who are unresponsive to indomethacin.[186] Early intervention is advised to reduce the likelihood of necrotizing enterocolitis and of bronchopulmonary dysplasia related to prolonged respirator and oxygen dependence. Less often, indications for pharmacological or surgical closure of the ductus consist of life-threatening episodes of apnea and bradycardia or a prolonged failure to gain weight and grow. FULL-TERM INFANTS AND CHILDREN.

In full-term newborns and older infants and children, patency of the ductus arteriosus occurs particularly in girls and in the offspring of pregnancies complicated by first-trimester rubella. Although most frequent in isolated form, the anomaly may coexist with other malformations, particularly coarctation of the aorta, VSD, pulmonic stenosis, and aortic stenosis. Flow across the ductus is determined by the pressure relation between the aorta and the pulmonary artery and by the cross-sectional area and length of the ductus itself.[187] Pulmonary pressures most commonly are normal, and a persistent gradient and shunt from aorta to pulmonary artery exist throughout the cardiac cycle. Physical examination reveals a characteristic thrill and a continuous machinery murmur, with a late systolic accentuation at the upper left sternal border. The left atrium and left ventricle enlarge to accommodate the increased pulmonary venous return, and flow murmurs across the mitral and aortic valves may be detected. With significant left-to-right shunting, the runoff of blood through the ductus causes a widened systemic pulse pressure and bounding peripheral pulses. The hemodynamic abnormality is

reflected in the ECG by left ventricular and occasionally left atrial hypertrophy, and in the chest roentgenogram by left atrial and ventricular enlargement, prominent ascending aorta and pulmonary artery, and pulmonary vascular engorgement (see Chaps. 8 and 44 ). The clinical diagnosis may be difficult when the findings do not conform to the classic presentation. As mentioned earlier, disappearance of the diastolic component of the murmur is common in premature infants because pulmonary arterial diastolic pressures are higher at that age. In older patients, both heart failure and pulmonary hypertension are associated with a reduction in the pressure gradient across the ductus arteriosus and result in atypical systolic murmurs. When severe pulmonary vascular obstructive disease results in reversal of flow through the ductus and preferential shunting of unoxygenated blood to the descending aorta, the toes, rather than the fingers, may show cyanosis and clubbing. Full-term infants with patent ductus arteriosus may survive for a number of years, although a large defect occasionally results in heart failure and pulmonary edema early in life. The leading causes of death in older children are infective endocarditis and heart failure. Beyond the third

Figure 43-18 Top panel, High parasternal view of a patent ductus arteriosus in the sagittal plane demonstrating the classic position of a ductus arteriosus (D) lying between the pulmonary trunk (PT) and the descending aorta (DAO). The transverse aorta (TAO) giving rise to vessels to the head and neck is seen lying above the pulmonary trunk. The left atrium (LA) is seen inferiorly. The pulmonary trunk appears continuous with a wide patent ductus into the descending aorta just above the origin of the left pulmonary artery (L). Bottom panel, Patent ductus arteriosus (PDA) in a conventional parasternal short-axis view arising from the main pulmonary artery (MPA). The left pulmonary artery lies immediately to the right of the ductus and the left pulmonary artery lies adjacent to the ascending aorta (AO). The ductus is continuous with the descending aorta (DAO). The AO lies between the MPA anteriorly, the right atrium (RA) and LA posteriorly, and the right pulmonary artery laterally to the left.

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Figure 43-19 Transcatheter closure of a patient ductus arteriosus is illustrated using the Rashkind double-umbrella technique. The catheter approaches the ductus via a long sheath advanced from the femoral vein. The right panel shows expansion of the distal umbrella. (From Castaneda A, Jonas RA, Mayer JE Jr, et al: Cardiac Surgery of the Neonate and Infant. Philadelphia, WB Saunders, 1994, p 136.)

decade of life, severe pulmonary vascular obstruction has been known to cause aneurysmal dilatation, calcification, and rupture of the ductus. [188] The patent ductus can be directly visualized by two-dimensional echocardiography (Fig. 43-18) ; range-gated pulsed Doppler echocardiography shows the characteristic flow abnormalities across the ductus, as well as a continuous flow disturbance in the

pulmonary artery. Cardiac catheterization may be indicated when additional lesions or pulmonary vascular obstruction is suspected. Management.

In the absence of severe pulmonary vascular disease with predominant right-to-left shunting, the anatomical presence of a patent ductus usually is considered sufficient indication for closure. Ligation or division of the ductus carries a low risk, whether performed electively in an asymptomatic child or at any age if symptoms are present. The operative risk is reduced if heart failure can be compensated by medical measures before surgery. Operation should be deferred for several months in patients treated successfully for infective endarteritis because the ductus may remain somewhat edematous and friable. Rarely, when the infection does not subside with intensive antibiotic treatment, surgical ligation may be necessary to eradicate the infection. Although strictly speaking still investigational, substantial experience exists with transcatheter closure of the patent ductus using various approaches, including coils, buttons, plugs, and umbrellas, with each occluder device introduced through a relatively large-diameter sheath from the femoral vein (Fig. 43-19) [189] [190] [191] [192] [193] [194] [195] (see Chap. 44 ). The approach is especially feasible in patients who weigh more than 10 kg and who have neither a long tubular ductus nor a ductus with a long, narrow aortic end. In experienced hands, initial occlusion is successful in 85 to 90 percent of patients; reocclusion adds 5 to 7 percent to the overall success rate. Potential complications in 5 to 10 percent of patients include embolization of the device, endocarditis, and hemolysis. Ductal closure by manually invasive surgery or thoracoscopy will undoubtedly undergo future evaluation.[196] [197] Aorticopulmonary Septal Defect

Aorticopulmonary window or fenestration, partial truncus arteriosus, and aortic septal defect are other designations applied to this relatively uncommon anomaly. Septation of the aortopulmonary trunk occurs by fusion of the conotruncal ridges (see Fig. 43-2 ). The right and left sixth aortic arches, destined to become the pulmonary arteries, join the pulmonary artery to complete great artery development (see Fig. 43-5 ). Congenital defects between the ascending aorta and the pulmonary artery result from faulty development of this area during embryonic life. The typical aortopulmonary septal defect results because of incomplete fusion of the distal aortopulmonary septum. [198] Malalignment of the conotruncal ridges results in unequal partitioning of the aortopulmonary trunk, which may result in partial or complete fusion of the right pulmonary artery to the aorta. The usual defect consists of a communication between the aorta and pulmonary artery just above the semilunar valves. Persistent patency of the ductus arteriosus is an associated lesion in 10 to 15 percent of cases. Less common accompanying cardiovascular lesions include VSD, aortic origin of the right pulmonary artery, aortic arch interruption, coarctation of the aorta, and right aortic arch. Aorticopulmonary septal defects usually are large and are accompanied by severe pulmonary arterial

hypertension and early-onset pulmonary vascular obstruction. PHYSICAL EXAMINATION.

The pulses typically are bounding, like those of a large patent ductus arteriosus. The murmur, however, seldom is continuous, and a basal systolic murmur is most common. Cardiomegaly is present, and pulmonary hypertension is reflected in a loud and palpable sound of pulmonary valve closure. Aorticopulmonary septal defect should be suspected whenever a large shunt into the pulmonary artery is demonstrated at catheterization. Diagnosis of the anomaly and its distinction from patent ductus and persistent truncus arteriosus usually can be done by two-dimensional echocardiography. Identification of the aortopulmonary window and associated malformations may also employ hemodynamic study and selective angiocardiography with the injection of contrast material into the left ventricle and/or the root of the aorta (Fig. 43-20) . Although some patients may survive to adulthood with uncorrected aorticopulmonary

Figure 43-20 Aortic root injection of contrast material in the frontal view produces simultaneous opacification of the aorta and pulmonary artery through a large aorticopulmonary septal defect (arrow). (Courtesy of Dr. Robert White.)

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septal defect, most die early in life unless surgical treatment is undertaken. Rarely, transcatheter closure by insertion of an occluding device may be feasible in infants with a small aortopulmonary window.[199] As a general rule, operative correction is indicated in all symptomatic infants when the diagnosis is made. Elective repair is advised at 3 to 6 months.[200] [201] Profound hypothermic total circulatory arrest or total cardiopulmonary bypass is required, and the defect is closed by way of a transaortic approach, usually with a prosthetic or xenograft pericardial patch. Persistent Truncus Arteriosus MORPHOLOGY.

Persistent truncus arteriosus is a rare but serious anomaly in which a single vessel forms the outlet of both ventricles and gives rise to the systemic, pulmonary, and coronary arteries.[202] The defect results from failure of septation of the embryonic truncus by the infundibular truncal ridges (see Fig. 43-4 , p. 1511). It is always accompanied by a VSD, frequently with a right-sided aortic arch. The VSD is due to the absence or underdevelopment of the distal portion of the pulmonary infundibulum. The truncal valve usually is tricuspid but is quadricuspid in about one-third of patients and rarely can be bicuspid. Truncal valve regurgitation and truncal valve stenosis are each seen in 10 to 15 percent of patients. There may be a single coronary artery,

displacement of the coronary ostia (usually the left ostium posteriorly), or a single posterior descending coronary artery arising from the right coronary or, less often, from the left circumflex artery, especially in patients with a single coronary artery. [203] Truncus malformations can be classified either anatomically according to the mode of origin of pulmonary vessels from the common trunk or from a functional point of view, based on the magnitude of blood flow to the lungs. In the common type (type I) of truncus arteriosus malformation, a partially separate pulmonary trunk of variable length exists because of the presence of an incompletely formed aorticopulmonary septum. The pulmonary trunk usually is very short and gives rise to left and right pulmonary arteries. When the aorticopulmonary septum is absent, there is no discrete main pulmonary artery component, and both pulmonary artery branches arise directly from the truncus. In type II, each pulmonary artery arises separately but close to the other from the posterior aspect of the truncus (Fig. 43-21) . In type III, each pulmonary artery arises from the lateral aspect of the truncus. Less commonly, one pulmonary artery branch may be absent, with collateral arteries supplying the lung that does not receive a pulmonary artery branch from the truncus. Truncus arteriosus malformation should not be confused with "pseudotruncus arteriosus," which is the severe form of tetralogy of Fallot with pulmonary atresia in which the single aorta arises from the heart accompanied by a remnant of atretic pulmonary artery. HEMODYNAMICS.

Pulmonary blood flow is governed by the size of the pulmonary arteries and the pulmonary vascular resistance. In infancy, pulmonary blood flow is usually excessive because pulmonary vascular resistance is not greatly increased. Thus, despite an obligatory admixture of systemic and pulmonary venous blood in the common trunk, only minimal cyanosis is present. Rarely, pulmonary blood flow is restricted by hypoplastic or stenotic pulmonary arteries arising from the truncus. Pulmonary vascular obstruction usually does not restrict pulmonary blood flow before 1 year of age.[204] CLINICAL FEATURES.

Infants with truncus arteriosus usually present with mild cyanosis coexisting with the cardiac findings of a large left-to-right shunt. Symptoms of heart failure and poor physical development usually appear in the first weeks or months of life. The most frequent physical findings include cardiomegaly, a systolic ejection sound accompanied by a thrill, a loud single second heart sound, a harsh systolic murmur, and a low-pitched mid-diastolic rumbling murmur and bounding pulses. Truncus arteriosus often is a measure of the DiGeorge's syndrome (see Table 43-2 (Table Not Available) ); thus, facial dysmorphism, a high incidence of extracardiac malformations (particularly of the limbs, kidneys, and intestines), atrophy or absence of the thymus gland, T-lymphocyte deficiency, and predilection to infection also may be features of clinical presentation.[205] Evidence suggests that genetically induced embryonic abnormalities in the cardiac neural crest play a major part in creation of the cardiovascular malformation as well as

the other components of the syndrome [206] (see Chap. 56 ). Truncal valve incompetence is suggested by the presence of a diastolic decrescendo murmur at the base of the heart. The physical findings are different if pulmonary blood flow is restricted by either high pulmonary vascular resistance or pulmonary arterial stenosis: Cyanosis is prominent, congestive failure is rare, and only a short systolic ejection may be audible, occasionally accompanied by continuous murmurs posteriorly of bronchial collateral flow.

Figure 43-21 Top, Subcostal coronal view of truncus arteriosus (Tr). The truncal valve lies above the ventricular septal defect (open arrow), which appears above the left ventricle (LV) and right ventricle (RV). The Tr is seen dividing into the transverse aortic arch (TAO), which gives rise to the vessels supplying the head and neck: the innominate artery (IA), the left carotid artery (LCA), and the left subclavian artery (LSA). Bottom, Doppler color flow image showing the superimposition of color flow into the truncus arteriosus, left pulmonary artery, transverse aorta, and branches to the head and neck. ELECTROCARDIOGRAPHY AND RADIOGRAPHY.

Left ventricular hypertrophy alone or in combination with right ventricular hypertrophy is present electrocardiographically when a prominent left-to-right shunt exists; right ventricular hypertrophy is observed in patients with restricted pulmonary blood flow. The radiographic findings depend on the hemodynamic circumstances. Gross cardiomegaly with left or combined ventricular enlargement, left atrial enlargement, and a small or absent main pulmonary artery segment with pulmonary vascular engorgement are the usual radiographic features. A right aortic arch is common (25 to 30 percent of patients). When pulmonary blood flow is reduced, both heart size and pulmonary vascular markings are less prominent. The echocardiographic features of truncus arteriosus (see Fig. 43-21 ) include a large truncal root overriding the ventricular septum and an outlet VSD. Additionally seen are

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truncal valve abnormalities with a variable number of cusps and leaflets, often thickened with rolled edges, an increase in the right ventricular dimension, and mitral valve-truncal root continuity. Differentiation between truncus arteriosus and tetralogy of Fallot by ultrasonography may be difficult unless either the separate origin of the pulmonary arteries or a single trunk from the ascending portion of a single arterial root can he identified. The origin of the pulmonary arteries is detected from various imaging planes, including high short-axis views, scanning superiorly from the truncal valve, or from a subcostal view (see Fig. 43-21 ). Diagnosis should be suspected at cardiac catheterization if the catheter fails to enter the central pulmonary arteries from the right ventricle. Selective angiocardiography and retrograde aortography are necessary to establish a precise diagnosis and to reveal the common trunk arising from the heart and the origin of the pulmonary arteries from the truncus.[207]

The early fatal course as well as early development of pulmonary vascular obstructive disease in patients surviving infancy is responsible for the poor prognosis associated with truncus arteriosus. In infants and young children with large left-to-right shunts, surgical banding of one or both pulmonary arteries to reduce pulmonary flow has been used with little success. Corrective operation is indicated before age 3 months to avoid the development of severe pulmonary vascular obstructive disease.[208] SURGICAL TREATMENT.

Operation consists of closure of the VSD, leaving the aorta arising from the left ventricle; the pulmonary arteries are excised from their truncus origin, and a valve-containing prosthetic conduit or aortic homograft valve conduit is used to establish continuity between the right ventricle and the pulmonary arteries (Fig. 43-22). Truncal valve insufficiency is a challenging problem and may require valve replacement or more moderate plastic repair to correct prolapse and improve central cusp coaptation. Important risk factors for perioperative death are severe truncal valve regurgitation, interrupted aortic arch, coronary artery anomalies, and age at operation greater than 100 days.[209] [210] Patients with only one pulmonary artery are especially prone to early development of severe pulmonary vascular disease but otherwise are not at increased risk from surgery. With truncus arteriosus defects, the possible inequalities of pressure and flow between the two pulmonary arteries often make precise calculation of pulmonary resistance difficult. Corrective operation may be performed in patients with at least one adequate pulmonary artery having low distal pressure or arteriolar resistance. Conversely, significant systemic arterial desaturation in a patient with two pulmonary arteries and with neither pulmonary artery stenosis nor a previous pulmonary artery band signifies that high pulmonary vascular resistance exists and that the condition is probably inoperable. It is not yet clear how often and at what age the conduit between the right ventricle and pulmonary artery must be replaced with a larger prosthesis because of either growth of the patient, in whom a small conduit causes eventual obstruction, heterograft valve degeneration, or obstruction created by neointimal proliferation within a prosthetic conduit.[211] When operation is carried out within a conduit in the first year of life, conduit replacement often is required within 3 to 5 years. Coronary Arteriovenous Fistula

Coronary arteriovenous fistula (see also Chap. 44 ) is an unusual anomaly that consists of a communication between one of the coronary arteries and a cardiac chamber or vein. The right coronary artery, or its branches, is the site of the fistula in about 55 percent of cases; the left coronary artery is involved in about 35 percent, and both coronary arteries in 5 percent. Connections between the coronary system and a cardiac chamber appear to represent persistence of embryonic intertrabecular spaces and sinusoids. Most of these fistulas drain into the right ventricle, right atrium, or coronary sinus; fistulous communication to the pulmonary artery, left atrium, or left ventricle is much less frequent. The shunt through the fistula most often is of small magnitude, and myocardial blood flow is not compromised.[212] Rarely, spontaneous closure may occur.

Potential complications include pulmonary hypertension and congestive heart failure if a large left-to-right shunt exists, bacterial endocarditis, rupture or thrombosis of the fistula or an associated arterial aneurysm, and myocardial ischemia distal to the fistula due to decreased coronary blood flow. Most pediatric patients are asymptomatic and are referred because of a cardiac murmur that is loud, superficial, and continuous at the lower or midsternal border. The site of maximal intensity of the murmur is related to the site of drainage and usually is different from the second left intercostal space--the classic site of the continuous murmur of

Figure 43-22 Operative correction of truncus arteriosus, type III. The pulmonary arteries arise separately from the truncus. An anterior incision is made, and a segment of aorta containing the orifices of both pulmonary arteries is excised from the truncus (a). The cuff of tissue containing the two pulmonary arteries is anastomosed to an extracardiac valved conduit (b). Aortic continuity is restored by direct suture (c) or by interposing a preclotted graft (d). The diagram does not show closure of the ventricular septal defect. (From Stark J, deLaval M: Surgery for Congenital Heart Defects. New York, Grune & Stratton, 1983, p 420.)

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persistent ductus arteriosus--except when the fistula drains into the pulmonary artery or right ventricle. In the latter situation, the murmur is louder in diastole than in systole because of compression of the fistula by contracting myocardium. The ECG and chest roentgenogram findings often are normal and seldom show selective chamber enlargement or myocardial ischemia. A significantly enlarged feeding coronary artery can usually be detected by two-dimensional echocardiography. The entire course and site of entry of the AV fistula can be traced by combining two-dimensional echocardiography and Doppler color flow mapping and imaging techniques. The shunt entry site is characterized by a continuous turbulent systolic and diastolic flow pattern (see Chaps. 7 and 44 ). [212] [213] Multiplane transesophageal echocardiography also accurately defines the origin, course, and drainage site of the fistula. Standard retrograde thoracic aortography, balloon occlusion angiography of the aortic root with a 45-degree caudal tilt of the frontal camera ("laid-back" aortogram),[214] or coronary arteriography can be used reliably to identify the size and anatomical features of the fistulous tract, which can be closed preferably by transcatheter coil embolization or suture obliteration in most cases.[215] [216] In the presence of a large left-to-right shunt and symptoms of heart failure, the decision to operate is clearly justified. The fistula most often is closed in asymptomatic patients to prevent future symptoms or complications, such as infective endocarditis. The prognosis after successful closure of a coronary artery-cardiac chamber fistula is excellent. Anomalous Pulmonary Origin of the Coronary Artery

This rare malformation occurs in about 0.4 percent of patients with congenital cardiac

anomalies. In almost all patients, the left coronary artery originates from the posterior sinus of the pulmonary artery.[217] In unusual cases that have been reported, the right coronary artery, or the entire coronary artery system, originates from the main pulmonary trunk. Embryologically, the distal coronary artery system is formed by 9 weeks from solid angioblastic buds that extend throughout the epicardium to form the major coronary artery branches. Proximally, the coronary network forms a ring around the truncus arteriosus, joining with coronary buds from the primitive aortic sinuses as the truncus partitions to form the great arteries. The varieties of anomalous pulmonary origin of the coronary artery are the result of displacement in this proximal process. PATHOPHYSIOLOGY.

During fetal life, pulmonary artery pressure is slightly greater than aortic pressure, and perfusion of the left coronary artery is antegrade ( Fig. 43-23 A). After birth, when pulmonary artery pressure falls below aortic pressure, perfusion of the left coronary artery from the pulmonary artery ceases, and the direction of flow in the anomalous vessel reverses. Blood flows from the aorta to the right coronary artery, then through collateral channels to the left coronary artery, and finally to the pulmonary artery ( Fig. 43-23 B). In effect, the left coronary artery behaves as a fistulous communication between the aorta and pulmonary artery. If adequate collateral channels exist or develop between the two coronary artery circulations, total myocardial perfusion through the right coronary artery increases ( Fig. 43-23 C). In 10 to 15 percent of patients, myocardial ischemia never develops because extensive intercoronary collaterals allow survival to adolescence or adulthood. In fact, if collateral blood flow is considerable, patients may develop the clinical manifestations of a large arteriovenous shunt and a continuous or diastolic murmur. By far the most common clinical presentation is that of an infant who suffers a myocardial infarction and develops congestive heart failure.[218] The infant syndrome usually becomes manifested at age 2 to 4 months with angina-like symptoms that may be misinterpreted as colic. Feeding and defecation often are accompanied by dyspnea, irritability and crying, pallor, diaphoresis, and occasional loss of consciousness. Older children or adults usually present with a continuous murmur or with mitral regurgitation resulting from dysfunction of ischemic or infarcted papillary muscles. In some instances, the coronary anomaly is unsuspected until a previously well adolescent or adult experiences angina, heart failure, or sudden death. DIAGNOSIS.

The diagnosis of anomalous origin of the coronary artery is supported by ECG demonstration of deep Q waves in association with ST segment alterations and T wave inversions in leads I, aVL , V5 , and V6 (Fig. 43-24) . These findings greatly assist the differentiation of this anomaly from myocarditis and dilated cardiomyopathy.[219] Chest roentgenograms show moderate to severe enlargement of the left atrium and ventricle. Echocardiography with Doppler color flow mapping has replaced cardiac catheterization

as the standard method of diagnosis. The pulmonary

Figure 43-23 Anomalous origin of the left main coronary artery from the pulmonary artery. A, In a fetus, both right and left coronary arteries receive forward flow from their respective great arteries. B, Soon after birth, before collaterals are well developed, there may be an anterolateral infarct and slight retrograde flow from the left coronary artery to the pulmonary artery. C, After collaterals have enlarged, there is high flow in the enlarged right coronary artery and the collaterals and significant retrograde flow into the pulmonary artery. Dotted arrows indicate direction and approximate magnitude of flow in the right and left coronary arteries and the collaterals between them. PV = pulmonary vein; LA = left atrium; LAA = left atrial appendage; RA = right atrium; LMCA = left main coronary artery; LCx = left circumflex coronary artery; LAD = left anterior descending coronary artery; RCA = right coronary artery. (From Hoffman JIE: In Emmanouilides GC, Riemenschneider TA, Allen HD, et al [eds]: Moss and Adams' Heart Disease in Infants, Children, and Adolescents. 5th ed. Baltimore, © Williams & Wilkins, 1994, p 776.)

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Figure 43-24 Typical electrocardiogram of an infant with anomalous left coronary artery before (above) and after (below) ligation of the anomalous left coronary artery. Note the abnormal Q waves in I, AVL, and V 6 . (Courtesy of Dr. Delores A. Danilowicz.)

origin of the anomalous left coronary artery is visualized from long- or short-axis views. Color flow mapping demonstrates retrograde flow in the left coronary system and an abnormal flow jet from the left coronary artery into the pulmonary trunk. Moreover, detection of anterograde flow in the left coronary system helps to preclude the diagnosis.[221] Color flow mapping of the jet from the origin of the left coronary artery as it enters the pulmonary artery is diagnostic. Detection of anterograde diastolic flow in the left coronary system virtually precludes this diagnosis.[220] If the echocardiographic diagnosis is unequivocal, coronary arteriography or aortography is not required to make the diagnosis. The origin of the anomalous left coronary artery occasionally may be visualized echocardiographically from long- or short-axis views of the pulmonary artery.[221] Absence of the left coronary artery from its usual origin in the left sinus of Valsalva does not distinguish this lesion from single coronary artery. Color flow Doppler examination may also reveal associated mitral regurgitation. Ischemia or infarction is suggested by the echocardiographic findings of segmental wall motion abnormalities, particularly involving the anterolateral free wall of the left ventricle. Electron beam CT after intravenous contrast infection may accurately define the malformation (see Chap. 10 ). Stress thallium scintigraphy shows a characteristic defect of the anterolateral wall of the left ventricle. Positron emission tomography reveals both the perfusion defect and its metabolic consequences (Fig. 43-25). Aortography or coronary angiography demonstrates the retrograde drainage of the coronary vessel into the pulmonary artery. It should be recognized that ventricular arrhythmias may complicate the course of hemodynamic study. The magnitude of shunting into the pulmonary artery may be determined by oximetry, indicator-dilution

curves, or angiography. MANAGEMENT.

Medical treatment is indicated in infants with myocardial infarction for congestive heart failure, arrhythmias, and cardiogenic shock. In patients with a small left-to-right shunt or no shunt at all, the prognosis is exceedingly poor with conservative management, justifying an attempt to reestablish a two-coronary artery system. The operations that have been used include reimplanting the left coronary artery into the aortic root, surgically creating an aortopulmonary window and a tunnel to convey blood from the window across the back of the pulmonary trunk to the origin of the anomalous left coronary artery, with reconstruction of the anterior wall of the pulmonary trunk, and anastomosis of the left coronary artery with the subclavian artery or with the aorta by means of a graft.[222] [223] If clinical deterioration occurs in infants with a sizable left-to-right shunt into the pulmonary artery, simple ligation of the left coronary artery at its origin prevents retrograde flow

Figure 43-25 Positron emission tomography (PET) transaxial images depict myocardial perfusion and glucose metabolism in a 7-month-old infant with anomalous origin of the left coronary artery (LCA) from the pulmonary artery. The ammonia (NH3 ) scan demonstrates hypoperfusion (left panel), whereas the fluorodeoxyglucose scan shows increased glucose metabolism (right panel) in the anterior lateral left ventricular wall (arrows) in the region perfused by the LCA. Under fasting conditions, normal myocardium has minimal glucose (FDG) uptake, whereas in this figure, hypoperfused myocardium preferentially metabolizes glucose. The "mismatch" pattern in this figure indicates ischemic but viable myocardium. This patient underwent reimplantation of the LCA with subsequent complete recovery of cardiac function and normalization of PET perfusion and metabolism. RV = right ventricle; LV = left ventricle; IVS = interventricular septum.

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and allows perfusion of the left ventricle with blood supplied through anastomoses with the right coronary artery. If medical management stabilizes the infant with significant intercoronary collaterals, operation may be postponed to allow the patient to grow, because increased size of the vessels enhances the likelihood of successful reimplantation or coronary arterial bypass surgery. The outcome of surgery and ultimate prognosis are significantly influenced by the degree of myocardial damage suffered preoperatively.[224] Uncommonly, it is necessary to consider aneurysmectomy or mitral valve replacement. Cardiac transplantation has been suggested as an option only if recovery of myocardial function is poor. Aortic Sinus Aneurysm and Fistula

Congenital aneurysm of an aortic sinus of Valsalva, particularly the right coronary sinus, is an uncommon anomaly that occurs three times more often in males than in females. The malformation consists of a separation, or lack of fusion, between the media of the

aorta and the annulus fibrosis of the aortic valve.[225] The receiving chamber of the aorticocardiac fistula usually is the right ventricle, but occasionally, when the noncoronary cusp is involved, the fistula drains into the right atrium. Five to 15 percent of aneurysms originate in the posterior or noncoronary sinus; seldom is the left aortic sinus involved. Associated anomalies are common and include bicuspid aortic valve, VSD, and coarctation of the aorta. The deficiency in the aortic media appears to be congenital. Reports in infants are exceedingly rare[226] and are infrequent in children, because progressive aneurysmal dilatation of the weakened area develops but may not be recognized until the third or fourth decade of life, when rupture into a cardiac chamber occurs. An unruptured aneurysm usually does not produce a hemodynamic abnormality, although pressure on the intracardiac conduction system by an unruptured aneurysm may be a rare cause of complete AV block; rarely, myocardial ischemia may be caused by coronary arterial compression. Rupture is often of abrupt onset, causes chest pain, and creates continuous arteriovenous shunting and volume loading of both right and left heart chambers, which results in heart failure. An additional complication is infective endocarditis, which may originate either on the edges of the aneurysm or on those areas in the right side of the heart that are traumatized by the jetlike stream of blood flowing through the fistula. DIAGNOSIS.

The presence of this anomaly should be suspected in a patient with a history of chest pain of recent onset, symptoms of diminished cardiac reserve, bounding pulses, and a loud superficial continuous murmur accentuated in diastole when the fistula opens into the right ventricle, as well as a thrill along the right or left lower parasternal border. The physical findings can be difficult to distinguish from those produced by a coronary arteriovenous fistula. Electrocardiography shows biventricular hypertrophy, and chest roentgenography demonstrates generalized cardiomegaly. Two-dimensional and pulsed Doppler echocardiographic studies may detect the walls of the aneurysm and disturbed flow within the aneurysm or at the site of perforation, respectively.[227] Transesophageal echocardiography may provide more precise information than the transthoracic approach. Cardiac catheterization reveals a left-to-right shunt at the ventricular or, less commonly, the atrial level; the diagnosis may be established definitively by retrograde thoracic aortography (Fig. 43-26) . MANAGEMENT.

Preoperative medical management consists of measures to relieve cardiac failure and to treat coexistent arrhythmias or endocarditis, if present. At operation, the aneurysm is closed and amputated, and the aortic wall is reunited with the heart, either by direct suture or with a prosthesis.[228] Every effort should be made to preserve the aortic valve in children because patch closure of the defect combined with prosthetic valve

replacement greatly enhances the risk of operation in small patients.

Figure 43-26 A retrograde aortogram shows the fistulous connection between the noncoronary sinus of Valsalva and the right ventricle (RV) (arrow). AO = aorta. (Courtesy of Dr. Robert White.)

VALVULAR AND VASCULAR LESIONS WITH OR WITHOUT RIGHT-TO-LEFT SHUNT Aortic Arch Obstruction

The conventional anatomical and clinical divisions into preductal and postductal coarctation or infantile and adult types, respectively, are misleading because the anatomical localization is inaccurate and the age dependence of the clinical presentation does not hold true (i.e., the adult type often is seen in the first weeks of life). A spectrum of anatomical lesions exists, causing obstruction of the aortic arch or proximal portion of the descending aorta. These range from a localized coarctation or constriction of the lumen, most commonly located just distal to the origin of the left subclavian artery and closely related to the attachment of the ductus arteriosus with the aorta, to diffuse narrowing or interruption of a portion of the aortic arch. In this chapter, aortic arch obstruction is divided into three types: (1) localized juxtaductal coarctation, (2) hypoplasia of the aortic isthmus, and (3) aortic arch interruption. Pseudocoarctation is used synonymously with "kinking" or "buckling" of the aorta, which is a subclinical form of localized juxtaductal coarctation of the aorta. Localized Juxtaductal Coarctation (See also p. 1600 ) MORPHOLOGY.

This lesion consists of a localized shelflike thickening and infolding of the media of the posterolateral aortic wall opposite the ductus arteriosus; the wall of the aorta into which the ductus or ligamentum arteriosum inserts is not involved.[229] Juxtaductal coarctation occurs two to five times more commonly in males than in females, and there is a high degree of association with gonadal dysgenesis (Turner's syndrome) and bicuspid aortic valve.[230] Other common associated anomalies include VSD and mitral stenosis or regurgitation. The most important extracardiac anomaly is aneurysm of the circle of Willis.

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PATHOGENESIS.

Juxtaductal coarctation is probably related to an abnormality in the pattern of ductus arteriosus blood flow in utero, which in turn may be the result of associated intracardiac

anomalies.[230] [231] Thus, in fetal life, blood flow through the aortic isthmus constitutes only 12 to 17 percent of the total cardiac output, whereas blood flow through the ductus arteriosus exceeds that across the aortic valve. The dorsal aortic wall directly opposite the ductus arteriosus resembles morphologically the apex of a normal branch point of the aorta if ductal flow pathways in utero diverge, with some flow directed cephalad into the aortic isthmus and the remainder proceeding into the descending aorta. The aortic branch point is identical histologically to the posterior shelf of juxtaductal aortic coarctation. A divergence of ductal flow is fostered by the presence of lesions in the fetus that create an imbalance between left and right ventricular outputs, with right-sided flow predominating (e.g., bicuspid aortic valve, mitral valve anomaly). In the absence of an anomaly fostering augmented ductal flow, a branch point may be created by an alteration in the angle at which the ductus arteriosus meets the aorta, pointing the ductal stream directly against the posterior aortic wall rather than obliquely down into the descending aorta. Cardiac anomalies that cause augmented ascending aortic blood flow (e.g., pulmonic atresia or stenosis, tetralogy of Fallot) prevent development of a branch point and indeed are almost never seen in association with juxtaductal coarctation of the aorta. During fetal life, the posterior aortic shelf is not obstructive because blood may pass readily from the ascending aorta to the descending aorta by traversing the anterior aortic segment and the aortic end of the ductus arteriosus. Postnatally, however, when the ductus undergoes obliteration at its aortic end, the shelflike projection of the posterior aortic wall unmasks the obstruction to aortic flow (Fig. 43-27) . After pharmacological interventions that dilate the ductus arteriosus (prostaglandin E1 infusion), the pressure difference may be obliterated across the site of coarctation because the fetal flow pattern is reestablished.[178] [232] The pathogenesis of juxtaductal coarctation already described explains the prevalence of associated intracardiac anomalies that foster reduced ascending aortic flow and augmented ductus arteriosus flow in utero, as well as the absence of associated intracardiac anomalies in which the converse flow conditions exist in utero. The dependence of aortic obstruction on constriction of the ductus arteriosus postnatally explains the variable onset after birth of the clinical manifestations of coarctation, as well as the dramatic alleviation of the obstruction produced pharmacologically by dilatation of the ductus arteriosus. CLINICAL FINDINGS.

The manifestations of juxtaductal coarctation of the aorta depend on the prominence of the posterolateral aortic shelf, which determines the intensity

Figure 43-27 Juxtaductal coarctation (COARCT) unmasked by constriction of the ductus arteriosus (DA). MPA = main pulmonary artery; D.Ao. = descending aorta; Ao.Isth. = aortic isthmus. (Courtesy of Dr. Norman Talner.)

of obstruction, and on the rapidity with which obstruction develops.

NEONATES AND INFANTS.

Rapid, severe obstruction in infancy is a prominent cause of left ventricular failure and systemic hypoperfusion. Substantial left-to-right shunting across a patent foramen ovale and pulmonary venous hypertension secondary to heart failure cause pulmonary arterial hypertension. Because little or no aortic obstruction existed during fetal life, the collateral circulation in the newborn period is often poorly developed. In these infants, peripheral pulses characteristically are weak throughout the body until left ventricular function is improved with medical management; a significant pressure difference then develops between the arms and the legs, allowing detection of a pulse discrepancy. Cardiac murmurs are nonspecific in infancy and commonly are derived from associated lesions. The ECG shows the right-axis deviation and right ventricular hypertrophy; the chest radiograph shows generalized cardiomegaly and pulmonary arterial and venous engorgement. Two-dimensional and Doppler echocardiography provide an accurate noninvasive assessment of the anatomy and physiology in most patients. Hemodynamic study also allows delineation of the site and extent of aortic obstruction and detection of associated cardiac malformations. Most infants with early-onset severe heart failure respond poorly to medical management, and balloon angioplasty, surgical excision of the coarctation, or a subclavian flap angioplasty often is required. We prefer an operation consisting of excision of the area of coarctation and extended end-to-end repair or end-to-side anastomosis with absorbable sutures to allow remodeling of the aorta with time.[233] Aortic obstruction may develop slowly in infants in whom the posterolateral aortic shelf is not prominent at birth and in whom ductus arteriosus constriction is gradual. In these babies, compensatory myocardial hypertrophy and an extensive collateral circulation have time to develop. If the obstruction does not intensify and cardiac failure does not occur by age 6 or 9 months, circulatory compensation is likely until adult life. CHILDREN.

Most children with isolated juxtaductal coarctation are asymptomatic. Complaints of headache, cold extremities, and claudication with exercise may be noted, although attention usually is directed to the cardiovascular system by detection of a heart murmur of upper extremity hypertension on routine physical examination. Mechanical factors rather than those of renal origin play the primary role in the production of hypertension. Absent, markedly diminished, or delayed pulsations in the femoral arteries and a low or unobtainable arterial pressure in the lower extremities with hypertension in the arms are the basic clues to the diagnosis. A midsystolic murmur over the anterior chest, back, and spinous processes is most frequent, becoming continuous if the lumen is sufficiently narrowed to result in a high-velocity jet across the lesion throughout the cardiac cycle. Additional systolic and continuous murmurs over the lateral thoracic wall may reflect increased flow through dilated and tortuous collateral vessels.

ECG reveals left ventricular hypertrophy of various degrees, depending on the height of arterial pressure above the obstruction and the patient's age. Combined with right ventricular hypertrophy, this usually implies a complicated lesion. Chest roentgenograms (see Chaps. 8 and 44 ) can show a dilated left subclavian artery high on the left mediastinal border and a dilated ascending aorta. Indentation of the aorta at the site of coarctation and prestenotic and poststenotic dilatation (the "3" sign) along the left premediastinal shadow is almost pathognomonic. Poststenotic dilation also may be detected by indentation of the barium-filled esophagus. Notching of the ribs, an important radiographic sign, is due to erosion by dilated collateral vessels, increases with age, and usually becomes apparent between the 4th and 12th years of life. The aortic coarctation may be visualized directly by two-dimensional echocardiography from high parasternal or suprasternal notch views with short focused transducers and from the subxiphoid window with extended focal range transducers (Fig. 43-28) . Doppler examination reveals a flow disturbance and high-velocity jet at the site of obstruction and provides a reasonable estimate of the transcoarctation pressure gradient.[234] [235] CT, magnetic resonance imaging[235] [236] ( Fig. 43-29 and Chap. 10 ), or cardiac catheterization and aortography (see Fig. 44-7 , p. 1601) also accurately localizes the site of

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Figure 43-28 Aortic coarctation (Coarc) is visualized from the suprasternal notch. The aorta (Ao) can be traced from the ascending aorta (AAo). The aortic arch is somewhat narrowed, and the relationship of the left subclavian artery (LS) to the coarctation is identified clearly. LA = left atrium; PA = pulmonary artery; IA = innominate artery; LC = left carotid artery.

obstruction, determines the length of coarctation, and, particularly, identifies associated malformations. Preoperative catheterization is avoided for selected patients with typical clinical and two-dimensional and Doppler echocardiographic findings.[237] Intravascular ultrasonography provides interesting morphological images suitable especially for comparison with postoperative status.[238] MANAGEMENT.

Controversy exists about the role of balloon angioplasty (see Chap. 38 ), with or without balloon-expandable stents, in the treatment of native coarctation, especially in neonates.[239] [240] [241] [241A] There is concern about residual pressure gradients, aneurysm formation, aortic dissection and rupture, and femoral arterial complications, especially late after angioplasty. It is clear that angioplasty can effectively reduce obstruction in many patients, albeit with an unpredictable late outcome. An extended end-to-end anastomosis with resection of the aortic isthmus and ductal

tissue yields a low mortality and a low rate of recoarctation. It is now the procedure of

Figure 43-29 Three-dimensional computer reconstruction of magnetic resonance images in a child with discrete coarctation and numerous large collateral vessels, displayed in a lateral projection. Dilated brachiocephalic and internal mammary arteries are evident. (Courtesy of Dr. W. James Parks, The Children's Heart Center, Emory University, Atlanta, GA.)

choice at many centers.[242] Subclavian flap aortoplasty, particularly in neonates and infants, or surgical resection and end-to-end anastomosis of uncomplicated juxtaductal coarctation of the aorta can be accomplished with excellent results in most patients[243] ; some surgeons prefer an onlay patch across the site of obstruction. In children who are asymptomatic, it is preferable to delay surgery until age 4 to 6 years, at which time coarctation seldom recurs. Paradoxical hypertension of short duration often is noted in the immediate postoperative period, a phenomenon much less common after balloon angioplasty.[244] [245] [246] [247] A resetting of carotid baroreceptors and increased catecholamine secretion appears to be responsible for the initial phase of postoperative systemic hypertension, with a later, second phase of prolonged elevation of systolic and particularly diastolic blood pressure related to activation of the renin-angiotensin system. A necrotizing panarteritis of the small vessels of the gastrointestinal tract of uncertain cause occasionally complicates the course of recovery. The risk of recurrent narrowing after repair of coarctation in infancy is 5 to 10 percent. Such narrowing is best detected by magnetic resonance imaging or Doppler ultrasonography.[235] This problem is treated most effectively by transcutaneous balloon angioplasty,[248] [248A] [249] which may be expected to markedly reduce but not entirely abolish the pressure differences across the site of recoarctation. In those patients who survive the first 2 years of life, complications of juxtaductal coarctation are uncommon before the second or third decade. The chief hazards to patients with coarctation result from severe hypertension and include the development of cerebral aneurysms and hemorrhage, hypertensive encephalopathy, rupture of the aorta, left ventricular failure, and infective endocarditis. Systemic hypertension in the absence of residual coarctation has been observed in resting or exercise-stressed patients postoperatively and appears to be related to the duration of preoperative hypertension.[250] Lifelong observation is desirable because of the late onset of hypertension in some postoperative patients.[251] Hypoplasia of the Aortic Arch MORPHOLOGY.

The aortic isthmus, the portion of the aorta between the left subclavian artery and the ductus arteriosus, normally is narrowed in the fetus and newborn. The lumen of the aortic isthmus is about two-thirds that of the ascending and descending portions of the aorta until age 6 to 9 months, when the physiological narrowing disappears.[252] Pathological tubular hypoplasia of the aortic arch usually is noted in the aortic isthmus

and often is referred to as preductal or infantile coarctation of the aorta. [253] Associated major cardiac malformations occur in virtually all such infants and include large VSD, AV septal defect, transposition of the great arteries, the Taussig-Bing type of anomaly, and double-outlet right ventricle. The VSD most often is subpulmonary, lying within the substance of the infundibular septum. Thus, muscle persists between the aortic and pulmonary valve leaflets, and when it is displaced leftward, it produces subaortic stenosis. Persistent patency of the ductus arteriosus commonly coexists, and right-to-left flow across the ductus arteriosus usually provides filling of the descending aorta. The adequacy of blood flow to the lower body depends on the degree of aortic hypoplasia, the caliber of the ductus arteriosus, and the relationship between pulmonary and systemic vascular resistance. Substantial right-to-left shunting through a wide-open ductus arteriosus minimizes the arterial blood pressure difference between the upper and lower body. CLINICAL FINDINGS.

Differential cyanosis of the toes and feet with normal color of the fingers and hands may be difficult to discern because intracardiac left-to-right shunting and pulmonary edema attenuate the differences in oxygen saturation in the ascending and descending aorta. Clinical deterioration is associated with ductal constriction or a decline in pulmonary vascular resistance. Moreover, the clinical presentation often is dictated by the hemodynamic effects of complex associated intracardiac malformations. Infants most often present with findings of a large left-to-right intracardiac shunt, pulmonary hypertension, and marked cardiac decompensation. Although tubular hypoplasia is detectable by two-dimensional echocardiography, cardiac catheterization may be required to evaluate the full extent of intracardiac and extracardiac lesions. Surgical repair of aortic

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Figure 43-30 An extended repair of aortic coarctation is used in the presence of a hypoplastic aortic arch. The broken lines in the left panel delineate resection sites of the coarcted segment. In the right panel, the ductus arteriosus has been ligated and the incisions are extended to the undersurface of the aortic arch and onto the distal aorta. When the suture line is completed, the reconstruction of the arch is generally excellent. (From Stark J, deLaval M: Surgery for Congenital Heart Defects. 2nd ed. Philadelphia, WB Saunders, 1994, p 292.)

arch hypoplasia usually must be accompanied by operative palliation or correction of associated intracardiac lesions. An extended end-to-end anastomosis (Fig. 43-30) , classic or reversed subclavian flap angioplasty, patch aortography, and bypass grafting are among the operative approaches to correct long segment narrowing.[247] Recoarctation is common and often necessitates transcatheter balloon aortoplasty and/or a second operation later in life to relieve anastomotic stenosis.[247] [248]

AORTIC ARCH INTERRUPTION.

Aortic arch interruption is a rare and usually lethal anomaly; unless treated surgically, almost all infants die within the first month of life. [254] Interruptions distal to the left subclavian artery (type A) occur with almost equal frequency to interruptions distal to the left common carotid artery (type B); interruptions distal to the innominate artery (type C) are extremely uncommon. The right subclavian artery often is of variable origin, frequently arising from the descending aortic segment distal to the interruption. The clinical presentation resembles that in tubular hypoplasia or severe juxtaductal coarctation of the aorta with a patent ductus arteriosus. Virtually all patients have associated intracardiac anomalies. A patent ductus arteriosus almost always connects the main pulmonary artery with the descending aorta. With rare exceptions, patients with interrupted aortic arch have either a VSD (80 to 90 percent of cases) or an aorticopulmonary window (10 to 20 percent). Because the ductus arteriosus provides lower body blood flow, its spontaneous constriction results in profound clinical deterioration. The latter may be temporarily ameliorated by prostaglandin E1 infusion. The VSD most often is subpulmonary, lying within the substance of the infundibular septum. Thus, muscle persists between the aortic and pulmonary valve leaflets; when the muscle is displaced leftward, it produces subaortic stenosis.[255] Other complex intracardiac malformations, such as transposition of the great arteries, aortopulmonary window, and truncus arteriosus, are common. CLINICAL FEATURES.

An association is frequent with the genetic 22q11 deletion of DiGeorge's syndrome, a constellation of cardiac, parathyroid, thymic, and facial anomalies attributed to disruption of the interaction of premigratory neural crest cells with endodermal pharyngeal pouch cells. In this syndrome, thymic hypoplasia or aplasia is accompanied by immunological and hypocalcemia problems.[256] [257] The major clinical problem is severe congestive heart failure as a consequence of volume overload of the left ventricle resulting from an associated intracardiac left-to-right shunt and of pressure overload imposed by systemic hypertension. Management.

The perioperative clinical condition of most patients can be improved by intensive medical management with mechanical ventilation, inotropic support, and prostaglandin infusion. Various forms of palliative operative techniques have fair to poor results. There has been increasing success with complete primary repair in infancy as the procedure of choice.[258] Greater mortality is associated when a two-stage approach with initial arch repair and pulmonary artery banding is followed by later repair of the intracardiac lesion. Recurrent narrowing at the aortic suture line can be treated by balloon angioplasty or reoperation.

Congenital Valvular Aortic Stenosis (See also p. 1599 ) MORPHOLOGY.

Congenital valvular aortic stenosis is a relatively common anomaly, estimated to occur in 3 to 6 percent of patients with congenital cardiovascular defects. However, it must be appreciated that the true incidence of the malformation is probably grossly underestimated because the congenital bicuspid aortic valve may be undetected in early life and becomes stenotic and of clinical significance only in adult life, at a time when it may be indistinguishable from the acquired forms of aortic stenosis. Congenital valvular aortic stenosis occurs much more frequently in males than in females, with the gender ratio approximating 4:1. Associated cardiovascular anomalies have been noted in as many as 20 percent of patients. [259] Patent ductus arteriosus and coarctation of the aorta occur most frequently with valvular aortic stenosis; all three of these lesions may coexist (see also Chap. 44 ). The basic malformation consists of thickening of valve tissue with various degrees of commissural fusion. The valve most commonly is the bicuspid, with a single fused commissure and an eccentrically place orifice. A third commissure, incomplete or rudimentary, is sometimes apparent. Less commonly, the valve has three fused cusps with a stenotic central orifice. In some patients, the stenotic aortic valve is unicuspid and dome shaped, with no or one lateral attachment to the aorta at the level of the orifice. In infants and young children with severe aortic stenosis, the aortic valve ring may be relatively underdeveloped. This lesion forms a continuum with the hypoplastic left heart syndrome and the aortic atresia and hypoplasia complexes. Secondary calcification of the valve is extremely rare in childhood, but the dynamics of blood flow associated with the congenitally deformed aortic valve ultimately lead to thickening of the cusps and calcification in adult life. When the obstruction is hemodynamically significant, concentric hypertrophy of the left ventricular wall and dilatation of the ascending aorta occur. HEMODYNAMICS (see also Chaps. 11 and 46 ).

The hemodynamic abnormalities produced by obstruction to left ventricular outflow are discussed in Chapter 46 . A peak systolic gradient exceeding 75 mm Hg in association with a normal cardiac output or an effective aortic orifice less than 0.5 cm 2 /m body surface area is considered to reflect critical or severe obstruction to left ventricular outflow.[259] The normal outflow orifice approximates 2.0 cm2 /m body surface area; areas of 0.5 to 0.8 cm2 /m2 signify moderate obstruction; when the area is larger than 0.8 cm2 /m2 , the obstruction is considered to be mild. The resting cardiac output and stroke volume usually are within normal limits. During exercise, most children with critical stenosis show an elevation of the cardiac output and an associated elevation in the transvalvular pressure gradient.[260] When left ventricular failure occurs, cardiac output decreases and left atrial, left ventricular end-diastolic, and

pulmonary vascular pressures increase. Studies of left ventricular performance in children with aortic stenosis often reveal supernormal pump function, as

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indicated by increases in ejection fraction and circumferential fiber shortening.[261] Despite high left ventricular systolic pressures, left ventricular wall stress appears to be lower than normal throughout systole, presumably because increases in wall thickness provide overcompensation for the pressure overload. Undoubtedly, a spectrum exists, from well-compensated patients at one end, who have supernormal pump function and normal contractile function, to patients with heart failure at the opposite end, who have both impaired pump function and a reduced contractile state. While pressure overload hypertrophy can preserve systolic function, it can also result in abnormal left ventricular early diastolic filling.[262] Thus, clinical studies seeking to analyze the determinants of left ventricular filling by a separate assessment of dynamic (elastic recoil, ventricular relaxation rate, and atrial driving pressure) and static (chamber stiffness and left ventricular hypertrophy) determinants suggest that diastolic function most importantly varies according to the severity of left ventricular hypertrophy and systolic function. Studies of children suggest that hypertrophy is a more important factor than excessive wall stress and depressed ejection performance in accounting for abnormal diastolic filling. The blood supply to the myocardium may be significantly compromised in infants and children with aortic stenosis, despite normal patency of the coronary arteries. [263] Coronary blood flow and arterial oxygen content are critical determinants of oxygen supply to the myocardium. Because intramyocardial compressive forces are greatest in the subendocardium, blood flow to that region of the left ventricle is entirely diastolic in the presence of elevated left ventricular systolic pressure. In patients with left ventricular outflow tract obstruction, coronary vasodilatation may give an inadequate response to an increase in the demands of the myocardium for oxygen at rest or with exercise. When subendocardial vessels are maximally dilated, the coronary artery driving pressure and the duration of diastole determine the magnitude of subendocardial flow. When the duration of systolic ejection lengthens across the stenotic orifice, diastole is shortened, especially at high heart rates. Moreover, a reduction occurs in coronary driving pressure if left ventricular end-diastolic pressure is high or if aortic diastolic pressure is low, e.g., with aortic regurgitation or heart failure. In patients with severe aortic stenosis, the redistribution of flow away from the subendocardium and the ischemia that results in that portion of ventricular muscle may be estimated by relating the diastolic pressure-time index (DPTI) (i.e., the area between the aortic and left ventricular pressures in diastole) to the systolic pressure-time index (SPTI) (a measure of myocardial oxygen demands). Inadequate subendocardial oxygen delivery has been shown to exist when the ratio [DPTI × arterial oxygen content/SPTI] falls below 10.[263]

NEONATES AND INFANTS

Reports exist of cardiac dysfunction and even nonimmunological fetal hydrops fetalis in association with severe aortic stenosis.[264] [265] [266] The hydrops can be the result of in utero left ventricular myocardial infarction or profound left ventricular systolic and diastolic dysfunction. Balloon dilation using coronary balloon catheters has been attempted via transabdominal echo-guided needle puncture of the fetal left ventricle. This approach is not established, and it is doubtful that it will become a management option. Fortunately, isolated aortic valvular stenosis seldom causes symptoms in infancy.[267] This lesion, however, occasionally can be responsible for profound and intractable heart failure, even in fetal life. Despite normal coronary arterial anatomy, infarction of left ventricular papillary muscles may occur, resulting in an acquired form of mitral valvular regurgitation that intensifies the heart failure state. In addition, endocardial fibroelastosis may result from limited subendocardial oxygen delivery, and myocardial degeneration may be significant. Symptomatic infants with isolated valvular aortic stenosis are irritable, pale, and hypotensive and present with tachycardia, cardiomegaly, and pulmonary congestion manifested by dyspnea, tachypnea, subcostal retractions, and diffuse rales. Cyanosis may be observed secondary to pulmonary venous desaturation. The systolic murmur in infants often is atypical; it is best heard at the apex or along the lower left sternal border and may be confused with that caused by a VSD. In infants with heart failure, the murmur occasionally may be absent or extremely soft, becoming louder when myocardial contractility is improved with digitalis and other medical measures. Infants with heart failure frequently have a poor response to medical management. The ECG findings may not be characteristic; left ventricular hypertrophy and/or strain as well as right atrial enlargement and right ventricular hypertrophy may be detected shortly after birth.[267] The latter signs of right heart involvement result from both pulmonary hypertension secondary to elevated left ventricular diastolic and left atrial pressures and from volume loading of the right ventricle caused by left-to-right shunting across the foramen ovale. Survival past the early neonatal period does not preclude subsequent difficulties, and clinical deterioration may recur with the onset of physiological anemia. Management

Congenital aortic stenosis must be considered a medical emergency in a seriously ill newborn, and echocardiography, and sometimes cardiac catheterization and angiocardiography, may be indicated in the first 24 hours of life. Two-dimensional echocardiographic studies show a severe immobility of the aortic valve, with little or no systolic opening, poststenotic dilation of the aorta, left ventricular hypertrophy, right ventricular enlargement, and a severely disturbed Doppler-determined pattern of ascending aortic flow velocity. The echo-Doppler examination must also identify associated intracardiac and extracardiac anomalies, one of the most important of which

is severe aortic arch obstruction. Dilation of the ductus arteriosus with prostaglandin E1 infusion may provide transitional support of the systemic circulation. In many centers, expeditious balloon aortic valvuloplasty follows the echo-Doppler examination in infants who are unstable and markedly symptomatic.[268] [269] [270] [271] [272] A number of approaches have been reported for performing this procedure, including the use of a carotid artery cutdown, which thus far does not appear to result in any abnormalities of the carotid pulse or any neurological sequelae. A transumbilical technique of balloon valvuloplasty can be performed quickly, safely, and effectively with preservation of the femoral artery. Because of a high risk of iliofemoral artery complications in infants with the transfemoral route to valvuloplasty, when this route is used it is advisable to use double-balloon techniques to allow insertion of small valvuloplasty catheters. The complications of balloon valvuloplasty are related to the small size and young age of the patient. Accordingly, if arterial access is a problem, and in infants younger than 1 month, surgical valvotomy remains a satisfactory option. Open repair under direct vision is the preferred type of operation. Hemodynamic findings in neonates and infants frequently include left-to-right shunting at the atrial level, elevated left atrial and left ventricular end-diastolic pressures, and a small pressure drop across the aortic valve as a result of markedly reduced cardiac output. Right-to-left shunting across a patent ductus arteriosus is encountered occasionally. The lesion may be distinguished from the hypoplastic left heart syndrome echocardiographically and angiographically by the presence of normal or enlarged left ventricular cavity and normal or dilated ascending aorta.[273] [274] Establishment of the diagnosis and prompt catheter valvuloplasty or surgical valvotomy are justified because prolonged periods of stabilization are uncommon with medical therapy. Poor myocardial performance resulting from endocardial fibroelastosis, subendocardial ischemia, reduced left ventricular compliance, and inadequate relief of obstruction with or without aortic insufficiency are some of the factors accounting for high mortality and morbidity after catheter-directed treatment or operation. At the extreme end of the spectrum of critical valvar aortic stenosis in newborns are patients with many small left-sided structures; in these patients, the adverse effects of small inflow, outflow, and/or cavity size of the left ventricle appear to be cumulative. [274] It is in this group that traditional treatment by aortic valvuloplasty or valvotomy, which is a two-sided ventricle repair, may be less effective than a multistaged Norwood approach.[274] The latter consists of an initial single-ventricle repair in which the main pulmonary artery is anastomosed to the aorta with creation of a systemic-to-pulmonary arterial shunt, followed later by a Fontan-type operation that creates an atriopulmonary connection, with or without a prior superior cava-pulmonary connection. The single-ventricle repair results in functional sacrifice of the left ventricle and the right ventricle supporting the systemic circulation without a pulmonary ventricle.

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CHILDREN

Congenital aortic stenosis may be responsible for severe obstruction to left ventricular outflow in the absence of clinical symptoms of diminished cardiac reserve that are so frequent in other forms of congenital heart disease.[275] Most children with congenital aortic stenosis grow and develop normally and are asymptomatic. Attention usually is called to these children when a murmur is detected on routine examination. When symptoms occur, those noted most commonly are undue fatigue, exertional dyspnea, angina pectoris, and syncope. Less often described are abdominal pain, profuse sweating, and epistaxis. A symptomatic child usually has critical stenosis. There is a distinct threat of sudden death in patients with severe obstruction[276] (see Chap. 26 ). Although the precise cause is poorly understood, ventricular arrhythmias, perhaps initiated by acute myocardial ischemia, are probably the most common inciting event. It has been speculated that an abrupt rise in intracavity left ventricular systolic pressure elicits a reflex hypotensive syncope that promotes acute ischemia and ventricular fibrillation. Bacterial endocarditis occurs in about 4 percent of patients with congenital valvular aortic stenosis.[277] DIAGNOSIS

Physical Findings.

When the magnitude of obstruction is significant, a left ventricular lift usually is palpable, and a precordial systolic thrill often is palpated over the base of the heart with transmission to the jugular notch and along the carotid arteries; presystolic expansion often is palpable. The obstruction usually is mild if neither a left ventricular lift nor a thrill is present. Opening of the aortic valve produces a systolic aortic ejection sound that typically is present at the cardiac apex when the valve is mobile, particularly in patients with mild to moderate stenosis. A delay in closure of the stenotic aortic valve leads to a single or a closely split second heart sound, and paradoxical splitting may be present. A fourth heart sound normally is associated with severe obstruction. A loud, harsh, rhomboid-shaped systolic murmur starts after completion of left ventricular isometric contraction and is best heard at the base of the heart. The murmur, like the thrill, radiates to the suprasternal notch and carotid vessel as well as to the apex. An early diastolic blowing murmur of aortic regurgitation is present in some patients, but unless the valve leaflets have been eroded by bacterial endocarditis, the regurgitation usually is not hemodynamically significant; uncommonly, in patients with a congenitally bicuspid valve, aortic regurgitation may be severe and may predominate. Electrocardiography.

ECG signs of left ventricular hypertrophy tend to vary with the severity of obstruction, although a normal or near-normal ECG does not preclude severe aortic stenosis, and excessive left ventricular voltages may be observed in children with mild obstruction.[275]

The lack of close correlation between the ECG and the transvalvular pressure gradient emphasizes the potential hazard of relying on the ECG in patient care. The most reliable index of the severity of obstruction is the presence of a left ventricular "strain pattern," consisting of left ventricular hypertrophy combined with ST segment depressions and T wave inversion in the left precordial leads (Fig. 43-31) . Roentgenography.

Overall heart size is normal or the degree of enlargement is slight in most children with congenital valvular aortic stenosis. Concentric left ventricular hypertrophy accompanies moderate or severe obstruction and is manifested by rounding of the cardiac apex in the frontal projection and posterior displacement in the lateral view. Echocardiography.

Two-dimensional and Doppler echocardiography are the current methods of choice for defining the anatomy and the hemodynamic severity of valvular aortic stenosis.[278] [279] Real-time cross-sectional echocardiography reveals impaired mobility of cusp tissue, an alteration in the phasic movement of the aortic valve with reduced lateral and increased superior excursions of valve echoes, and an increase in the internal aortic root dimension beyond the level of the valve annulus.[259] Imaging of the valve must be performed many times in order to display the

Figure 43-31 Electrocardiogram in congenital aortic stenosis. This tracing shows left ventricular hypertrophy and the typical left ventricular "strain" pattern (V6 ). (Courtesy of Dr. Delores A. Danilowicz.)

valve through the long axis of the left ventricular outflow tract and then through a plane parallel to the valve annulus. The long-axis view of the left ventricular outflow tract allows evaluation of the valve mobility and cusp separation; it is the best view for demonstrating doming of the aortic valve. The parasternal short-axis view bisects the face of the valve, demonstrating the anatomy of the commissures (Fig. 43-32) . The echocardiogram also reveals associated left ventricular hypertrophy and the presence of endocardial fibroelastosis (seen as bright endocardial echoes). Further, measurements of mitral valve diameter, left ventricular enddiastolic dimension, and left ventricular cross-sectional area serve to distinguish those infants with critical aortic stenosis from those with a hypoplastic left ventricle.[274] Among these calculations suggesting the latter are an end-diastolic volume less than 20 ml/m 2 , an inflow dimension of 25 mm, a narrow ventricular aortic junction less than 5 mm, or a small mitral orifice less than 9 mm. Pulsed-wave Doppler echocardiography allows inspection of the pattern of flow velocity within the circulation. This technique detects the altered and disturbed turbulence of flow in patients with aortic stenosis. A highly accurate noninvasive approach to quantifying the severity of obstruction combines continuous-wave Doppler flow analysis with the cross-sectional echocardiographic determination of the area of the orifice. [280] A simplified Bernoulli equation uses the

measurement of the maximum velocity of the aortic jet and time-averaged pressure drop obtained from planimetry of the maximal velocity spectral reading. A simpler estimate of the transvalvular gradient (in mm Hg) may be calculated as four times the square of the peak Doppler velocity (m/sec). The Doppler method records a peak instantaneous pressure difference, which may differ importantly from the gradient recorded by a cardiac catheter, which is a peak-to-peak pressure difference.[281] Doppler mean gradient is more

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Figure 43-32 Standard short-axis view of aortic cusps in the closed position in a patient with a bicuspid aortic valve. Left frame, The right (R) and noncoronary (NC) left (L) cusps are seen within the aortic root. The arrows indicate the points of adherence of the cusps to the aortic wall. The right ventricle (RV) is seen anteriorly; the right atrium (RA), and left atrium (LA) are seen posteriorly. Middle frame, Same patient, with open valve leaflets in systole, shows fusion between the right and left coronary cusps. The fused raphe (arrow) between these cusps is typical of a bicuspid aortic valve. Right frame, Taken in systole from another patient with a bicuspid aortic valve, this frame demonstrates similar features but with a fused raphe (arrow) between the right and noncoronary cusps.

accurate than the instantaneous gradient when compared with the pressures found at cardiac catheterization. Management decisions often depend on estimation of the severity of obstruction, and all pressure gradient estimations depend on flow velocity across the valve, which may be confounded by low cardiac output or concomitant valvar regurgitation. Thus, an important argument can be made that the determination of the stenotic valve systolic area is often more important than calculation of a systolic gradient.[279] [280] [281] The most widely accepted technique for correcting the gradient for flow is to use the continuity equation, which measures the flow velocity ratio across the aortic valve and therefore corrects for high and low flow rates. The continuity equation presumes that for flow in a series, the product of mean velocity and cross-sectional area is constant at all points in the flow circuit. In patients with aortic stenosis, the area of the left ventricular outflow tract is determined by two-dimensional echocardiography, the flow velocity of the outflow tract by pulsed-wave Doppler, and the flow velocity immediately above the valve by continuous-wave Doppler, all of which, taken together, allow determination of the valve area by the continuity equation: Aortic valve area: [(area)LVOT × V(LVOT)]/(V)AV (obtained by converting the diameter to area and assuming that it is circular); (V)LVOT = peak outflow tract velocity, and (V)AV = peak velocity across the aortic valve. Transesophageal two-dimensional echocardiographic determination of aortic valve area has been applied in adults with aortic stenosis.[282] The approach offers considerably better resolution of cardiac anatomy than does conventional transthoracic two-dimensional echocardiography and may also prove to be more accurate in estimating pressure gradients and aortic valve areas. The approach is applicable to

older children but has not yet been reported in young children in sufficient detail to make specific recommendations. Diagnostic Cardiac Catheterization

Cardiac catheterization is now rarely used to establish the site and severity of obstruction to left ventricular outflow because the malformation is readily diagnosed and the evaluation of the intensity of stenosis is accurate by echo-Doppler examination.[283] Instead, catheterization is undertaken when therapeutic interventional transcatheter balloon aortic valvuloplasty is indicated. During the catheterization procedure, cardiac output is measured by the indicator-dilution, thermodilution, or Fick technique. Retrograde left heart catheterization allows withdrawal pressure recordings across the site of stenosis, and left ventricular angiocardiography can be carried out, permitting an evaluation of the size of the left ventricular cavity, the thickness of the wall, the competence of the mitral valve, the patency of the coronary arteries, and the diameter of the aortic root and ascending aorta. If aortic insufficiency is thought to be present, cineaortography is performed with injection of contrast material into the aortic root. The severity of aortic insufficiency can be assessed qualitatively by cineaortography and quantitatively by ventriculography, with calculation of regurgitant volume by subtraction of net forward flow (calculated by the Fick method) from angiographically determined total forward flow. The typical angiocardiographic features of valvar stenosis are thickening of the aortic cusps, poststenotic dilation of the ascending aorta, and, occasionally, a jet of contrast material entering the ascending aorta through a central or eccentric narrowed valve orifice (Fig. 43-33) . The leaflets of the bicuspid valve are domed in systole, and a central jet corresponds to the orifice of the stenotic valve. In contrast, the stenotic orifice of the unicommissural valve can be visualized by the systolic jet in contact with the posterior wall of the aorta, with leaflet tissue and valve motion seen only anteriorly.[259] Balloon Valvuloplasty.

Balloon dilatation may be indicated in any infant or child who has a clinical diagnosis of aortic stenosis and in whom the clinical examination, roentgenogram, resting or exercise ECG, or Doppler echocardiogram suggests the possibility of severe obstruction.[284] Even in the absence of such findings, balloon valvuloplasty may be performed if symptoms that might be related to aortic stenosis exist, such as dizziness, fainting, or angina. We prefer to catheterize the left side of the heart via a retrograde approach by femoral percutaneous puncture. The goals of the study are to analyze the severity of obstruction and assess the function of the left ventricle. In most centers, balloon valvuloplasty is recommended if the severity of the aortic stenosis would otherwise require surgical treatment--that is, a peak systolic pressure gradient exceeding 70 mm Hg measured in the basal state or a calculated effective orifice less than 0.5 cm 2 /m 2 of body surface area. In the

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Figure 43-33 A, Left ventricular angiocardiogram obtained by the transseptal method in a patient with congenital valvular aortic stenosis. Ao = poststenotic dilatation of the aorta; LV = left ventricle. Arrow denotes the thickened valve cusp. B, Selective angiocardiogram in a patient with discrete subvalvular stenosis (bottom arrow). Associated mitral regurgitation is evident from the reflux of contrast material into an enlarged left atrium (LA). The aortic valve (top arrow) is normal, and the right coronary artery is visualized. (From Friedman WF, Kirkpatrick SE: Congenital aortic stenosis. In Adams FH, Emmanouilides GC, Riemenschneider TA, et al: Moss' Heart Disease in Infants, Children, and Adolescents. 4th ed. Baltimore, © Williams & Wilkins, 1989.)

presence of symptoms or left ventricular strain pattern on the ECG or an abnormal exercise ECG, there is less rigid regard to the hemodynamic assessment of the severity of stenosis. Further, some centers go forward with balloon valvuloplasty with peak systolic gradients greater than or equal to 50 mm Hg. There is general agreement that there be no significant aortic regurgitation (less than grade 2 of 4) and that other associated cardiac anomalies be absent, except aortic coarctation. Balloon dilatation of the aortic valve began in the mid-1980s; truly long-term follow-up studies are not yet available. Early studies and our experience suggest that the diameter of the balloon should not exceed that of the aortic valve ring. Most centers prefer a balloon with a diameter 80 to 100 percent that of the aortic annulus or at least 1 mm smaller than it. The expected hemodynamic result is a reduction in the catheterization-measured peak-to-peak ejection gradient of about 60 to 70 percent. The appearance of aortic regurgitation or its progression is the major complication of valvuloplasty, although the aortic regurgitation is mild in the great majority of patients.[284] Significant aortic regurgitation appears to accompany the development of aortic valve prolapse, which is likely due to tearing of the valve cusp or its raphe or partial detachment of the valve from the valve ring, all of which undermine the support mechanism of the valve. In those patients whose balloon valvuloplasty has resulted in very significant aortic regurgitation, valve surgery may be required to either replace the valve or repair a tear in the valve. Other complications from balloon aortic valvuloplasty include bleeding, arrhythmias, cerebral vascular accidents, iliofemoral arterial complications, injury to the mitral valve, and, rarely beyond infancy, death.[284] Natural History.

Congenital aortic stenosis frequently is a progressive disorder, even early in life, in a significant fraction of patients presenting initially with mild obstruction.[285] [286] [287] Thus, clinical deterioration may be anticipated because of an intensification in the severity of stenosis rather than the development of significant aortic regurgitation. Progression of obstruction usually is the result of the increase in cardiac output that occurs concurrently with increased body growth. Less often, a decrease in the area of the orifice is an added factor in the intensification of obstruction. The onset of symptoms or changes in the phonocardiogram or graphic pulse tracings, chest roentgenograms, ECGs, or vectorcardiograms cannot be depended on to indicate progressive obstruction in the

individual patient; Doppler echocardiography is most reliable. MANAGEMENT.

A malformed aortic valve is a potential site of bacterial infection; antibiotic prophylaxis is recommended for all patients, regardless of the severity of obstruction. Strict avoidance of strenuous physical activity is advised if severe aortic stenosis is present. Participation in competitive sports also should probably be restricted in patients with milder degrees of obstruction. Digitalis should be administered to patients who have symptoms of diminished cardiac reserve and also should be considered for patients with left ventricular hypertrophy, even if they are not in heart failure. Surgery.

Percutaneous balloon aortic valvuloplasty is a useful palliation to delay open valvulotomy, the Ross procedure (see below), or valve replacement. For those patients in whom balloon valvuloplasty is unsuccessful, operation is carried out under direct vision after institution of cardiopulmonary bypass, and the fused commissures are opened. When this is done precisely and judiciously, the commissural incision enlarges the valve orifice and does not result in significant aortic regurgitation.[288] When operation is performed in childhood, a mortality rate of less than 2 percent can be expected.[289] Among the factors influencing the indications, techniques, and results of operation are the patient's age, the nature of the valvar deformity, and the experience of the surgical team. Long-term follow-up studies indicate that aortic valvotomy is a safe and effective means of palliative treatment with excellent relief of symptoms.[289] [290] Aortic insufficiency can occasionally be progressive and require valve replacement. Moreover, after commissurotomy, the valve leaflets remain somewhat deformed, and it is likely that further degenerative changes, including calcification, will lead to significant stenosis in later years.[259] Thus, prosthetic valve replacement is required in approximately 35 percent of patients within 15 to 20 years of the original operation. Because the valve is not rendered normal, antibiotic prophylaxis is indicated in postoperative patients, even if the systolic pressure gradient has been abolished. For those patients eventually requiring aortic valve replacement, the surgical options include replacement with a prosthetic aortic valve, an aortic homograft, or a pulmonary autograft in the aortic position. Accumulating evidence shows that the pulmonary autograft may ultimately be preferable to the aortic homograft for aortic reconstruction, and many surgeons

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prefer the procedure to palliative surgical valvotomy as the initial operation of choice. In the pulmonary autograft, called the Ross procedure, the patient's pulmonary valve is removed and used to replace the diseased aortic valve, and the right ventricular outflow tract is reconstructed with a pulmnary valve allograft. [291] [292] [293] [294] We consider it likely that the Ross procedure will emerge as the approach of choice in the future. Neither

homografts nor autografts require anticoagulation. There is a finite incidence of valve degeneration of approximately 2 percent per patient per year with the former, whereas primary tissue failure has not been observed among pulmonary autografts. Discrete Subaortic Stenosis (See also p. 1599)

This malformation accounts for 8 to 10 percent of all cases of congenital aortic stenosis and occurs twice as frequently in males as in females. The lesion consists of a membranous diaphragm or fibrous ring encircling the left ventricular outflow tract or a long fibromuscular narrowing just beneath the base of the aortic valve. Subaortic stenosis is rarely diagnosed in infancy, when it is usually the result of a malalignment VSD with deviation posteriorly of the outlet septum into the left ventricular outflow tract, often associated with coarctation of the aorta or interruption of the aortic arch. Distinction of subvalvular from valvular aortic stenosis is extremely difficult by means of clinical findings alone.[259] Rarely, a systolic ejection sound is heard, and the diastolic murmur of aortic regurgitation is more common than it is in valvular aortic stenosis. Dilatation of the ascending aorta is common, but valvular calcification is not observed. Echocardiography is useful in differentiating between valvular and subvalvular stenosis (see Chap. 7 ).[295] The criterion for diagnosis of the latter is demonstration of a localized subvalvar discrete ridge or long segment narrowing in the left ventricular outflow tract. Further, because of the possibility of recurrence of subvalvular aortic stenosis, careful postoperative follow-up echocardiography is required. Two-dimensional echocardiographic studies from the apical two-chamber and left parasternal and subxiphoid long-axis views demonstrate persistent, prominent echoes in the subaortic left ventricle in both systole and diastole (Fig. 43-34) . Doppler sampling proximal to the aortic valve shows increased flow velocity.[295] Most important, echocardiography also can identify hypertrophic subaortic stenosis when it coexists with fixed subaortic stenosis and can differentiate between the two forms of obstruction. Definitive distinction between valvular and subvalvular obstruction is also provided by transesophageal Doppler echocardiography[296] and by recording pressure tracings as a catheter is withdrawn across the outflow tract and valve, or by localizing the site of obstruction with selective left ventricular angiocardiography (see Fig. 43-33 ). Mild degrees of aortic valvular regurgitation commonly are observed in patients with discrete subaortic stenosis and appear to be caused by thickening of the valve and impaired mobility of the cusps secondary to the trauma created by the high-velocity jet passing through the subaortic diaphragm. Further deformation of these abnormal valve cusps by the vegetations of bacterial endocarditis often results in severe aortic regurgitation. MANAGEMENT.

Because of the likelihood of both progressive obstruction and aortic regurgitation, the presence of even mild or moderate subaortic stenosis warrants consideration of elective

operation.[297] [298] [299] Reports describe transluminal balloon dilation for discrete subaortic stenosis, but it is unlikely that this palliative approach will be an acceptable alternative, since the relief of obstruction is not

Figure 43-34 Parasternal long axis (P Lax.) view of membranous subaortic stenosis. The ventricular septum (SEPT), right ventricle (RV), left ventricle (LV), and left atrium (LA), as well as the aorta (AO), are seen. The arrows indicate the attachments of the subvalvar membrane to the septum anteriorly and to the mitral valve posteriorly.

likely to be as complete or as long as in those patients undergoing surgical resection. The risks of operation in patients with discrete subaortic stenosis and valvular aortic stenosis are essentially the same. Surgical treatment of discrete subaortic stenosis has evolved from simply excising the membrane or fibrous ridge to adding a generous ventricular myotomy and myectomy to the membranectomy.[300] Operation may be expected to improve the hemodynamic state substantially; it frequently is totally curative. Evidence indicates that muscle resection combined with membrane excision lowers the risk of reoperation for recurrent subaortic stenosis. [301] Discrete membranous subaortic stenosis may tend to recur after operation, although we and others consider these recurrences to be often related, at least in part, to incomplete removal of the lesion at initial operation. Intraoperative echocardiography has been used as an adjunct to operation to enable immediate assessment of the adequacy of relieving obstruction. Studies have suggested that abnormal flow patterns may predispose to pathological proliferation of subvalvar aortic tissue, which reinforces the requirement that careful echocardiographic and surgical exploration of the outflow tract, even well below the subvalvar stenosis, be undertaken to detect and resect structures that cause turbulence.[302] For patients with recurrent obstruction, operation may consist of repeat resection plus creation of an outlet VSD extending up to but not across the aortic valve. This iatrogenic VSD is patched on the right side to further enlarge the subaortic area. For patients in whom the aortic valve cannot be repaired, the Ross pulmonary valve autograft procedure is used.[303] UNCOMMON FORMS OF SUBAORTIC STENOSIS

COMBINED VALVULAR AND SUBVALVULAR STENOSIS.

In some patients, valvular and subvalvular aortic stenosis coexist with hypoplasia of the aortic valve ring and thickened valve leaflets, producing a tunnel-like narrowing of the left ventricular outflow tract. Additional findings often include a small ascending aorta. The subvalvular fibrous process usually extends onto the aortic valve cusps and almost always makes contact with the ventricular aspect of the anterior mitral leaflet at its base. The presence of "tunnel stenosis" may be suspected echocardiographically or angiographically from the appearance of the outflow tract and the aortic root. Operative treatment often is complicated by the need for an aortoventriculoplasty, consisting of

prosthetic or homograft replacement of the aortic valve as well as enlarging the aortic annulus, proximal aorta, and left ventricular outlet tract (the Kono-Rastan operation). The modified Kono-Rastan operation preserves the native aortic valve if the annulus is normal or near normal. Alternatively, a conal enlargement technique may be used.[304] [305]

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Various anatomical lesions other than a discrete membrane or ridge may produce subaortic stenosis.[306] [307] [308] Among these are abnormal adherence of the anterior leaflet of the mitral valve to the left septal surface, and the presence in the left ventricular outflow tract of accessory endocardial cushion tissue. In some patients with an AV canal, the part of the ventricular septum that contributes to the wall of the left ventricular outflow tract is deficient, and the ventricular aspect of the anterior leaflet of the common AV valve is adherent to the posterior edge of the deficient septum, resulting in a narrow left ventricular outflow tract. Malalignment of the conoventricular septum, resulting in an inferior VSD, produces a leftward superior deviation and insertion of the conal septum, obstructing left ventricular outflow. In patients with a single ventricle and an outflow chamber, the bulboventricular foramen serves as a potential site of aortic outflow obstruction. Additionally, rarer causes of subaortic stenosis include redundant dysplastic left AV valve tissue in patients with congenitally corrected transposition of the great arteries and anomalous muscle bundles of the left ventricular outflow tract. MUSCULAR SUBAORTIC STENOSIS.

A muscular type of subaortic stenosis may result from a convergence of all the mitral chordae into one or two fused papillary muscles; a "parachute" deformity of the mitral valve is produced, and it is often seen in association with supravalvular stenosis of the left atrium and coarctation of the aorta. In some of these patients, discrete membranous subvalvular aortic obstruction also has been noted. In patients with VSD, muscular subaortic stenosis has been shown to develop after surgical banding of the pulmonary artery, possibly as a result of hypertrophy of the conal septum or crista supraventricularis encroaching on the left ventricular outflow tract above the septal defect. Subaortic muscular hypertrophy secondary to diffuse involvement of the myocardium by glycogen storage disease (Pompe's disease) is an extremely rare cause of obstruction to left ventricular outflow. A positive family history, symptoms of muscle weakness, heart failure in infancy, and the characteristic ECG findings of a short PR interval, high-voltage QRS and T waves, and left ventricular hypertrophy warrant skeletal muscle biopsy or fibroblast culture, permitting an antemortem diagnosis. The last, relatively uncommon form of subaortic stenosis to be mentioned occurs infrequently in patients with congenitally corrected transposition of the great arteries; in

these patients, an anomalous muscle bundle in the subaortic area of the arterial ventricle obstructs outflow. Supravalvular Aortic Stenosis

Supravalvular aortic stenosis is a congenital narrowing of the ascending aorta that may be localized or diffuse, originating at the superior margin of the sinuses of Valsalva just above the levels of the coronary arteries. The clinical picture of supravalvular obstruction usually differs in major respects from that observed in the other forms of aortic stenosis. Chief among these differences is the association of supravalvular aortic stenosis with idiopathic infantile hypercalcemia, a disease that occurs in the first years of life and may be associated with deranged vitamin D metabolism.[309] [310] [310A] [311] [312] It is helpful to classify patients according to their clinical presentation into nonfamilial, sporadic cases with normal facies and intelligence; autosomal dominant familial cases with normal facies and intelligence; and the Williams syndrome with abnormal facial appearance and mental retardation (Fig. 43-35) . In contrast to the other forms of aortic stenosis, no gender predilection is noted in any of these three categories. WILLIAMS SYNDROME.

The designations supravalvular aortic stenosis syndrome or Williams syndrome or Williams-Beuren syndrome[310] [310A] have been applied to the distinctive picture produced by coexistence of the cardiac and multiple-system disorders. Beyond infancy in these patients, a challenge with vitamin D or calcium loading tests unmasks abnormalities in the regulation of circulating 25-hydroxyvitamin D. Unanimity of opinion about the exact relation between Williams syndrome and calcium metabolism does not exist[311] [312] . Infants with Williams syndrome often exhibit feeding difficulties, failure to thrive, and gastrointestinal problems in the form of vomiting, constipation, and colic. The entire spectrum of clinical manifestations includes auditory hyperacusis, inguinal hernia, a hoarse voice, and a typical personality that is outgoing and engaging. Other manifestations of this syndrome include mental retardation, "eifin facies" (see Fig. 43-32 ), narrowing of peripheral systemic and pulmonary arteries, strabismus, and abnormalities of dental development consisting of microdontia, enamel hypoplasia, and malocclusion[312A] . Many medical conditions can complicate the course of Williams syndrome,[312B] including systemic hypertension, gastrointestinal problems, and urinary tract abnormalities. Particularly in an older child or adult, progressive joint limitation and hypertonia may become a problem. Adult patients are usually handicapped by their developmental disabilities. Williams syndrome was previously considered to be nonfamilial. Interestingly, a number of families in which parent-to-child transmission of Wllliams syndrome has occurred

have now been identified. These are not families with autosomal dominant supravalvular aortic stenosis whose members are normal in appearance and intelligence. All of these families show a parent and child to be affected with Williams syndrome, including one instance of male-to-male transmission. This supports autosomal dominant inheritance as the likely pattern, with most cases of Williams syndrome probably occurring as the result of a new mutation. New information indicates that a genetic defect for supravalvular aortic stenosis is located in the same chromosomal subunit as elastin on chromosome 7.[312B] [313] Elastin is an important component of the arterial wall, but precisely how mutations in elastin genes cause the phenotypes of supravalvular aortic stenosis is not known for certain. The various aspects of Williams syndrome may represent a contiguous gene deletion syndrome (see Chap. 56 ). FAMILIAL AUTOSOMAL DOMINANT PRESENTATION.

Most commonly, supravalvular aortic stenosis is a feature of the distinctive Williams syndrome described earlier.[312A] [312B] However, the aortic anomaly and peripheral

Figure 43-35 Typical elfin facies in three patients with supravalvular aortic stenosis. (From Friedman WF, Kirkpatrick SE: Congenital aortic stenosis. In Adams FH, Emmanouilides GC, Riemenschneider TA, et al: [eds]: Moss' Heart Disease in Infants, Children, and Adolescents. 4th ed. Baltimore, © Williams & Wilkins, 1989.)

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pulmonary arterial stenosis are also found in familial and sporadic forms unassociated with the other features of the syndrome. Thus, affected patients have normal intelligence and are normal in facial appearance. Genetic studies suggest that when the anomaly is familial, it is transmitted as autosomal dominant with variable expression. Some family members may have peripheral pulmonary stenosis either as an isolated lesion or in combination with the supravalvular aortic anomaly. Linkage analyses in two unrelated families with autosomal dominant supravalvular aortic stenosis were performed. Linkage was identified between the supravalvular aortic stenosis phenotype and polymorphic markers on the long arm of chromosome 7. These findings indicate that the gene for supravalvular aortic stenosis is located in the same chromosomal subunit as elastin. Further, a family has been identified as having autosomal dominant supravalvular aortic stenosis and a balanced translocation, which disrupts the elastin gene and cosegregates with the disease in this family, also supporting the hypothesis that mutations in the elastin gene may cause supravalvular aortic stenosis.[314] Hemizygosity at the elastin locus is likely responsible for the vascular pathology in Williams syndrome, although it is unlikely that elastin deletions account for all features of the syndrome. Because the deletions responsible for Williams syndrome extend well beyond the elastin locus, it is probable that the syndrome is a contiguous gene disorder.

MORPHOLOGY.

Three anatomical types of supravalvular aortic stenosis are recognized, although some patients may have findings of more than one type. Most common is the hourglass type, in which marked thickening and disorganization of the aortic media produce a constricting annular ridge at the superior margin of the sinuses of Valsalva. The membranous type is the result of a fibrous or fibromuscular semicircular diaphragm with a small central opening stretched across the lumen of the aorta. Uniform hypoplasia of the ascending aorta characterizes the hypoplastic type.[315] Because the coronary arteries arise proximal to the site of outflow obstruction in supravalvular aortic stenosis, they are subjected to the elevated pressure that exists within the left ventricle. These vessels often are dilated and tortuous, and premature coronary arteriosclerosis has been observed. Moreover, if the free edges of some or all of the aortic cusps adhere to the site of supravalvular stenosis, coronary artery inflow may be reduced. The formation of thoracic aortic aneurysms has been described in several patients. CLINICAL FEATURES.

Patients with Williams syndrome are mentally retarded and resemble one another in their facial features. The typical appearance is similar to that of the elfin facies observed in the severe form of idiopathic infantile hypercalcemia and is characterized by a high prominent forehead, stellate or lacy iris patterns, epicanthal folds, underdeveloped bridge of the nose and mandible, overhanging upper lip, strabismus, and anomalies of dentition (see Fig. 43-35 ). Recognition of this distinctive appearance, even in infancy, should alert the physician to the possibility of underlying multisystem disease. In addition, a positive family history in a patient with a normal appearance and clinical signs suggesting left ventricular outflow obstruction should lead to the suspicion of either supravalvular aortic stenosis or hypertrophic obstructive cardiomyopathy. Patients with supravalvular aortic obstruction appear to be subject to the same risks of unexpected sudden death [in some of whom myocardial infarction has been found at autopsy[316] ] and endocarditis as those with valvular aortic stenosis. Studies of the natural history of the principal vascular lesions in these patients[317] --supravalvular aortic stenosis and peripheral pulmonary artery stenosis--indicate that the aortic lesion is usually progressive, with an increase in the intensity of obstruction related often to poor growth of the ascending aorta. In contrast, the patients with pulmonary branch stenosis, whether or not associated with the aortic lesion, tend to show no change or a reduction in right ventricular pressure with time. With few exceptions, the major physical findings resemble those observed in patients with valvular aortic stenosis. Among these exceptions are accentuation of aortic valve closure due to elevated pressure in the aorta proximal to the stenosis, an infrequent systolic ejection sound, and the especially prominent transmission of a thrill and murmur into the jugular notch and along the carotid vessels. Found uncommonly is an early

diastolic, decrescendo, blowing murmur of aortic regurgitation caused by the fusion of one or more cusps to the area of stenosis. The narrowing of the peripheral pulmonary arteries that often coexists in these patients frequently produces a late systolic or continuous murmur that may help to distinguish this anomaly from valvular aortic stenosis. This differentiation is reinforced by the frequent finding of a significant disparity between the arterial pressures in the upper extremities in supravalvular aortic stenosis; the systolic pressure in the right arm tends to be the higher than in the left and occasionally exceeds that in the femoral arteries. The disparity in pulses may relate to the tendency of a jet stream to adhere to a vessel wall (Coanda effect) and selective streaming of blood into the innominate artery.[318] [319] ECG usually reveals left ventricular hypertrophy when obstruction is severe. Biventricular or even right ventricular hypertrophy may be found if significant narrowing of peripheral pulmonary arteries coexists. Radiographically, in contrast to valvular and discrete subvalvular aortic stenosis, poststenotic dilation of the ascending aorta seldom is seen. The sinuses of Valsalva usually are dilated, and the ascending aorta and aortic arch appear small or of normal size. Echocardiography is the most valuable technique for localizing the site of obstruction to the supravalvular area (Fig. 43-36) . Most often the sinuses of Valsalva are dilated, and the ascending aorta and arch appear small or of normal size. A useful ratio can be constructed of the measurements of the aortic annulus and the sinotubular junction, in which the latter is always less than the former in patients with supravalvular stenosis, a finding not present in normal persons.[320] Intraluminal ultrasound imaging has also been used to visualize the vascular pathology in Williams syndrome.[321] Doppler examination and retrograde aortic catheterization can determine the degree of hemodynamic abnormality.[322] Because of the nature of the anatomical defect, we do not think that transcatheter balloon angioplasty,[323] with or without stenting, is an effective treatment option. For several reasons, depending primarily on the anatomical variant of the lesion, supravalvular aortic stenosis may be less amenable to operative treatment than either valvular or discrete subvalvular stenosis. The lumen of the aorta at the supravalvular level may be widened by the insertion of an oval- or diamond-shaped fabric prosthesis or pericardial symmetric aortoplasty in those patients with a normal or near-normal ascending aorta. If the aorta is markedly hypoplastic, however, this operation merely displaces the pressure gradient distally without abolishing the obstruction.

Figure 43-36 Supravalvar aortic stenosis is seen in a parasternal long-axis view. The constriction is distal to the sinuses of Valsalva in the ascending aorta (AAO). RV = right ventricle; LV = left ventricle; LA = left atrium.

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Under these circumstances, repair may require replacement or widening of the entire

hypoplastic aorta with an appropriate prosthesis.[324] [325] [326] [327] Hypoplastic Left Heart Syndrome

This designation is used to describe a group of closely related cardiac anomalies characterized by underdevelopment of the left cardiac chambers, atresia or stenosis of the aortic and/or the mitral orifices, and hypoplasia of the aorta. [327] These anomalies are an especially common cause of heart failure in the first week of life. The left atrium and ventricle often exhibit endocardial fibroelastosis. Pulmonary venous blood traverses a patent foramen ovale, and a dilated and hypertrophied right ventricle acts as the systemic, as well as pulmonary, ventricle; the systemic circulation receives blood by way of a patent ductus arteriosus (Fig. 43-37) (Figure Not Available) . The diagnosis should be considered in infants, particularly boys, with the sudden onset of heart failure, systemic hypoperfusion, and nonspecific murmur. ECG frequently reveals right-axis deviation, right atrial and ventricular enlargement, and ST and T wave abnormalities in the left precordial leads. Chest roentgenography may show only slight enlargement shortly after birth, but with clinical deterioration there are marked cardiomegaly and increased pulmonary venous and arterial vascular markings. The echocardiographic findings usually are diagnostic (Fig. 43-38) . The aortic root is usually diminutive, less than 4 to 5 mm in diameter at the level of the sinuses of Valsalva and narrowed farther above. The left ventricle is frequently absent or is a small slit with a diminutive mitral valve. The endocardium is often thickened, consistent with endocardial fibroelastosis or papillary muscle infarction, features usually more suggestive of aortic stenosis. Indeed, distinction from the latter is pivotal to determine if a biventricular, rather than a Fontan, approach is feasible. Ultrasound study also determines the extent of patency of the interatrial communication; substantial restriction is predictive of Figure 43-37 (Figure Not Available) Hypoplastic left heart with aortic hypoplasia, aortic valve atresia, and a hypoplastic mitral valve and left ventricle. RA = right atrium; RV = right ventricle; RC = right coronary artery; PA = pulmonary artery; PV = pulmonary vein; LC = left coronary artery; LV = left ventricle; AD = anterior descending coronary artery. (From Neufeld HN, Adams P Jr, Edwards JE, et al: Diagnosis of aortic atresia by retrograde aortography. Circulation 25:278, 1962.)

severe pulmonary edema and death. Retrograde aortography shows hypoplasia of the ascending aorta. MANAGEMENT.

Medical therapy directed at cardiac decompensation, hypoxemia, and metabolic acidemia seldom prolongs survival beyond the first days of life.[328] Constriction of the patent ductus arteriosus and limited flow

Figure 43-38 Left, Four-chamber view of hypoplastic left heart syndrome demonstrating the right ventricle (RV) anteriorly, considerably larger than the diminutive left ventricle (LV) seen posteriorly. A small mitral valve (MV) separates the left atrium (LA) from the left ventricle. The apex of the heart is formed by the right ventricle. Right, Parasternal long-axis view demonstrating the discrepant relative sizes

between the right ventricle and the left heart chambers. The aorta (AO) is diminutive and measures approximately 4 mm in diameter. The larger pulmonary valve plate is seen anteriorly. A small platelike mitral valve (MV, dashed arrow) is seen between the left atrium and left ventricle.

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through a restrictive patent foramen ovale are the principal factors responsible for early death. Prostaglandin E1 infusion is effective in maintaining ductal patency. SURGICAL TREATMENT.

Many centers are attempting staged surgical management in an effort to provide long-term palliation.[329] [330] The first stage, often referred to as Norwood procedure, consists of creating an unobstructed communication between the right ventricle and aorta and enlargement of the ascending aorta. The right ventricular-aortic connection has been accomplished with homograft or prosthetic conduits from the right ventricle or pulmonary trunk to the descending aorta, or by direct connection between the proximal pulmonary trunk and ascending aorta, which also enlarges the ascending aorta. Pulmonary blood flow and pressure are controlled by a tubed interposition systemic-pulmonary shunt to the distal pulmonary artery. The patent ductus arteriosus is ligated. A large interatrial communication also must be ensured in stage 1 to allow free access of pulmonary venous blood to the tricuspid valve. Most surgeons prefer to perform a stage 2 modified superior vena cava-pulmonary artery shunt (bidirectional Glenn operation) or a hemi-Fontan procedure as an intermediate step before a Fontan correction (stage 3). In some centers, the preferred operation is cardiac transplantation.[331] [332] Stenting of the ductus arteriosus can be used as an ambulatory bridge to transplantation.[333] Congenital Aortic Regurgitation

Congenital aortic valve regurgitation is a rare isolated congenital cardiac lesion.[334] [345] Aortic regurgitation most often occurs in association with congenital valvular aortic stenosis in which the valve commissures are fused, inhibiting cusp mobility; subvalvular aortic stenosis in which the aortic ring is dilated and the valve cusps are deformed; coarctation of the aorta when the aortic ring is dilated and the aortic valve is bicuspid; VSD; and endocardial fibroelastosis. Aortic valve regurgitation may accompany various complex cardiac anomalies and also may accompany aortic sinus aneurysm or be secondary to dilatation of the ascending aorta in patients with Marfan syndrome, Turner syndrome, cystic medial necrosis, or osteogenesis imperfecta, in which the aortic lesions are manifestations of the underlying connective tissue disorder. Severe aortic regurgitation also may occur through channels other than the aortic valve.[336] Thus, aortic-left ventricular tunnel is a rare anomaly that must be distinguished from congenital aortic valve regurgitation, because the approach to management of the former usually does not include consideration for prosthetic valve replacement. The

aortic-left ventricular tunnel is an abnormal channel beginning in the ascending aorta above the right coronary orifice and ending in the left ventricle below the right aortic cusp. The channel usually passes behind the right ventricular infundibulum and through the ventricular septum. Echocardiography, Doppler studies, and aortography combine to establish a precise diagnosis. Exercise testing[337] and magnetic resonance velocity mapping[338] are useful to assess the severity of the lesion. In infants and children with congenital aortic regurgitation, the severity of regurgitation increases with time, and valve replacement rather than plication is almost always necessary to correct the lesion. Operation should be deferred until symptoms, signs, and noninvasive assessment dictate its necessity.[339] Conversely, closure of an aortic-left ventricular communication is advisable before progressive dilation of the aortic annulus creates secondary changes in the aortic valve itself, which may necessitate aortic valve replacement. Pulmonary Vein Atresia and Stenosis

Pulmonary vein atresia is a rare anomaly in which the pulmonary veins do not connect with the heart or with a major systemic vein. The lesion is incompatible with life, but infants may survive for days, probably because communications exist between the pulmonary veins and the bronchial or esophageal veins and allow limited egress for pulmonary venous blood. Pulmonary vein stenosis may occur as a focal stenosis at the atrial junction or generalized hypoplasia of one or more pulmonary veins. The incidence of associated cardiac malformations is extremely high, including atrial septal defect, tetralogy of Fallot, tricuspid and mitral atresia, and endocardial cushion defect. The severe pulmonary vein obstruction imposed by pulmonary vein abnormalities causes severe cyanosis, congestive cardiac failure, and early death. Focal stenosis of one or more pulmonary veins at the atrial junction, recognized by two-dimensional echocardiography, magnetic resonance imaging, or angiography, may be relieved surgically. Results of transcutaneous balloon angioplasty have been disappointing. Cor Triatriatum

In this malformation, failure of resorption of the common pulmonary vein results in a left atrium divided by an abnormal fibromuscular diaphragm into a posterosuperior chamber receiving the pulmonary veins and an anteroinferior chamber giving rise to the left atrial appendage and leading to the mitral orifice.[340] The communication between the divided atrial chambers may be large, small, or absent, depending on the size of the opening in the subdividing diaphragm, which determines the degree of obstruction to pulmonary venous return. Elevations of both pulmonary venous pressure and pulmonary vascular resistance result in severe pulmonary artery hypertension. The diagnosis is established by two-dimensional or transesophageal echocardiography[341] [342] ; cardiac catheterization and angiography are necessary only if major associated cardiac anomalies are suspected. The obstructive membrane is visualized in the parasternal long- and short-axis and four-chamber (Fig. 43-39) views and can be distinguished from a supravalvular mitral ring[343] by its position superior to the left atrial appendage, which forms part of the distal chamber. Also present are

diastolic fluttering of the mitral leaflets and high-velocity flow detected by Doppler examination in the distal atrial chamber and at the mitral orifice. The diagnosis should be suspected at cardiac catheterization if the pulmonary arterial wedge pressure is higher than a simultaneous left atrial pressure. The diagnosis also may be established by visualizing the obstructing lesion angiographically. Although rare, the malformation is important to recognize because it may be easily correctable at operation.[344] Congenital Mitral Stenosis

Anatomical types of mitral stenosis include the parachute deformity of the valve, in which shortened chordae tendineae converge and insert into a single large papillary muscle; thickened leaflets with shortening and fusion of the chordae tendineae; an anomalous arcade of obstructing papillary muscles; accessory mitral valve tissue; and a supravalvular circumferential ridge of connective tissue arising at the base of the atrial aspect of the mitral leaflets.[345] [346] Associated cardiac defects are common, including endocardial fibroelastosis, coarctation of the aorta, patent ductus arteriosus, and left ventricular outflow tract obstruction. Two-dimensional echocardiography, combined with Doppler studies, often provides a complete analysis of the anatomy and function of congenital left ventricular inflow lesions.[346] The clinical and hemodynamic consequences of isolated congenital mitral stenosis are similar to those of acquired mitral obstruction, with modifications imposed by coexisting anomalies. The prognosis is poor; symptoms attributable to pulmonary vein obstruction usually begin in infancy, and the majority of patients expire before age 1 year unless catheter balloon dilation or operation is successful.[347] [348] Conduit bypass of the mitral valve and prosthetic valve replacement are required if a reparative operation is not possible.[349] [350] The use of a porcine bioprosthesis is contraindicated because of its rapid degeneration in an infant or young child.

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Figure 43-39 Echocardiograms demonstrating the membrane (M) of cor triatriatum. The apical four-chamber view (top panel) shows the membrane lying within the left atrial chamber. The atrial appendage is distal to the membrane, and the pulmonary veins drain into the proximal portion. The parasternal long-axis view (center panel) shows the membrane posterior to the aortic root (Ao) and mitral valve, dividing the left atrium into two chambers. In the parasternal short-axis view (bottom panel), the membrane is within the left atrium close to the posterior aortic root. RA = right atrium; RV = right ventricle; LV = left ventricle. Congenital Mitral Regurgitation

The syndrome of mitral valve prolapse is discussed in Chapter 46 . This condition usually is quite benign in children.[351] [352] However, occasional difficulties exist with

infective endocarditis, arrhythmias, atypical chest pain, and sudden death. Isolated congenital mitral regurgitation of hemodynamic significance is an unusual lesion in infants and children. MORPHOLOGY.

Congenital malformations of the mitral valve producing insufficiency most often are encountered in association with endocardial cushion defect, congenitally corrected transposition of the great arteries, endocardial fibroelastosis, anomalous pulmonary origin of the coronary artery, congenital subaortic stenosis, hypertrophic obstructive cardiomyopathy, and coarctation of the aorta. Mitral valve dysfunction also is common in various metabolic disorders (e.g., the mucopolysaccharidoses), primary and secondary cardiomyopathies, connective tissue disease (e.g., rheumatoid arthritis, Marfan's syndrome, Ehlers-Danlos syndrome, pseudoxanthoma elasticum), and rheumatic and nonrheumatic inflammatory diseases of the myocardium.[353] The various anatomical lesions that result in isolated congenital mitral regurgitation include prolapse of one or both mitral leaflets, cleft or perforated mitral leaflet, inadequate leaflet tissue, double orifice of the mitral valve, anomalous insertion of chordae tendineae (anomalous mitral arcade), redundant leaflet tissue, displacement inferiorly of the ring of the inferior leaflet into the left ventricle, and abnormal length of the chordae tendineae. CLINICAL FINDINGS.

The clinical, echocardiographic, and hemodynamic findings in patients with isolated congenital mitral incompetence resemble those observed in acquired mitral regurgitation. Mitral annuloplasty (which is preferred) and prosthetic valve replacement are procedures reserved for infants and children who are at least moderately symptomatic despite comprehensive medical treatment, often with repeated episodes of pulmonary infection or with cardiac failure with anorexia and retarded growth and development.[353] Operative candidates are shown by echocardiographic, Doppler, hemodynamic, and angiographic studies to have pulmonary hypertension, a regurgitant fraction in excess of 50 percent, and a marked increase in left ventricular end-diastolic volume. Pulmonary Arteriovenous Fistula

Abnormal development of the pulmonary arteries and veins in a common vascular complex is responsible for this rare congenital anomaly (see also Chap. 44 ). A variable number of pulmonary arteries communicate directly with branches of the pulmonary veins; in some cases, the fistula receives systemic arterial branches. [354] Most patients have an associated Weber-Osler-Rendu syndrome; additional associated problems include bronchiectasis and other malformations of the bronchial tree, as well as absence of the right lower lobe. Venoarterial shunting depends on the extent of the fistulous communications and may result in cyanosis and secondary polycythemia. Paradoxical

emboli and brain abscess may cause major neurological deficits. Patients with hereditary hemorrhagic telangiectasis often are anemic owing to repeated blood loss and may have less obvious cyanosis. Systolic and continuous murmurs are audible over areas of the fistula. Rounded opacities of various sizes in one or both lungs on chest roentgenogram may suggest the presence of the lesion. Pulmonary angiography reveals the site and extent of the abnormal communication. Unless the lesions are widespread throughout both lungs, surgical treatment aimed at removing the lesions with preservation of healthy lung tissue commonly is indicated to avoid the complications of massive hemorrhage, bacterial endocarditis, and rupture of arteriovenous aneurysms. Pulmonary arteriovenous fistulas may also be acquired and the result of surgical creation of cavopulmonary shunts. [355] Transcatheter balloon or plug or coil occlusion embolotherapy may prove to be the therapeutic procedure of choice.[356] Peripheral Pulmonary Artery Stenosis

Stenosis of the pulmonary artery may occur as single or numerous lesions located anywhere from the main pulmonary trunk to the smaller peripheral arterial branches.[357] Associated defects are observed in most patients and include pulmonic valvular stenosis, VSD, tetralogy of Fallot, and supravalvular aortic stenosis. ETIOLOGY.

The most important cause of significant pulmonary artery stenoses producing symptoms in newborns is intrauterine rubella infection.[358] Diagnosis is facilitated in these infants by finding elevations of the IgM fraction and rubella antibody titer. Other cardiovascular malformations commonly found in association with congenital rubella include patent ductus arteriosus, pulmonic valve stenosis, and atrial septal defect. Generalized systemic arterial stenotic lesions also may be a feature of the rubella embryopathy, often involving large and medium-sized vessels such as the aorta and coronary, cerebral, mesenteric, and renal arteries. Cardiovascular lesions are but one manifestation of intrauterine rubella infection because cataracts, microphthalmia, deafness, thrombocytopenia, hepatitis, and blood dyscrasias also are common. Thus, the clinical picture in infants with rubella syndrome depends on the severity of the cardiovascular lesions and the associated abnormalities of other organs and systems.

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Peripheral pulmonary stenosis also often is associated with supravalvular aortic stenosis in patients with the familial form of the latter anomaly or in patients with Williams syndrome.

MORPHOLOGY.

Obstruction within the pulmonary arterial tree may be classified into four types: (1) stenosis of the main pulmonary trunk or the main left or right branch; (2) narrowing at the bifurcation of the pulmonary artery, extending into both right and left branches; (3) numerous sites of peripheral branch stenosis; and (4) a combination of main and peripheral stenosis. Pulmonary artery obstruction may be produced by localized narrowing, diffuse constrictions, or, rarely, a membrane or diaphragm. Poststenotic dilatation is usual when the stenosis is localized but may be absent or minimal with elongated constriction. It should be recognized that a physiological branch pulmonary artery stenosis often is present in normal newborns in whom both right and left main pulmonary arteries are small and arise almost perpendicular from a large main pulmonary artery.[359] The branch vessels increase in size with growth and become less angulated in their takeoff from the main pulmonary artery. CLINICAL FINDINGS.

The degree of obstruction is the principal determinant of clinical severity; the type of obstruction determines the feasibility of direct surgical relief. The clinical features vary; most infants and children are asymptomatic.[360] An ejection systolic murmur heard at the upper left sternal border and well transmitted to the axillae and back is most common. The presence of an ejection sound suggests that pulmonic valve stenosis coexists. The pulmonic component of the second heart sound may be slightly accentuated but occasionally is extremely loud if multiple peripheral stenoses exist. A continuous murmur is audible, especially in patients with main or branch stenosis and particularly if an associated cardiovascular anomaly produces increased pulmonary blood flow. ECG shows right ventricular hypertrophy when obstruction is severe; left-axis deviation with counterclockwise orientation of the frontal QRS vector is common in the rubella syndrome and when the lesion coexists with supravalvular aortic stenosis. Mild or moderate stenosis usually produces normal findings on chest roentgenogram; detectable differences in vascularity between regions of the lungs or dilated pulmonary artery segments are uncommon. When obstruction is bilateral and severe, right atrial and ventricular enlargement may be observed. Diagnosis.

This is confirmed by observing pressure gradients within the pulmonary arterial system at cardiac catheterization; digital subtraction and/or selective pulmonary angiography defines the exact location, extent, and distribution of the lesion (Fig. 43-40) . Mild to moderate unilateral or bilateral stenosis does not require surgical relief; numerous stenotic areas are not amenable to correction, even with intraoperative balloon angioplasty. Well-localized obstruction of severe degree in the main pulmonary artery or its

Figure 43-40 Right ventricular angiocardiogram showing numerous sites of peripheral pulmonic stenosis and poststenotic dilatation of the peripheral pulmonic arteries.

major branches may be alleviated by percutaneous transcatheter balloon angioplasty (see Chap. 38 ),[361] often accompanied by endovascular stent implantation[362] [363] or with a patch graft or bypassed with a tubular conduit. The natural history of peripheral pulmonary stenosis is not clear. Obstruction may increase by discrepant growth between a stenotic area and normal portions of the pulmonary artery tree, or as a result of an increase in cardiac output, especially during adolescence. Rarely, hypertrophy of right ventricular infundibular muscle is progressive and results in hypercyanotic spells. Pulmonic Stenosis with Intact Ventricular Septum (See also p. 1602 )

Valvular pulmonic stenosis, resulting from fusion of the valve cusps during mid- to late intrauterine development, is the most common form of isolated right ventricular obstruction and occurs in about 7 percent of patients with congenital heart disease. Hypertrophy of the septal and parietal bands narrowing the right ventricular infundibulum often accompanies the pulmonic valve lesion, especially if it is severe. Fused cusps of varying thickness and rigidity form a fibrous dome in the severest forms. Pulmonic valve dysplasia, especially common in patients with Noonan's syndrome (see Chap. 56 ), produces obstruction in the absence of adherent leaflets because leaflets are thickened, rigid, and myxomatous and are limited in their lateral movement because of the presence of tissue pads within the pulmonic valve sinuses.[364] NEONATES AND INFANTS.

The clinical presentation and course of circulation in a newborn with pulmonic stenosis depends on the severity of obstruction and the degree of development of the right ventricle and its outflow tract, the tricuspid valve, and the pulmonary arterial tree. The greater the degree of pulmonic valve stenosis, the more closely the manifestations resemble those observed with pulmonary atresia and intact ventricular septum. Severe pulmonic stenosis is characterized by cyanosis caused by right-to-left shunting through the foramen ovale, cardiomegaly, and diminished pulmonary blood flow in the absence of persistent patency of the ductus arteriosus. Hypoxemia and metabolic acidemia rather than right ventricular failure are the main clinical disturbances in symptomatic neonates and can be alleviated temporarily by infusion of prostaglandin E1 to dilate the ductus arteriosus and increase pulmonary blood flow. Distinction of these babies from those with tetralogy of Fallot or tricuspid or pulmonary atresia usually is possible because infants with tetralogy usually do not have roentgenographic evidence of cardiomegaly; infants with tricuspid and pulmonary atresia show a preponderance of left ventricular forces by ECG, in contrast to the right ventricular hypertrophy usually observed with critical pulmonic stenosis in the absence of right ventricular hypoplasia. Combined two-dimensional echocardiographic and continuous-wave Doppler examination (see Chap. 7 ) characterizes the anatomical valve abnormality and its severity and has essentially eliminated the requirement for cardiac catheterization and

angiographic studies to establish a precise diagnosis (Fig. 43-41) .[365] [366] Balloon Valvuloplasty.

Balloon dilatation of the pulmonary valve is the therapeutic procedure of choice,[365] [366] [367] [368] [369] [370] but a pulmonary valvotomy and systemic-to-pulmonary arterial shunt may be necessary in infants with underdevelopment of the right ventricular cavity.[371] In this group, success has been achieved by modification of balloon valvuloplasty with predilation initially using a coronary dilatation catheter to facilitate introduction of a definitive balloon catheter. Transcatheter balloon valvuloplasty can be expected to reduce but not abolish the pressure difference in neonates with mobile doming valves. Sustained relief of the severe obstruction is usual, and so is good growth of the right ventricle. This approach is of lesser efficacy in those patients with dysplastic valves and is contraindicated if valve dysplasia is associated with annular hypoplasia.[372] CHILDREN.

The clinical profile of patients with valvular pulmonic stenosis beyond infancy usually is distinctive.[373] The severity of obstruction is the most important determinant of the clinical course. In the presence of a normal cardiac output, a peak systolic transvalvular pressure gradient between 50 and 80 mm Hg or a peak systolic right ventricular pressure between 75 and 100 mm Hg is considered to be indicative of moderate stenosis; levels below and above that range are classified as mild and severe, respectively. Most patients with mild pulmonic stenosis are asymptomatic, and the condition is discovered during routine examination. In patients with more significant obstruction, the severity of stenosis may increase with time. Progression

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Figure 43-41 Right ventriculogram in an infant with critical pulmonic stenosis shows the thickened, nonmobile pulmonic valve (arrow) in the lateral projection (left). Both the lateral and frontal (right) projections show regurgitation of contrast material across the tricuspid valve into the right atrium (ra), with subsequent shunting across the foramen ovale to the left atrium (la). rv = right ventricle; pa = pulmonary artery. (Courtesy of Dr. Norman Talner).

may be relative and reflect disproportional physical growth of the patient, infundibular narrowing due to progressive hypertrophy of the right ventricular outflow tract, or fibrosis of the valve cusps. Symptoms, when present, vary from mild exertional dyspnea and mild cyanosis to signs and symptoms of heart failure, depending on the degree of obstruction and the level of myocardial compensation. Exertional fatigue, syncope, and chest pain are related to an inability to augment pulmonary blood flow during exercise in some patients with moderate or severe obstruction.

PHYSICAL EXAMINATION.

The severity of obstruction often is suggested by the physical findings. Right ventricular hypertrophy reduces compliance of that chamber, and a forceful right atrial contraction is necessary to augment right ventricular filling. Prominent a waves in the jugular venous pulse, a fourth heart sound, and, occasionally, presystolic pulsations of the liver reflect a vigorous atrial contraction and suggest the presence of severe stenosis. Cardiomegaly and a right ventricular parasternal lift accompany moderate or severe obstruction. A systolic thrill is palpable along the upper left sternal border in all but the mildest forms of stenosis. The first heart sound is normal and is followed by a systolic ejection sound at the upper left sternal edge produced by sudden opening of the stenotic valve; an ejection sound is not heard in patients with pulmonic valve dysplasia. The ejection sound typically is louder during expiration; when it is inaudible or occurs less than 0.08 second from the onset of the Q wave on ECG, severe obstruction is suggested. Right ventricular ejection is prolonged in patients with moderate or severe stenosis, and the sound of pulmonic valve closure is delayed and soft. The characteristic feature of valvular pulmonic stenosis on auscultation is a harsh, diamond-shaped systolic ejection murmur heard best at the upper left sternal border. The systolic murmur becomes louder and its crescendo occurs later in systole, obscuring the aortic component of the second sound with more severe degrees of valvular obstruction because these patients have a greater prolongation of right ventricular systole. The holosystolic decrescendo murmur of tricuspid regurgitation may accompany severe pulmonic stenosis, especially in the presence of congestive heart failure. Cyanosis, reflecting venoarterial shunting through a patent foramen ovale, is absent with mild stenosis and infrequent with moderate obstruction. Cyanosis may not be apparent in patients with severe obstruction if the atrial septum is intact. ELECTROCARDIOGRAPHY.

This technique may be helpful in assessing the degree of obstruction to right ventricular output.[374] In mild cases, the ECG often appears normal, whereas moderate and severe stenoses are associated with right-axis deviation and right ventricular hypertrophy. In the latter patients between ages 2 and 20 years, an estimate of right ventricular pressure can be made by multiplying the height of the R wave in lead V4R or V1 by 5. A tall QR wave in the right precordial leads with T wave inversion and ST segment suppression (right ventricular "strain") reflects severe stenosis. When an rSR pattern is observed in lead V1 (20 percent of patients), lower right ventricular pressures are found than in patients with a pure R wave of equal amplitude. High-amplitude P waves in leads II and V1 indicating right atrial enlargement are associated with severe stenosis. CHEST ROENTGENOGRAPHY.

In patients with mild or moderate pulmonic stenosis, chest roentgenography often shows a heart of normal size and normal pulmonary vascularity (see Chap. 8 ). Poststenotic dilatation of the main and left pulmonary arteries often is evident. Right

atrial and right ventricular enlargement are observed in patients with severe obstruction and resultant right ventricular failure. The pulmonary vascularity may be reduced in patients with severe stenosis, right ventricular failure, and/or a venoarterial shunt at the atrial level. ECHOCARDIOGRAPHY.

Reliable localization of the site of obstruction and assessment of its severity are obtained by combined continuous-wave or pulsed-wave Doppler and two-dimensional echocardiography[375] (see Chap. 7 and Fig. 43-42 ). The latter usually shows prominent pulmonary valve echoes with restricted systolic motion as well as poststenotic dilation of the main pulmonary artery and its branches. In contrast to these findings in classic valvular pulmonic stenosis, patients with a dysplastic valve show thickened and immobile leaflets with hypoplasia of the pulmonary valve annulus and absent poststenotic dilatation of the pulmonary artery. Parasternal and subcostal views are required to detect most accurately maximal pulmonary artery blood flow velocity, which is converted to a pressure difference across the valve using a modified Bernoulli equation (pressure difference [mm Hg] = 4 × the squared peak Doppler velocity [m/sec]) ( Fig 43-42 ). A semiquantitative estimation of pulmonary and tricuspid regurgitation can be

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Figure 43-42 A, Severe valvular pulmonic stenosis seen from a parasternal short-axis view. The thickened pulmonary valve can be seen lying between the right ventricular outflow tract (RVO) and a dilated pulmonary artery (PA). The arrows are at the annulus of the pulmonary valve; the thickened, domed valve can be identified clearly. LV = left ventricle; AO = aorta; LA = left atrium. B, Doppler ultrasound from the subcostal (SC) transducer position. The velocity signal is approximately 3.8 m/sec at its height; predicted peak gradient (PGRAD) is 58 mm Hg, predicted mean gradient (MnGRAD) is 34 mm Hg.

obtained. The peak systolic velocity of the tricuspid regurgitant jet provides a reliable indirect measurement of the severity of obstruction because the reverse gradient between the right ventricle and right atrium allows derivation of the ventricular peak systolic pressure. The constant value of 14 is used for right atrial pressure in the calculation. CARDIAC CATHETERIZATION AND ANGIOCARDIOGRAPHY.

These techniques are now used only rarely to establish or preclude other diagnostic possibilities. The usual indication for cardiac catheterization is to provide definitive therapy for the lesion. Cardiac catheterization, however, may also localize the site of obstruction, evaluate its severity, and document the coexistence of additional cardiac malformations. The resting cardiac output usually is normal, even in cases of severe stenosis, and most children show the ability to increase cardiac output with exercise.[376]

Right ventricular dysfunction occurs especially when venoarterial shunting is significant and produces systemic arterial desaturation. In patients with critical stenosis, care must be taken during hemodynamic study that the cardiac catheter does not dangerously occlude the stenotic valve opening. The angiographic appearance of a typical valvular pulmonic stenosis differs from that of a dysplastic valve. The former is thickened and domed during systole, returning to normal configuration in diastole. Poststenotic dilatation of the main pulmonary trunk and sometimes of the left pulmonary artery is usual. The leaflets of the dysplastic valve are not fused anatomically but are thickened and immobile, creating little change in the angiographic picture during the cardiac cycle. Moreover, a small annulus and narrow sinuses of Valsalva are common accompaniments of valve dysplasia. With either type of valve, systolic narrowing of the right ventricular infundibulum usually is associated with moderate or severe obstruction. NATURAL HISTORY.

Mild and moderate pulmonic valve stenoses have a generally favorable course; uncommonly, progression occurs in the severity of obstruction, particularly in infancy.[377] Serial hemodynamic studies reveal unchanged pressure gradients over 4- to 8-year intervals in three-fourths of patients. Equal percentages of the remainder have an increase or a decrease in the severity of obstruction; significant increases in the pressure gradient occur especially in children with a gradient in excess of 50 mm Hg at initial examination.[373] MANAGEMENT.

Percutaneous transluminal balloon valvuloplasty (see Chap. 38 ) is the initial procedure of choice in patients with typical pulmonary valve stenosis and moderate to severe degrees of obstruction (Fig. 43-43). [372] This approach provides palliative improvement with the great likelihood that the improvement is permanent. In these same patients, surgical relief also can be accomplished at extremely low risk.[378] The valve is approached through an incision in the pulmonary arterial trunk, and resection of infundibular muscle, if necessary, may be accomplished through the pulmonic valve. Reoperation or subsequent balloon valvuloplasty is seldom required. In patients with a dysplastic valve, in whom transcatheter valvuloplasty is ineffective, the thickened valve tissue is removed and a patch often is required to widen the annulus and proximal main pulmonary artery. In children with mild pulmonic valve stenosis, prophylaxis against infective endocarditis is recommended; these patients need not restrict their physical activities. After relief of stenosis, cardiac performance as judged by exercise testing improves in children in whom postoperative resolution of right ventricular hypertrophy is expected. In contrast, myocardial fibrosis can explain a lack of improvement in adults.[379] Pulmonic Atresia with Intact Ventricular Septum MORPHOLOGY.

This anomaly is an uncommon and highly lethal cause of neonatal cyanosis that may

respond well to aggressive medical and surgical treatment.[380] [381] In almost all infants, the pulmonic valve is atretic; in the majority, both the valve ring and the main pulmonary artery are hypoplastic. The right ventricular infundibulum may occasionally be atretic or extremely narrowed. Right ventricular cavity size and configuration span the spectrum from a diminutive right ventricular chamber, often with tricuspid stenosis, to a large right ventricle, frequently with tricuspid regurgitation (Fig. 43-44) . In most infants, the right ventricle is hypoplastic, and sinusoidal communications

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Figure 43-43 Right ventriculogram (RV) in the lateral projection (top left) from a patient with valvular pulmonic stenosis. The pulmonary valve (PV) is thickened and domes in systole. Poststenotic dilatation of the pulmonary artery (PA) is seen. At the top right, successful balloon valvuloplasty shows almost complete disappearance of the stenotic waist (arrow). The bottom panel shows the pre- (left) and post(right) valvuloplasty hemodynamics, showing a reduction from moderately severe to mild pulmonic stenosis. AO = aorta. (Courtesy of Dr. Thomas G. DiSessa.)

exist in half the patients between the right ventricular cavity and the coronary circulation.[382] [383] The intramyocardial sinusoids may end blindly or communicate with coronary arteries. Further, these communications may be numerous and may feed both the left and right coronary systems, or they may be fed via a single dilated vessel. The proximal coronary arteries in some patients may be atrophic, proximal to a communication between the sinusoids and the distal coronary artery, particularly

Figure 43-44 Pulmonic atresia with intact ventricular septum. With a competent tricuspid valve, the right ventricular chamber is diminutive (A); significant tricuspid regurgitation is associated with a normal or large right ventricular cavity (B). VC = vena cava; RA = right atrium; RV = right ventricle; PT = pulmonary trunk; PV = pulmonary vein; LA = left atrium; LV = left ventricle; Ductus A. = ductus arteriosus; LPA = left pulmonary artery; RPA = right pulmonary artery; LPV = left pulmonary vein. (From Edwards JE: Congenital malformations of the heart and great vessels. In Gould SE [ed]: Pathology of the Heart. 2nd ed, 1960. Courtesy of Charles C Thomas, Publisher, Ltd., Springfield, Illinois.)

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Figure 43-45 Right ventricular angiocardiogram in the frontal projection in a 1-day-old infant with an atretic pulmonic valve (arrow). The cavity of the right ventricle (RV) is small and eccentrically shaped. (Courtesy of Dr. Robert Freedom.)

in hearts with severe hypoplasia of the right ventricle. In these circumstances, the distal coronary vessels are supplied by communications with the right ventricle, and the coronary circulation therefore is right ventricle dependent. In this group, decompression of the right ventricle by a surgical procedure would be associated with a high risk of myocardial ischemia and death.[384] [385] Because the pulmonic valve is imperforate and completely obstructed, systemic venous blood returning to the heart bypasses the right ventricle through an interatrial communication. Right ventricular output does not contribute to the effective cardiac output and is proportional to the magnitude of tricuspid regurgitation and the size and extent of the sinusoidal communications with the coronary arterial tree. The blood supply to the lungs is derived from the bronchial circulation and from flow through a persistently patent ductus arteriosus. The size and patency of the ductus arteriosus are critical determinants in postnatal survival; ductus closure results in death. Reduced pulmonary blood flow by way of a partially constricted ductus arteriosus results in profound hypoxemia, tissue hypoxia, and metabolic acidemia. DIAGNOSIS.

The diagnosis is suggested by roentgenographic findings of pulmonary hypoperfusion and the ECG observation of a normal QRS axis, absent or diminished right ventricular forces, and/or dominant left ventricular forces. In the minority of infants with marked tricuspid regurgitation, the right ventricle and right atrium are massively enlarged. The echocardiogram in the usual infant shows a small right ventricular cavity and diminutive or absent pulmonic valve echoes.[386] Doppler examination shows continuous retrograde flow to the pulmonary artery and/or its branches through a patent ductus arteriosus, which usually is narrow and tortuous. Only if tricuspid valve echoes are imaged by ultrasound examination can tricuspid atresia be distinguished from pulmonic atresia. Although the diagnosis of this entity can be made by echocardiography, angiocardiography is required to assess treatment options because key determinants are the identification and nature of ventriculocoronary connections, which are not well characterized by echocardiography. Cardiac catheterization is usually performed on an emergency basis. Because survival depends on patency of the ductus arteriosus, intravenous infusion of prostaglandin E1 , (0.05 to 0.1 mug/kg/min) may dramatically reverse clinical deterioration and improve arterial blood gases and pH. The usual hemodynamic findings are right atrial and right ventricular hypertension, with right ventricular pressure often greater than systemic pressure, and a massive right-to-left interatrial shunt. Selective angiocardiography establishes the diagnosis and allows evaluation of the degree of separation between the right ventricular infundibular and pulmonary trunk, the size of the right ventricular cavity and the pulmonary arteries (Fig. 43-45) , the anatomy and function of the tricuspid valve, and the anatomical and functional details of the coronary circulation. MANAGEMENT.

Initial stabilization is usually required in infants, necessitating infusion of prostaglandin

E1 to dilate the ductus arteriosus and measures to correct metabolic acidosis. The rare infant with membranous pulmonary atresia may be a candidate for balloon valvotomy. Initial surgical considerations focus on whether the patient is a candidate for a biventricular or univentricular (Fontan) repair (Fig. 43-45) .[384] [387] [388] [389] The angiographic delineation of coronary artery anatomy determines the feasibility of early decompression of the right ventricle, because this approach is contraindicated when there are ventriculocoronary connections with part or all of the coronary circulation right ventricle dependent. Patients in this latter group cannot undergo operation that decompresses the right ventricle and are ultimately candidates for a lateral tunnel Fontan procedure, after initial palliation by balloon atrial septostomy followed by a systemic-pulmonary artery shunt.[390] At the other end of the spectrum, babies with only mild hypoplasia of the right ventricle and tricuspid valve are candidates for a transventricular closed pulmonary valvotomy, followed later by balloon angioplasty or repeat surgical valvotomy. Ultimately, the size of the tricuspid valve and right ventricle, and occasionally the presence of coronary artery obstructive lesions in association with right ventricle to coronary artery fistulas, will dictate whether patients will be candidates for two-ventricle repair or whether a less corrective procedure such as the Fontan operation will be the most definite surgical option.[387] In infants with moderate right ventricular hypoplasia, a biventricular repair is preferred, often using a homograft valve in the outflow tract. In this group, the smaller the size of the right ventricle and tricuspid valve, the more likely a partial biventricular repair will be necessary, relieving the outflow tract obstruction with insertion of a valve, coupled with a bidirectional cavopulmonary (Glenn) shunt to ensure obligatory pulmonary blood flow. Intraventricular Right Ventricular Obstruction

Infundibular pulmonic stenosis with an intact ventricular septum and the presence of anomalous muscle bundles are the two principal causes of intraventricular right ventricular obstruction (Fig. 43-46) .[391] SUBPULMONIC INFUNDIBULAR STENOSIS.

This anomaly usually occurs at the proximal portion of the infundibulum and consists of a fibrous band at the junction of the right ventricular cavity and outflow tract. The clinical manifestations, course, and prognosis of infundibular stenosis are similar to those of valvular stenosis, although the former diagnosis is suggested by the absence of a systolic ejection

Figure 43-46 Intraventricular right ventricular obstruction. The right ventricular inflow (RVI) and outflow (RVO) tracts are separated by bands (arrowheads), creating intraventricular right ventricular obstruction. PA = pulmonary artery.

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sound and a systolic murmur lower along the left sternal border. Doppler echocardiography, withdrawal pressure tracings, and selective right ventricular angiocardiography permit localization of the site of obstruction and assessment of its extent and severity. Surgical treatment consists of resection of the fibrotic narrowed area and hypertrophied muscle. It may occasionally be necessary to widen the outflow tract with a pericardial or prosthetic patch. ANOMALOUS MUSCLE BUNDLES.

A two-chambered right ventricle is formed by right ventricular obstruction due to anomalous muscle bundles; most of the patients have an associated malalignment or perimembranous VSD, and about 5 percent have subaortic stenosis.[392] Aberrant hypertrophied muscle bands, occasionally in association with a VSD, traverse the right ventricular cavity, extending from its anterior wall to the crista supraventricularis and/or the portion of the adjacent interventricular septum. The anomalous pyramid-shaped muscle mass obstructs blood flow through the body of the right ventricle and produces a proximal high-pressure inflow chamber and a distal low-pressure chamber. Thus, this type of obstruction is distinguishable from that in tetralogy of Fallot, in which hypertrophied infundibular muscle protrudes into but does not cross the cavity of the right ventricle. The clinical, ECG, and chest roentgenographic findings resemble those observed in pulmonic valvular or subvalvular infundibular obstruction, although the systolic thrill and murmur may be displaced lower along the left sternal border. Progressive obstruction occurs in some patients. The diagnosis may be established by two-dimensional echocardiography.[393] Selective right ventricular angiocardiography provides the most accurate diagnosis and reveals a filling defect in the midportion of the right ventricle; this defect often does not change significantly with systole and diastole. Management.

The treatment for anomalous muscle bundles consists of surgical removal.[394] In the absence of preoperative recognition of the anomaly, the surgeon should be alerted to the correct diagnosis by the presence of a dimple during contraction on the ordinarily smooth anterior surface of the right ventricle and/or the inability to view the tricuspid valve through a longitudinal ventriculotomy because of the presence of the abnormal muscle mass. Tetralogy of Fallot DEFINITION.

The overall incidence of this anomaly approaches 10 percent of all forms of congenital

heart disease, and it is the most common cardiac malformation responsible for cyanosis after 1 year of age. The four components of this malformation are (1) VSD, (2) obstruction to right ventricular outflow, (3) overriding of the aorta, and (4) right ventricular hypertrophy. The basic anomaly is the result of an anterior deviation of the septal insertion of the infundibular ventricular septum from its usual location in the normal heart between the limbs of the trabecular septum. The interventricular malalignment defect usually is large, approximating the aortic orifice in size, and is located high in the septum just below the right cusp of the aortic valve, separated from the pulmonic valve by the crista supraventricularis. The aortic root may be displaced anteriorly and straddle or override the septal defect, but as in a normal heart, it lies to the right of the origin of the pulmonary artery. In most cases, no dextroposition of the aorta exists; overriding of the aorta is a phenomenon secondary to the subaortic location of the VSD. HEMODYNAMICS.

The degree of obstruction to pulmonary blood flow is the principal determinant of the clinical presentation.[395] The site of obstruction is variable[396] ; infundibular stenosis is the only major obstruction in about 50 percent of patients and coexists with valvular obstruction in another 20 to 25 percent (Fig. 43-47) . Supravalvular and peripheral pulmonary arterial narrowing may be observed, and unilateral absence of a pulmonary artery (usually the left) is found in a small number of patients. Circulation to the abnormal lung is accomplished by bronchial and other collateral arteries.[397] [398] Atresia of the pulmonic valve, infundibulum, or main pulmonary artery is occasionally referred to as "pseudotruncus arteriosus." True truncus arteriosus with absent pulmonary arteries (type 4) differs from

Figure 43-47 Tetralogy of Fallot with infundibular and valvular pulmonic stenosis. The arrows indicate direction of blood flow. A substantial right-to-left shunt exists across the ventricular septal defect. RA = right atrium; LA = left atrium; RV = right ventricle; LV = left ventricle; Ao = aorta; PA = pulmonary artery.

tetralogy of Fallot, in which pulmonary artery branches are present but are fed by a patent ductus arteriosus and/or bronchial arteries (see Fig. 43-50 ). A right-sided aortic knob, aortic arch, and descending aorta occur in about 25 percent of patients with tetralogy of Fallot. The coronary arteries may have surgically important variations [399] : The anterior descending artery may originate from the right coronary artery; a single right coronary artery may give off a left branch that courses anterior to the pulmonary trunk; a single left coronary artery may give off a right branch that crosses the infundibulum of the right ventricle. Enlargement of the infundibulum branch of the right coronary artery often presents a problem with respect to a right ventriculotomy. Associated cardiac anomalies exist in about 40 percent of patients. Major associated cardiac anomalies include patent ductus arteriosus, numerous (usually muscular) VSDs, and complete AV septal defects. Localized single or multiple peripheral pulmonary arterial stenotic lesions are common; rarely, the right or left pulmonary artery may arise anomalously from the ascending aorta. Infrequently, aortic valve regurgitation results

from aortic cusp prolapse. Associated extracardiac anomalies are present in 20 to 30 percent of patients. The relation between the resistance of blood flow from the ventricles into the aorta and into the pulmonary vessels has a major role in determining the hemodynamic and clinical picture.[400] Thus, the severity of obstruction to right ventricular outflow is of fundamental significance. When right ventricular outflow tract obstruction is severe, the pulmonary blood flow is markedly reduced, and a large volume of unsaturated systemic venous blood is shunted from right to left across the VSD. Severe cyanosis and polycythemia occur, and symptoms and sequelae of systemic hypoxemia are prominent. At the opposite end of the spectrum, the term "acyanotic" or "pink" tetralogy of Fallot often is used to describe an interventricular communication and a milder degree of obstruction to right ventricular outflow with little or no venoarterial shunting. In many infants and children, the obstruction to right ventricular outflow is mild but progressive, so that early in life pulmonary exceeds

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systemic blood flow and the symptoms resemble those produced by a simple VSD. CLINICAL MANIFESTATIONS.

Few children with tetralogy of Fallot remain asymptomatic or acyanotic (see Chap. 44 ). Most are cyanotic from birth or develop cyanosis before age 1 year. In general, the earlier the onset of systemic hypoxemia, the more likely the possibility that severe pulmonary outflow tract stenosis or atresia exists. Dyspnea with exertion, clubbing, and polycythemia is common. When resting after exertion, children with tetralogy characteristically assume a squatting posture. The latter may be obvious even in infancy; many cyanotic infants prefer to lie in a knee-chest position. Spells of intense cyanosis related to a sudden increase in renoarterial shunting and a reduction in pulmonary blood flow most often have their onset between 2 and 9 months of age and constitute an important threat to survival.[401] [402] The attacks are not restricted to patients with severe cyanosis; they are most common in the morning after awakening and are characterized by hyperpnea and increasing cyanosis that progresses to limpness and syncope and occasionally terminates in convulsions, a cerebrovascular accident, and death. Physical Examination.

This reveals variable degrees of underdevelopment and cyanosis. Clubbing of the terminal digits may be prominent after the first year of life. The heart is not hyperactive or enlarged; a right ventricular impulse and systolic thrill often are palpable along the left sternal border. An early systolic ejection sound that is aortic in origin may be heard at the lower left sternal border and apex; the second heart sound is single, the pulmonic component rarely being audible. A systolic ejection murmur is produced by flow across the narrowed right ventricular infundibulum or pulmonic valve. The intensity and duration

of the murmur vary inversely with the severity of obstruction--the opposite of the relation that exists in patients with pulmonic stenosis and an intact ventricular septum. Polycythemia, decreased systemic vascular resistance, and increased obstruction to right ventricular outflow may all be responsible for a decrease in intensity of the murmur; with extreme outflow tract stenosis or pulmonic atresia and during an attack of paroxysmal hypoxemia, no murmur or only a very short, faint murmur may be detected. A continuous murmur faintly audible over the anterior or posterior chest reflects flow through enlarged bronchial collateral vessels. A loud continuous murmur of flow through a patent ductus arteriosus occasionally may be heard at the upper left sternal border. LABORATORY EXAMINATIONS.

The ECG ordinarily shows right ventricular and, less frequently, right atrial hypertrophy. In a patient with acyanotic tetralogy, combined ventricular hypertrophy may be noted initially, progressing to right ventricular hypertrophy as cyanosis develops. Roentgenographic examination characteristically reveals a normal-sized boot-shaped heart (coeur en sabot) with prominence of the right ventricle and a concavity in the region of the underdeveloped right ventricular outflow tract and main pulmonary artery. The pulmonary vascular markings are typically diminished, and the aortic arch and knob may be on the right side; the ascending aorta usually is large. A uniform, diffuse, fine reticular pattern of vascular markings is noted in the presence of prominent collateral vessels. Echocardiography.

Findings include aortic enlargement, aortic-septal discontinuity, and aortic overriding of the ventricular septum.[403] Two-dimensional echocardiography (see Chap. 7 ) shows the right ventricular outflow tract to be narrowed and in a more horizontal orientation than normal. The main pulmonary artery and its branches are mildly to severely hypoplastic. The usual ventricular septal malalignment defect lies superior to the tricuspid valve and immediately below the aortic valve cusps. These findings are best displayed in views of the long axis of the right ventricular outflow tract, which are the subxiphoid short axis and the high transverse parasternal echo windows. Echo views that show the anteroposterior coordinates best indicate the overriding of the aorta; these are the parasternal long-axis, apical two-chamber, and subxiphoid views (Fig. 43-48) . The echocardiographic examination also reveals the origin of the main pulmonary artery from the right ventricle, as well as continuity of the main pulmonary artery with its right and left branches, and is accurate for diagnosing coronary abnormalities,[404] [405] although the latter are identified best by angiography. Delineation or complex pulmonary vascular abnormalities may require combined angiography and advanced CT[406] (see Chaps. 10 and 11 ). Combined angiography and three-dimensional CT has been shown to be useful for assessing systemic-to-pulmonary collaterals. The demonstration of mitral-semilunar valve continuity helps to distinguish tetralogy from double-outlet right ventricle with pulmonic stenosis, in which discontinuity of the mitral valve echo and the aortic cusp echo is a critical feature. Cardiac Catheterization and Angiocardiography (Fig. 43-49) .

Despite the accuracy of noninvasive approaches, many centers still consider invasive study necessary to confirm the diagnosis; assess the magnitude of right-to-left shunting; provide details of additional muscular VSDs, if present; evaluate the architecture of the right ventricular outflow tract, pulmonic valve, and annulus and the morphology and caliber of the main branches of the pulmonary arteries; and analyze the anatomy of the coronary arteries. Axial cineangiography, using the sitting-up projection, greatly facilitates evaluation of the pulmonary outflow tract and arteries.[137] Preoperative assessment of tetralogy with pulmonic atresia must include delineation of the arterial supply to both lungs by selective catheterization and visualization of bronchial collateral arteries with late serial filming; pulmonary arteries may be opacified only after the bronchial collateral arteries have cleared of contrast material (Fig. 43-50) . A patient with pulmonic atresia should not be ruled out as a candidate for surgical correction unless an inadequate pulmonary arterial supply to the lungs is clearly demonstrated.[397] Rarely, injection of contrast through a catheter in the pulmonary venous capillary wedge position is required to assess the possibility that anatomical pulmonary arteries are present. CT may visualize central pulmonary arteries when conventional angiography cannot. MANAGEMENT.

Among the factors that may complicate the management of tetralogy are iron deficiency anemia,

Figure 43-48 Tetralogy of Fallot in a parasternal long-axis (PLAx) view, which demonstrates the aorta overriding the ventricular septum (Sept). RV = right ventricle; RVO = right ventricular outflow tract; LV = left ventricle; LA = left atrium; AO = aorta; AAO = ascending aorta.

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Figure 43-49 Lateral view of a right ventriculogram in a child with tetralogy of Fallot showing simultaneous opacification of the pulmonary artery (PA) and aorta (Ao). PV = pulmonic valve; VSD = ventricular septal defect; RV = right ventricle.

infective endocarditis, paradoxical embolism, polycythemia, coagulation disorders, and cerebral infarction or abscess. Paroxysmal hypercyanotic spells may respond quickly to oxygen, placing the child in the knee-chest position, and morphine. If the spell persists, metabolic acidosis develops from prolonged anaerobic metabolism, and infusion of sodium bicarbonate may be necessary to interrupt the attack. Vasopressors, beta-adrenoceptor blockade, or general anesthesia occasionally may be necessary.[402]

Total Surgical Correction.

This operation is advisable ultimately for almost all patients with tetralogy of Fallot. Early definitive repair, even in infancy, is currently advocated in most centers that are experienced in intracardiac surgery in infants.[407] [408] [409] Successful early correction appears to prevent the consequences of progressive infundibular obstruction and acquired pulmonic atresia, delayed growth and development, and complications secondary to hypoxemia and polycythemia with bleeding tendencies. The anatomy of the right ventricular outflow tract and the size of the pulmonary arteries, rather than the age or size of the infant or child, are the most important determinants in assessing candidacy for primary repair; a transannular patch may be used in infants with severe outflow narrowing.[410] Marked hypoplasia of the pulmonary arteries is a relative contraindication for early corrective operation.

Figure 43-50 Selective systemic collateral bronchial arteriogram demonstrates gull-wing configuration of the hypoplastic right pulmonary artery (rpa) and left pulmonary artery (arrows) in a patient with tetralogy of Fallot and pulmonic atresia. (Courtesy of Dr. Robert Freedom.) Palliative Surgery.

When marked hypoplasia of the pulmonary arteries exists, a palliative operation designed to increase pulmonary blood flow is recommended and usually consists in the smallest infants of a systemic-pulmonary arterial anastomosis.[411] A transventricular infundibulectomy or valvulotomy is an alternative palliative procedure that may be considered. Balloon dilatation of the pulmonary valve may afford palliation in selected infants.[412] Total correction can then be carried out at a lower risk later in childhood. The palliative procedures relieve hypoxemia caused by diminished pulmonary blood flow and reduce the stimulus to polycythemia. Because pulmonary venous return is augmented, the left atrium and ventricle are stimulated to enlarge their capacity in anticipation of total correction. In the most severe forms of tetralogy of Fallot with pulmonic atresia, the goals of operation include establishment of nonstenotic continuity between the right ventricle and pulmonary arteries, closure of the intracardiac shunt, and interruption of surgically created shunts or major collateral arteries to the lungs. Transcatheter coil occlusion of significant aorta-pulmonary collateral vessels as well as of modified Blalock-Taussig shunts and ascending aorta to pulmonary artery interposition grafts can be used before corrective operation.[413] [414] When atresia is confined to the infundibulum or pulmonic valve, repair may be accomplished by infundibular resection and reconstruction of the outflow tract with a pericardial patch. If a long segment of pulmonary arterial atresia exists, a valve-containing conduit is inserted from the right ventricle to the distal pulmonary artery.[415] The presence of a single pulmonary artery in the hilus of either lung is a prerequisite for repair of pulmonic atresia. Prior unifocalization to incorporate several systemic to pulmonary artery collaterals into a neopulmonary artery may be required in selected patients.[416] A conduit also may be necessary in less severe forms of right ventricular outflow tract obstruction when an

anomalous coronary artery crosses the right ventricular outflow tract. Postoperative Complications.

Various complications are common in the postoperative period after palliative or corrective operation. Mild to moderate left ventricular decompensation may be secondary to the sudden increase in pulmonary venous return; various degrees of pulmonic valvular regurgitation increase right ventricular cavity size further. Patients with progressive pulmonary insufficiency and severe right ventricular dilatation are candidates for prosthetic pulmonary valve insertion.[417] Bleeding problems are common, especially in older polycythemic patients (see Chap. 44 ). Complete right bundle branch block or the pattern of left anterior hemiblock often is seen, but disabling dysrhythmias are infrequent.[418] [419] Restricted pulmonary arterial flow is the greatest

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cause of early and late mortality and poor late results.[420] After convalescence from intracardiac repair, symptoms of hypoxemia and severe exercise intolerance are relieved even in the presence of some residual right ventricular outflow tract obstruction, pulmonic valve incompetence, and/or cardiomegaly. However, cardiovascular performance at rest or during exercise may remain below normal,[421] [422] [423] and major complications, such as trifascicular block, complete heart block, ventricular arrhythmias, and sudden death, may rarely occur many years after surgical treatment.[419] Late ventricular arrhythmias are rare in patients with successful early correction of the malformation unless complex or numerous operations were performed. Because widespread use of ambulatory ECG monitoring has resulted in greater detection of ventricular arrhythmias, usually isolated ventricular extrasystoles or nonsustained tachycardia, some have suggested that the asymptomatic patients in this category should have pharmacological suppression of their arrhythmias. It would appear that both ventricular depolarization and repolarization abnormalities contribute to the pathogenesis of ventricular arrhythmias after repair of the anomaly (see Chaps. 25 and 44 ). Most studies, however, do not support the use of potentially dangerous long-term antiarrhythmic treatment for asymptomatic postoperative patients, and a large-scale long-term follow-up study is indicated before prophylactic therapeutic options can be established definitively (see Chap. 23 ). Congenital Absence of the Pulmonic Valve

PATHOLOGY AND PATHOGENESIS.

In the majority of cases of this rare malformation, the lesion is associated with a VSD, a narrowed obstructive annulus of the pulmonic valve, and marked aneurysmal dilatation of the pulmonary arteries. The combination of anomalies often is referred to as tetralogy

of Fallot with absent pulmonic valve. The obstructing lesion principally consists of underdeveloped, primitive valve tissue within a hypoplastic annulus; infundibular obstruction and the VSD do not differ from classic tetralogy of Fallot. Reports indicate that deletion within chromosome 22 is common in patients with this anomaly.[424] The massively dilated pulmonary arteries often are the major determinant of the clinical course because they frequently result in upper airway obstruction and severe respiratory distress in infancy.[425] Smaller intrapulmonary bronchi may also be compressed by abnormally branching distal pulmonary arteries, and in some cases the number of bronchial generations or alveolar multiplications is reduced.[426] Poststenotic pulmonary artery aneurysms develop in utero, and their size and location appear to be related to the magnitude of pulmonic regurgitation in fetal life, the orientation of the right ventricular infundibulum to the right or left, and the size of the ductus arteriosus.[427] CLINICAL AND LABORATORY FINDINGS.

The clinical features often are distinctive, with an early onset of severe respiratory distress caused by tracheobronchial compression accompanied by a systolic ejection and a widely transmitted low-pitched, decrescendo diastolic murmur at the upper left sternal border. In the absence of pulmonary complications, cyanosis is commonly mild. Roentgenographically, the heart is moderately enlarged; hyperinflated lung fields are observed, with large hilar densities representing the aneurysmally dilated pulmonary arteries. The echocardiographic features are similar to those seen in classic tetralogy of Fallot, in addition to massive dilatation of the main pulmonary artery and branch pulmonary arteries. Remnants of pulmonary cusps may be visible. Right ventricular dilatation is produced by significant pulmonary regurgitation; the latter is identified by retrograde diastolic flow in the pulmonary arteries and right ventricle at Doppler examination. These findings may be detected before birth (Fig. 43-51) . Definitive diagnosis is established by cardiac catheterization and selective angiocardiography. Magnetic resonance imaging is a complementary diagnostic modality and is particularly useful for demonstrating bronchial morphology and the severity of bronchial obstruction.[428] NATURAL HISTORY AND MANAGEMENT.

Prognosis is related to the intensity of upper airway obstruction; pulmonary complications are the usual cause of death in infancy. If survival beyond infancy is accomplished, the respiratory symptoms usually diminish, probably because of maturational changes in the structure of the tracheobronchial tree. The surgical approach in infancy often is unsatisfactory; various procedures have been attempted, ranging from aneurysmorrhaphy to pulmonary artery suspension to transection and reanastomosis of pulmonary artery segments to homograft insertion.[429] Also suggested are ligation of the main pulmonary artery and creation of a systemic-pulmonary shunt, as well as primary repair of the VSD with pulmonary arterial plication. In older patients, the stenotic annulus

Figure 43-51 Two-dimensional (top panel) and Doppler (lower panel) echocardiogram of a 30-week-gestation fetus with tetralogy of Fallot and an absent pulmonary valve. The pulmonary artery (PA) is aneurysmally dilated, and the right ventricle (RV) is also dilated. The arrow points to the stenotic pulmonary valve annulus. Pulmonary valve leaflets are not detectable. The Doppler study at the level of the pulmonary valve annulus demonstrates to-and-fro flow with increased forward velocity in systole. LV = left ventricle. (Courtesy of Dr. James C. Huhta.)

may be widened with a patch and the VSD closed. It seldom is necessary to replace the pulmonic valve. Tricuspid Atresia MORPHOLOGY.

This anomaly is characterized by absence of the tricuspid orifice, an interatrial communication, hypoplasia of the right ventricle, and the presence of a communication between the systemic and pulmonary circulations, usually a VSD.[430] Thus formed is a univentricular AV connection, consisting of a left-sided mitral valve between the morphological left atrium and left ventricle. Unequal division of the AV canal by fusion of the right-sided endocardial cushions has been proposed as the embryological fault. Patients may be subdivided into those with normally related great arteries (70 to 80 percent of cases) and those with dextro- or D-transposition of the great arteries; further classification depends on the presence of pulmonic stenosis or atresia and the absence or size of the VSD (Fig. 43-52) . Additional cardiovascular malformations often are present, especially in patients with D-transposition of the great arteries, and include persistent left superior vena cava, patent ductus arteriosus, coarctation of the aorta, and juxtaposition of the atrial appendages. PATHOPHYSIOLOGY.

The association with other cardiac malformations determines whether or not pulmonary blood

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Figure 43-52 A, Tricuspid atresia with normally related great arteries, a small ventricular septal defect, diminutive right ventricular chamber, and narrowed outflow tract. B, An example of tricuspid atresia and complete transposition of the great arteries in which the left ventricular chamber is essentially a common ventricle, with the aorta arising from an infundibular component (RV) of the common ventricle. VC = vena cava; RA = right atrium; LA = left atrium; RV = right ventricle; LV = left ventricle; LPV = left pulmonary vein; LPA = left pulmonary artery; PT=pulmonary trunk. (Modified from Edwards JE, Burchell HB: Congenital tricuspid atresia: Classification. Med Clin North Am 33:1177, 1949.)

flow is decreased, normal, or increased and therefore the degree of systemic hypoxemia.[431] The clinical picture usually is dominated by symptoms resulting from

greatly diminished pulmonary blood flow with severe cyanosis. Cyanosis results from an obligatory admixture of systemic and pulmonary venous blood in the left atrium, and its intensity primarily depends on the magnitude of pulmonary blood flow. Heart failure, rather than cyanosis, is the predominant problem in infants with torrential pulmonary blood flow, which results when D-transposition of the great arteries, a VSD, and an unobstructed pulmonary outflow tract coexist. If these patients survive infancy, they are at risk for pulmonary vascular obstructive disease; a favorable response to pulmonary arterial banding is common early in life. CLINICAL FEATURES.

The diagnosis is easily established in the vast majority of infants with tricuspid atresia and pulmonary hypoperfusion. The ECG findings of left-axis deviation, right atrial enlargement, and left ventricular hypertrophy in a cyanotic infant strongly suggest tricuspid atresia. Echocardiography reveals a small or absent right ventricle, large left ventricle, and absent tricuspid valve echoes (Fig. 43-53 ; see also Chap. 7 ); further, it may demonstrate the relation of the great arteries unless pulmonic atresia is present. Color flow and pulsed Doppler echocardiography reveal the abnormal flow patterns; apical and subxiphoid cross-sectional views best reveal the atretic tricuspid orifice. Seen roentgenographically are diminished pulmonary vascular markings and a concavity in the region of the cardiac silhouette usually occupied by the main pulmonary artery. The right atrial shadow may be prominent unless left-sided juxtaposition of the atrial appendages exists, which produces a straight and flattened right heart border. CARDIAC CATHETERIZATION AND ANGIOGRAPHY.

The right ventricle cannot be entered directly from the right atrium. When the great arteries are related normally, pulmonary blood flow is found to be derived from shunting through a VSD or by way of a patent ductus arteriosus; the latter and the bronchial collaterals are the source of pulmonary flow if the ventricular septum is intact. In complete transposition, the pulmonary artery fills directly from the left ventricle and the aorta indirectly through a VSD and the hypoplastic right ventricle. Because complete admixture exists in the left atrium of pulmonary and systemic venous return, the degree of systemic arterial hypoxemia depends on the pulmonary-systemic flow ratio. Right atrial angiography does not opacify the right ventricle unless by way of a VSD. Selective left ventricular angiography permits identification of the hypoplastic right ventricle, the size and location of the VSD, the type of pulmonary obstruction, the relation between the great arteries, and the size of the distal pulmonary arterial tree. MANAGEMENT.

Balloon atrial septostomy in those infants with a restrictive interatrial communication and palliative operations designed to increase pulmonary blood flow (systemic arterial--or venous--pulmonary artery anastomosis) are capable of producing clinical improvement of significant duration in patients with diminished blood flow.[431] Functional correction of the anomaly has been accomplished in children older than 12

months by an intraatrial cavopulmonary baffle (lateral tunnel Fontan) (Fig. 43-54) or connection of the left pulmonary artery to the superior vena cava and inferior vena cava to the right pulmonary artery. [432] An adjustable snare around the atrial septal defect or a fenestrated cavocaval baffle with later transcatheter closure appears to prevent acute increases in systemic venous pressure, improve cardiac output, and enhance surgical survival.[433] [434] In patients with tricuspid atresia and complete transposition of the great arteries, subaortic obstruction can be anticipated when the VSD becomes restrictive, also referred to as an obstructive bulboventricular foramen. In most patients, the subaortic tissue must be resected, or preferably, a main pulmonary artery to ascending aorta anastomosis (Damus-Stansel-Kaye procedure) is performed at the time of the Fontan operation.[435] Candidates for these corrective procedures must have normal pulmonary vascular resistance and a mean pulmonary artery pressure less than 15 mm Hg, pulmonary arteries of adequate size, pulmonary vascular resistance less than 3 units/m, and good left ventricular function.[436] The postoperative period usually is characterized transiently by a superior vena cava syndrome with right heart failure, edema, ascites, and hepatomegaly. Long-term results have been generally good, but late management issues after Fontan operation are concerned with ventricular dysfunction,

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Figure 43-53 Apical four-chamber views of a patient with tricuspid atresia. In these views, the right atrium (RA) and left atrium (LA) can be seen above, and the small right ventricle (RV) and large left ventricle (LV) can be seen below. Top, Diastole with the mitral valve in the open position. Note the intense tissue echoes from the right atrioventricular groove between the right atrium (RA) and right ventricle (RV), indicating absence of the tricuspid valve. The descending aorta (DAO) can be identified posterior to the left atrium (LA). Bottom, Doppler color flow map of the same patient taken toward end-systole, showing the passage of blood across the ventricular septal defect (arrow).

atrial ventricular valve regurgitation, atrial arrhythmia, cyanosis, thromboembolism, and protein-losing enteropathy.[437] [438] Late postoperative exercise studies show subnormal exercise tolerance.[439] Late atrial arrhythmias can be a consequence of adverse preoperative hemodynamic function or the type of surgical correction (see Chap. 25 ).[440] Ebstein Anomaly of the Tricuspid Valve (See also p. 1603 )

This malformation is characterized by a downward displacement of the tricuspid valve into the right ventricle due to anomalous attachment of the tricuspid leaflets ( Fig. 43-55 ; see also (Fig. 44-8 (Figure Not Available) ).[441] Case-control studies suggest that maternal exposure in the first trimester to lithium carbonate, used in the management of manic-depressive psychosis, is associated with a greatly increased risk of this anomaly in exposed offspring.[442] Tricuspid valve tissue is dysplastic, and a variable portion of the septal and inferior

Figure 43-54 Fontan operation by total cavopulmonary connection. Top, The pulmonary trunk has been divided close to the pulmonary valve, and both ends have been closed. The right atrium is opened, and a pump sump sucker is placed across the foramen orale and into the left atrium (not shown). Marking stitches are placed at the proposed site of transection of the superior vena cava (SVC) and at the proposed sites of the two longitudinal incisions on the superior and inferior aspects of the right pulmonary artery (RPA). Middle, The anastomosis is made between the distal end of the divided superior vena cava and the incision in the superior aspect of the right pulmonary artery. The cardiac end of the superior vena cava is rarely enlarged; anastomosis is made to an incision in the inferior aspect of the right pulmonary artery. Bottom, A tunnel is created from a cylinder of either Dacron, Gore-Tex, or pericardium connecting the inferior vena cava (IVC) to the atrial orifice of the superior vena cava. The right pulmonary veins drain behind the tunnel. Ao=aorta. (From Kirklin, JW, Barratt-Boyes BG: Cardiac Surgery. 2nd ed. New York, Churchill Livingstone, 1993, p 1068.)

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Figure 43-55 Anatomical specimen of Ebstein's anomaly of the tricuspid valve, cut in the same plane as an apical four-chamber echocardiographic view (see Fig. 43-56 ). The septal and anterior leaflets of the tricuspid valve (SLTV, ALTV) are displaced into the right ventricle (RV), producing a large atrialized right ventricle (ARV). VS = ventricular septum; RA = right atrium; LA = left atrium; MV = mitral valve; LV = left ventricle. (Courtesy of Dr. Thomas DiSessa.)

cusps adheres to the right ventricular wall some distance away from the AV junction. Because of the abnormally situated tricuspid orifice, a portion of the right ventricle lies between the AV ring and the origin of the valve, which is continuous with the right atrial chamber. This proximal segment is "atrialized," and a distal, functionally small ventricular chamber exists. The degree of impairment of right ventricular function depends primarily on the extent to which the right ventricular inflow portion is atrialized and on the magnitude of tricuspid valve regurgitation. CLINICAL MANIFESTATIONS.

These are variable because the spectrum of pathology varies widely and because of the presence of associated malformations. [443] [444] If the tricuspid valve is severely deformed, neonatal heart failure or even fetal hydrops and intrauterine death may occur.[445] At the other end of the spectrum, patients with a mildly deformed tricuspid valve may remain symptom free well into adulthood. The severity of symptoms also depends on the presence or absence of associated malformations. An interatrial communication consisting of a patent foramen ovale or an ostium secundum atrial septal defect is present in more than half the cases. The most common important associated defect is pulmonic stenosis or atresia. Other coexistent anomalies may include an ostium primum type of atrial septal defect and VSD alone or in combination with other lesions. The Ebstein lesion commonly is observed in association with congenitally corrected transposition of the great arteries, in which the tricuspid valve is in the left AV orifice. The usual manifestations in infancy are cyanosis, a cardiac

murmur, and severe congestive heart failure. The magnitude of tricuspid regurgitation in neonates is enhanced because the pulmonary vascular resistance is normally high early in life.[446] In this regard, newborn infants with Ebstein anomaly and massive tricuspid regurgitation must be distinguished by two-dimensional and Doppler echocardiography from those with organic pulmonary atresia and the presence of elevated perinatal pulmonary vascular resistance. The tricuspid regurgitation in infants with Ebstein anomaly may lessen substantially, and cyanosis may disappear early in life as pulmonary vascular resistance falls, only to occur at a later age when right ventricular dysfunction and/or paroxysmal arrhythmias develop. In some infants with Ebstein malformation, cyanosis is suddenly intensified as the degree of pulmonary hypoperfusion is unmasked by spontaneous closure of a patent ductus arteriosus.[447] Beyond infancy, the onset of symptoms is insidious; the most common complaints are exertional dyspnea, fatigue, and cyanosis. About 25 percent of patients suffer episodes of paroxysmal atrial tachycardia. A prominent systolic pulsation of the liver and a large v wave in the jugular venous pulse accompany the systolic thrill and murmur of tricuspid regurgitation. Wide splitting of the first and second heart sounds and prominent third and fourth heart sounds may produce a characteristically rhythmic auscultatory cadence with a triple, quadruple, and quintuple combination of sounds. LABORATORY FINDINGS.

The ECG abnormalities commonly fall into two categories--those with a right bundle branch block pattern and those with a Wolff-Parkinson-White (WPW) pattern (see Chap. 25 ). The ECG presentation in the latter is always from a right-sided accessory pathway, resembling left bundle branch block with predominant S waves in the right pericardial leads. The presence of a WPW pattern increases the risk of supraventricular paroxysmal tachycardia (WPW syndrome).[448] The ECG most often shows giant P waves, a prolonged PR interval (in the absence of WPW), and prolonged terminal QRS depolarization, producing variable degrees of right bundle branch block. These distinctive findings help to distinguish Ebstein's anomaly from other forms of right ventricular dysplasia (see Chaps. 25 and 48 ), whose presenting problem often is an arrhythmia. Roentgenographic studies (see Chap. 8 ) usually demonstrate an enlarged right atrium, a small right ventricle, and a pulmonary artery with reduced pulsations; the pulmonary vascularity can be reduced if a large right-to-left shunt is present. Echocardiographic Findings.

Echocardiography clearly defines the features of Ebstein malformation.[449] The apical four-chamber plane shows the downward displacement of the attachment of the septal leaflet of the tricuspid valve, a finding overemphasized in the literature. The most important valvar displacement is that of the posterior or mural leaflet of the tricuspid valve, which is not well seen in the four-chamber view but rather in the subcostal view in infants and smaller children and in the parasternal long-axis or apical two-chamber view in older children and adults (Fig. 43-56) . Subcostal echocardiography also defines the dysplasia of the leaflets of the valve, the right atrial dilatation, and the displacement of

the entire tricuspid valve into the right ventricle. An additional challenge posed by the malformation, especially important for operative repair, is to determine whether the valvular attachment of the anterosuperior tricuspid leaflet is attached to the underlying myocardium. Echocardiographic identification of the chordae tendineae informs the surgeon of the need for freeing the valve during annuloplasty. Doppler color flow imaging defines the degree of tricuspid regurgitation. Mapping determines the magnitude of regurgitation and the site of origin well within the body of the right ventricle. In addition, the presence of valvular stenosis (or nonopening) is determined by Doppler, particularly in neonates in whom patent ductus arteriosus supported systemic pressure may hold the pulmonary valve leaflets shut, simulating pulmonary atresia. The faint detection of pulmonary regurgitation by Doppler flow mapping aids differentiation of these two entities. Invasive Study.

These are rarely necessary. When cardiac catheterization is performed, the intracavitary ECG recorded just proximal to the tricuspid valve shows a right ventricular type of complex, while the pressure recorded is that of the right atrium. A right-to-left atrial shunt is normally present. The hemodynamic findings depend on the degree of tricuspid regurgitation. The cardiac muscle is unusually irritable, and a high incidence of significant arrhythmias during catheterization has been noted. Selective right ventricular angiocardiography shows the position of the displaced tricuspid valve, the size of the right ventricle, and the configuration of the outflow portion of the right ventricle. MANAGEMENT.

Ebstein anomaly may be compatible with a relatively long and active life, with most patients surviving into the third decade of life[450] (see Chap. 44 ). In

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Figure 43-56 Apical four-chamber view of Ebstein's malformation in anatomical orientation. The left atrium (LA) and right atrium (RA) are seen above, and the right ventricle (RV) and left ventricle (LV) are seen below. Arrows point to the anterior leaflet of the tricuspid valve (AL) and septal leaflet (SL). The space between the septal attachment of the tricuspid valve and the mitral valve arrows is enlarged. This area between the true right atrium and the atrioventricular valve indicates the area of atrialized right ventricle.

symptomatic infants with severe cardiomegaly, the initial surgical approach is similar to that in patients with tricuspid atresia, creating a systemic pulmonary shunt, and at a later age the Fontan approach, which necessitates suture or pericardial patch closure of the tricuspid valve. Consideration may be given in some of these patients to creating a bidirectional Glenn shunt from the superior vena cava to the pulmonary arteries, to

divert systemic venous return from the right atrium and to increase pulmonary blood flow. In older patients, significant benefit has resulted from reconstruction of the tricuspid valve, closure of the atrial septal defect, plication of the free wall of the right ventricle, posterior tricuspid annuloplasty, and a reduction in right atrial size.[443] [455] Because late results of this latter approach are encouraging, we now recommend operation for all symptomatic patients and even asymptomatic patients if their heart size is increasing significantly.[451] [452] [453] [454] Some surgeons have sought to minimize postoperative tricuspid regurgitation by inserting a bioprosthetic valve if tricuspid valve tissue is inadequate for a good result.[456] In patients with a preexcitation syndrome (see Chap. 25 ) that is producing life-threatening rhythm disturbances, the accessory conduction pathways are either catheter ablated or surgically divided (see Chap. 23 ).[457] TRANSPOSITION COMPLEXES The term transposition identifies a group of malformations that have in common an abnormal relation between the cardiac chambers and great arteries. In this chapter the term is used to include both anomalous insertion of the pulmonary veins and cardiac malpositions. Complete Transposition of the Great Arteries (See also p. 1609) MORPHOLOGY.

This is a common and potentially lethal form of heart disease in newborns and infants.[458] The malformation consists of the origin of the aorta arising from the morphological right ventricle and that of the pulmonary artery from the morphological left ventricle. With rare exceptions, there is no fibrous continuity between the aortic and mitral valves. The origin of the aorta usually is to the right and anterior to the main pulmonary artery but may be lateral to it. Thus, dextro- or D-transposition is a term often used interchangeably with complete transposition. In other classifications, the anomaly is described as concordant AV and discordant ventriculoarterial connections. The embryogenesis of complete transposition of the great arteries is controversial. The consensus is that the ventricular origins of the great arteries are reversed after development of a straight rather than a spiral infundibulotruncal septum. Transposition appears to result from a transfer of the pulmonary artery, instead of the aorta, from the heart tube's outlet zone to the left ventricle. [459] The latter can result from maldevelopment of the infundibulum or from a combination of both infundibulum maldevelopment and truncal malseptation; the former results if the subpulmonary rather than the subaortic infundibulum is absorbed. The anatomical arrangement results in two separate and parallel circulations. Some communication between the two circulations must exist after birth to sustain life; otherwise, unoxygenated systemic venous blood is directed inappropriately to the systemic circulation and oxygenated pulmonary venous blood is directed to the pulmonary circulation. Almost all patients have an interatrial communication ( Fig. 43-57 ; see also Fig. 44-17 (Figure Not Available) ). Two-thirds have a patent ductus arteriosus, and about one-third have an associated VSD. Complete transposition occurs

more frequently in the offspring of diabetic mothers and more often in males than in females. Without treatment, about 30 per cent of these infants die within the first week of life, 50 percent within the first month, 70 percent within 6 months, and 90 percent

Figure 43-57 Complete transposition of the great arteries. Intercirculatory mixing occurs only at the atrial level. RA = right atrium; LA = left atrium; RV = right ventricle; LV = left ventricle; Ao = aorta; PA = pulmonary artery.

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within the first year.[458] Those who live beyond infancy have, as a general rule, either an isolated large atrial septal defect or a single ventricle, or VSD and pulmonic stenosis. Current aggressive medical and surgical approaches to this group of patients have transformed the prognosis for an infant with this malformation from hopeless to very good. HEMODYNAMICS.

The clinical course is determined by the degree of tissue hypoxia, the ability of each ventricle to sustain an increased workload in the presence of reduced coronary arterial oxygenation, the nature of the associated cardiovascular anomalies, and the anatomical and functional status of the pulmonary vascular bed. [460] A bidirectional shunt is always present because continuous unidirectional shunting would result in progressive depletion of the circulating volume in either the pulmonary or the systemic vascular bed. A major determinant of the systemic arterial oxygen saturation is the amount of blood exchanged between the two circulations by intercirculatory shunts. The net volume of blood passing left to right from the pulmonary to the systemic circulation represents the anatomical left-to-right shunt and is in fact the effective systemic blood flow (i.e., the amount of oxygenated pulmonary venous return reaching the systemic capillary bed). Conversely, the volume of blood passing right to left from the systemic to the pulmonary circulation constitutes the anatomical right-to-left shunt and is in fact the effective pulmonary blood flow (i.e., the net volume of unsaturated systemic venous return perfusing the pulmonary capillary bed). The net volume exchange between the two circulations per unit time is equal. The magnitude of the intercirculatory mixing volume is modified by the number of intercirculatory communications that exist, the presence of associated obstructive intracardiac and extracardiac anomalies, the extent of the bronchopulmonary circulation, and the relation between pulmonary and systemic vascular resistance. For example, in newborns with an intact ventricular septum and a constricted or closed patent ductus arteriosus, inadequate mixing through a small patent foramen ovale often is the cause of severe hypoxemia. If a large interatrial communication or a VSD exists, systemic arterial oxygen saturation is influenced more importantly by the pulmonary-systemic

blood flow relation than by the adequacy of mixing; augmented pulmonary blood flow produces a higher systemic arterial saturation if the left ventricle can sustain a high-output state without the intervention of congestive heart failure and pulmonary edema. The systemic arterial oxygen saturation is low, despite adequate intercirculatory mixing sites, if pulmonary blood flow is reduced by left ventricular outflow tract obstruction or increased pulmonary vascular resistance. Pulmonary Vascular Changes.

Infants with complete transposition of the great arteries are particularly susceptible to the early development of pulmonary vascular obstructive disease.[460] Moderately severe morphological alterations develop in the pulmonary vascular bed by the age of 6 to 12 months in many infants and by 2 years in almost all patients with an associated large VSD or large patent ductus arteriosus in the absence of obstruction to left ventricular outflow. Advanced pulmonary vascular disease is also noted within this same time frame in 15 to 30 percent of patients without a patent ductus arteriosus and with an intact ventricular septum. Systemic arterial hypoxemia, increased pulmonary blood flow, and pulmonary hypertension contribute to the development of pulmonary vascular obstruction in these patients, as they do in other forms of congenital heart disease. Among the additional factors implicated in the accelerated and more widespread pulmonary vascular obstruction found in patients with complete transposition is the presence of extensive bronchopulmonary anastomotic channels, which enter the pulmonary vascular bed proximal to the pulmonary capillary bed; thus, oxygen tension is reduced at the precapillary level, causing pulmonary vasoconstriction.[461] Beyond the early neonatal period, many patients have an abnormal distribution pattern of pulmonary blood flow, with preferential flow to the right lung. The asymmetrical distribution of pulmonary blood flow in these individuals results from an abnormal rightward inclination of the main pulmonary artery in the transposition malformation that favors flow from the main to the right pulmonary artery. Persistently increased pulmonary blood flow to the right lung would be expected to contribute to pulmonary vascular obstructive changes within the lung; in the left pulmonary vascular bed, thrombotic changes may occur because of the combination of reduced flow and polycythemia. Finally, it should be recognized that a prenatal alteration in pulmonary vascular smooth muscle may exist because blood perfusing the fetal lungs in complete transposition of great arteries has a higher than normal PO2 and may serve to dilate pulmonary vessels in utero. Postnatally, such vessels may have an enhanced capacity to constrict in response to vasoactive stimuli and suffer anatomical, obliterative changes. CLINICAL FINDINGS.

Average birth weight and size of infants born with complete transposition of the great arteries are greater than normal. The usual clinical manifestations are dyspnea and cyanosis from birth, progressive hypoxemia, and congestive heart failure. Early in postnatal life, the clinical manifestations and course are influenced principally by the magnitude of intercirculatory mixing. The most severe cyanosis and hypoxemia are observed in infants who have only a small patent foramen ovale or ductus arteriosus

and an intact ventricular septum and in whom mixing is inadequate, or in those infants with relatively reduced pulmonary blood flow because of left ventricular outflow tract obstruction.[462] With a large persistent patent ductus arteriosus or a large VSD, cyanosis may be minimal and heart failure is the usual dominant problem after the first few weeks of life.[458] It should be recognized that a patent ductus arteriosus is present in about half of newborn infants with transposition, although it closes functionally and anatomically soon after birth in almost all cases. If the ductus arteriosus remains open, better mixing of the venous and arterial circulations usually is at the expense of pulmonary artery hypertension.[463] Cardiac murmurs are of little diagnostic significance and are absent or insignificant in about 30 to 50 percent of infants with complete transposition of the great arteries and an intact ventricular septum. In infants with a large persistent patent ductus arteriosus, fewer than half exhibit physical signs typical of ductus arteriosus, such as continuous murmur, bounding pulses, or a prominent mid-diastolic rumble. Moreover, differential cyanosis caused by reversed pulmonary-to-systemic shunting across the ductus arteriosus is difficult to detect because of generalized arterial desaturation. In those infants with a large VSD, a pansystolic murmur usually emerges within the first 7 to 10 days of life. In newborns with transposition and severe pulmonic stenosis or atresia, the clinical findings are similar to those in infants with tetralogy of Fallot. ELECTROCARDIOGRAPHY AND ROENTGENOGRAPHY.

The most usual ECG findings include right-axis deviation, right atrial enlargement, and right ventricular hypertrophy, reflecting that the right ventricle is the systemic pumping chamber. Combined ventricular hypertrophy may be present in those patients with a large VSD and elevated pulmonary blood flow. Isolated left ventricular hypertrophy is encountered rarely in patients with a VSD and a hypoplastic right ventricle, in many of whom the tricuspid valve is displaced abnormally and straddles a VSD. In the first days of life, the chest radiograph may appear normal, particularly

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in infants with an intact ventricular septum. Thereafter, roentgenographic findings often are highly suggestive of the diagnosis,[464] and consist of (1) progressive cardiac enlargement in early infancy; (2) a characteristic oval or egg-shaped cardiac configuration in the anteroposterior view, and a narrow vascular pedicle created by superimposition of the aortic and pulmonary artery segments; and (3) increased pulmonary vascular markings (Fig. 43-58) . A right aortic arch is seen in about 4 percent of infants with an intact ventricular septum and 11 percent of infants with VSD. CT scanning and magnetic resonance imaging (see Chap. 10 ) are also capable of establishing the diagnosis. ECHOCARDIOGRAPHY.

Two-dimensional echocardiography is the procedure of choice in the diagnosis of complete transposition of the great arteries and the detection of significant associated cardiac anomalies[465] ( Figs. 43-59 and 43-60 ; see also Fig. 44-21 ). Indeed, prenatal detection, leading to early management, favorably modifies neonatal morbidity and mortality.[465] Postnatally, in sagittal cross sections, the aorta is observed to ascend retrosternally, in contrast to the normal posterior sweep of the pulmonary artery. With transverse short-axis cross-sectional imaging, the diagnosis is confirmed by demonstrating that the anterior great artery (the aorta) is to the right of the posterior great artery (pulmonary) or that the two arteries are visualized side by side (see Fig. 43-59 ). Moreover, from subcostal views (see Fig. 43-60 ), the course of the two great arteries may be traced to delineate their ventricle of origin, demonstrating that the anterior rightward vessel (aorta) originates from the right ventricle and the posterior leftward vessel (pulmonary artery) originates from the left ventricle (see Fig. 43-60 ). In addition, echocardiography allows sensitive demonstration of the proximal coronary artery position, branching, and course. The intramural proximal course of a coronary artery has also been recognized.[467] [468] Echocardiography also readily identifies associated defects. VSDs may be localized to the membranous, AV, and trabecular muscular septa, and malalignment types of VSDs may be identified if the infundibular septum is shifted either anteriorly or posteriorly.[469] A subaortic obstruction may be created by anterior shifting of the infundibular septum, whereas a posterior shift may narrow the subpulmonary area. The nature of left ventricular outflow tract obstruction may be further identified as a fixed obstruction caused by a fibromuscular ridge or as a dynamic obstruction caused by deviation of the interventricular

Figure 43-58 Chest roentgenogram in a 4-day-old infant with complete transposition of the great arteries showing an oval-shaped heart with a narrow base and increased pulmonary vascular markings.

Figure 43-59 Top, A two-dimensional echocardiographic short-axis scan demonstrates normal great artery relations. The right ventricular outflow tract (RVO) wraps around the aorta (AO) in a clockwise direction. The pulmonic valve (PV) is to the left of the aortic valve. Bottom, Parasternal short-axis (P S AX) view showing the aorta (AO) anteriorly and the pulmonary artery (PA) posteriorly bifurcating into its left and right branches (arrow). LA = left atrium; RA = right atrium; TV = tricuspid valve.

septum toward the left ventricular cavity and the apposition between a thickened interventricular septum and systolic anterior motion of the mitral valve. Ultrasound imaging has become a standard procedure to guide catheter placement and manipulation during balloon atrial septostomy[470] and to assess the anatomical adequacy of the septostomy. Because echocardiography so clearly delineates the arterial transposition, the coronary arteries, and associated anomalies, many infants may proceed to surgery without prior cardiac catheterization.

CARDIAC CATHETERIZATION.

The major abnormal hemodynamic findings include right ventricular pressure at systemic levels and either a high or low left ventricular pressure, depending on pulmonary blood flow, pulmonary vascular resistance, and the presence or absence of left ventricular outflow tract obstructive lesions. Oxygen saturation in the aorta is lower than that in the pulmonary artery. Application of the Fick principle to the calculation of pulmonary and systemic blood flow rates in these patients is an important source of error. Assumed values of oxygen consumption are unreliable in severely hypoxemic infants.

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Figure 43-60 Composite subcostal views of transposition of the great arteries. Top, Subcostal coronal view showing the main pulmonary artery (MPA) arising directly from the left ventricle (LV) and dividing into the right (R) and left (L) pulmonary arteries. The right atrium (RA) and right ventricle (RV) lie adjacent in this view to the liver. Middle, The scan plane has been rotated 90 degrees clockwise (note the change in spatial orientation and the position of the spine). The thymus (TH) is seen anteriorly, and the innominate vein (IV) lies anterior to the aortic arch (indicated by arrows, respectively). The right ventricle (RV) lies anteriorly above the diaphragm and behind the thymus and gives rise to the aorta (AO), its arch, and the descending aorta (DAO). The main pulmonary artery (PA) lies in the crux of the aortic arch. Bottom, An intermediate subcostal view, lying oblique in a plane between the top two panels. The entire ventriculoarterial connection is imaged in this plane, showing the right ventricle connecting to the aortic arch, a small ventricular septal defect indicated by the small arrow, and the pulmonary artery (PA) arising from the left ventricle (LV). The left atrium (LA) can be seen below the pulmonary artery.

Moreover, because systemic and particularly pulmonary arteriovenous oxygen differences may be quite reduced, small errors in oxygen saturation values result in large errors in flow calculations. Furthermore, because bronchial collaterals enter the pulmonary circuit at the precapillary level, a true mixed pulmonary artery saturation cannot be sampled; pulmonary blood flow is therefore overestimated when one uses a sample from the central pulmonary artery, and pulmonary vascular resistance values often are underestimated. Infants who have simple, complete transposition of the great arteries and who present in the first few weeks of life to a center prepared to correct the anomaly by the arterial switch operation (discussed later) often are taken to the operating room shortly after two-dimensional echocardiography and Doppler examination are performed.[21] In these cases, transcatheter balloon atrial septostomy is not performed unless a delay is expected in taking the patient to the operating room. In essentially all other patients, under echocardiographic or fluoroscopic guidance at cardiac catheterization, balloon septostomy is the initial approach to the patient. The diagnostic portion of the cardiac catheterization allows confirmation of the anatomical derangement of the great arteries and establishes the presence of

associated lesions; in newborns, unless prompt arterial switch repair is planned, it should always be accompanied by a palliative balloon atrial septostomy, which serves to enlarge the interatrial communication and improve oxygenation. In older neonates, usually beyond age 3 weeks, thickening of the atrial septum may preclude satisfactory balloon septostomy. In those instances, transcatheter blade septostomy is the preferred approach to palliation. Two-dimensional echocardiography, with or without fluoroscopy, may be used as the imaging mode for both balloon and blade creation of an atrial septal defect.[471] Subcostal four-chamber and sagittal views image cardiac anatomy and catheter position during the procedure, substantially reducing radiation dose. Both the diagnostic and the palliative procedures can be performed by percutaneous entry into the femoral vein, umbilical vein catheterization, or direct cutdown into the femoral or saphenous vein. The catheter passes easily across the foramen ovale into the left atrium and left ventricle and may be manipulated into the pulmonary artery by means of a flow-directed balloon-guided catheter or by manipulation of a standard catheter bent in the form of a J loop within the left ventricle, with the tip pointed posteriorly to the pulmonary artery. When a large VSD is present, the catheter can often be manipulated directly across it from the right ventricle into the pulmonary artery. ANGIOGRAPHY.

This is diagnostic and demonstrates that the anteriorly placed aorta arises from the right ventricle and that the posteriorly placed pulmonary artery in continuity with the mitral valve arises from the left ventricle. The status of the ductus arteriosus and the site and size of a VSD can be well visualized by angiography. Interventricular defects posterior and inferior to the crista supraventricularis occur in about half of these patients; less often, the defects are anterior and superior to the crista supraventricularis or are of the AV septal type.[472] Various lesions may be

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identified as the cause of left ventricular outflow tract obstruction, including ventricular septal hypertrophy with systolic anterior movement of the mitral valve, discrete or tunnel fibromuscular subpulmonic stenosis, valvular and supravalvular stenosis, and, rarely, an aneurysm of the membranous ventricular septum or redundant tricuspid valve tissue protruding through a VSD. Both angiographic and echocardiographic imaging may be required to detect the coronary arterial patterns seen in patients with complete transposition of the great arteries.[467] [468] [473] [474] In the majority, the left coronary artery originates in the left sinus and the right coronary artery originates in the posterior sinus, with a single ostium above both the left and the posterior sinus. In almost 20 percent of patients, the left circumflex artery arises as a branch of the right coronary artery; a single coronary artery is present in about 6 percent; in 3 to 4 percent of patients, either the right coronary and anterior descending arteries originate in the left sinus, with the left circumflex originating in the posterior sinus, or two ostia are present above one sinus, one giving rise to the right and

the other to the left coronary artery. To avoid the danger of excision during transfer of the coronary arteries as part of the arterial switch corrective operation, the intramural course of the left coronary artery or the left anterior descending coronary artery should be identified, a finding in up to 5 percent of patients. An intramural course should be assumed when the vessel has an aberrant origin from the right sinus or when it is in intimate relationship with the commissure between the right and left sinuses and courses between the great arteries. MANAGEMENT

Medical Treatment.

This often is of limited help but should be vigorous because both functional and anatomical corrections of the malformation achieve good results. Conservative measures include the use of oxygen, digitalis, diuretics, iron (if an associated iron-deficiency anemia is present), and intravenous sodium bicarbonate for severe hypoxemic metabolic acidosis. Dilatation of the ductus arteriosus by prostaglandin E1 in the early neonatal period both augments pulmonary blood flow and enhances intercirculatory mixing. Atrial Septostomy.

Creation or enlargement of an interatrial communication is the simplest procedure for providing increased intracardiac mixing of systemic and pulmonary venous blood; this is preferably achieved by rupturing the valve of the foramen ovale by balloon catheter during transseptal catheterization of the left side of the heart (Rashkind procedure) or by blade septostomy. Surgical atrial septectomy seldom is required. The balloon should be inflated to a diameter of about 15 mm before pull-back to the right atrium. Salutary results consist of a fall in left atrial pressure, equalization of mean left and right atrial pressures, and an increase in the systemic arterial oxygen saturation. When the foramen ovale is stretched by the balloon without accomplishing rupture of the septum primum valve of the fossa ovalis, the improvement in oxygenation is short lived. Infusion or reinfusion intravenously of prostaglandin E1 (0.05 to 0.1 mg/kg/min) has been shown to improve systemic oxygenation temporarily in the latter situation by dilating the ductus arteriosus and thereby facilitating intercirculatory mixing. Although balloon atrial septostomy usually is successful in stabilizing the infant's condition and allowing survival in the neonatal period, the initial rise in systemic arterial oxygen saturation to 65 to 75 percent often is not sustained beyond 6 to 9 months of age. SURGICAL TREATMENT

The development of corrective operations for infants born with transposition of the great arteries has greatly improved prognosis.[475] It has also been suggested that prenatal detection of the anomaly reduces neonatal morbidity and mortality.

ARTERIAL SWITCH OPERATION.

A one-stage anatomical correction is the approach of choice in major centers that care for infants with congenital heart disease.[475] [476] [477] [478] [479] In this operation, both coronary arteries are transposed to the posterior artery; the aorta and pulmonary arteries are transected, contraposed, and anastomosed (Jatene operation) ( Fig. 43-61 ; see also Fig. 44-18 (Figure Not Available) ). The arterial switch anatomical correction may be complicated by coronary ostial stenosis, acquired supravalvular aortic and/or pulmonary stenosis, and pulmonic and/or aortic incompetence. The major advantages of the arterial switch procedure, when compared with the atrial switch procedure, are restoration of the left ventricle as the systemic pump and the potential for long-term maintenance of sinus rhythm.[480] Within the first month of life or rarely two, [477] the arterial switch operation may be performed as a single-stage repair. In such patients, the origin and branching patterns of the coronary arteries are reliably defined preoperatively by two-dimensional echocardiography. One of the main limiting factors for success in the arterial switch procedure is proper relocation of the coronary arteries. Thus, it is particularly important to know the precise variations in coronary arterial anatomy. In approximately 5 percent of the patients, the arteries follow an intramural course, requiring reroofing to allow coronary transfer.[458] Most centers consider that in infants beyond age 1 month it is necessary to prepare the left ventricle to withstand the systemic pressure that is produced after switching the great arteries, because if the ventricular septum is intact, left ventricular pressure and left ventricular wall thickness diminish normally in relation to the postnatal reduction in pulmonary artery pressure. In these infants, a two-stage approach is used, the first of which consists of banding the pulmonary artery; the arterial switch is performed soon thereafter, in some centers as early as 1 to 2 weeks later.[481] In the unusual infant with an intact ventricular septum and a significant patent ductus arteriosus, an early neonatal arterial switch corrective operation with closure of the ductus is indicated. The optimal management of a large VSD is a one-stage intraarterial switch anatomical correction as early in life as possible. In some patients, after early arterial repair of transposition of the great arteries, abnormally enlarged bronchial arteries are identified at postoperative catheterization, and they explain continuous murmurs or persistent cardiomegaly. When these vessels are large enough to produce a volume load to the systemic ventricle, catheter-directed coli embolization is indicated.[482] Follow-up studies after the arterial switch operation have demonstrated good left ventricular function

Figure 43-61 Complete transposition of the great arteries, corrected by a modified arterial switch operation (a). The aorta and pulmonary artery are transected, and the orifices of the coronary arteries are excised with a rim of adjacent aortic wall (b). The aorta is brought under the bifurcation of the pulmonary artery, and the proximal pulmonary artery and the aorta are anastomosed without necessitating graft interposition. The coronary arteries are transferred to the pulmonary artery (c). The mobilized pulmonary artery is directly anastomosed to the proximal aortic stump (d). (From Stark J, deLaval M: Surgery for

Congenital Heart Defects. New York, Grune & Stratton, 1983, p 379.)

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and normal exercise capacity.[483] [484] Potential sequelae of the operation include supravalvular pulmonary stenosis (which may be treated by either reoperation or balloon angioplasty), supravalvular aortic stenosis, and neoaortic regurgitation, usually mild. Long-term patency and growth of the coronary arteries appear satisfactory.[485] [486] [487] Infants with transposition of the great arteries plus a VSD and left ventricular outflow tract obstruction may require a systemic-pulmonary artery anastomosis when a pronounced diminution in pulmonary blood flow exists. A later corrective procedure for these patients bypasses the left ventricular outflow obstruction and uses an intracardiac ventricular baffle connecting the left ventricle to the aorta and an extracardiac prosthetic conduit between the right ventricle and the distal end of a divided pulmonary artery (Rastelli procedure).[488] An alternative approach (Lecompte procedure) couples an intraventricular tunnel and the arterial switch operation, avoiding the use of an extracardiac conduit.[489] ATRIAL (VENOUS) SWITCH OPERATION.

This correction, by either the Mustard or Senning techniques, diverts systemic venous return into the left ventricle through the mitral valve and thence through the left ventricle and pulmonary artery, while the pulmonary venous blood is diverted through the tricuspid and right ventricle to the aorta. Because midterm results of atrial switch procedures disclosed numerous problems involving late right ventricular failure, tricuspid insufficiency, and arrhythmias, most centers have abandoned the use of the atrial switch approach in favor of the more anatomical arterial switch operation. [490] [491] [492] [493] [494] [495] [496]

After physiological correction by atrial switch, postoperative complications are directly related to the intraatrial repair (shunts across the intraatrial patch and obstruction to either systemic or pulmonary venous return or both). There is a high incidence of early and late postoperative dysrhythmias that are more likely to have their basis in injury to the sinoatrial node and/or its arterial supply than in disruption of internodal tracts or damage to the AV node.[491] Tricuspid regurgitation is a less common complication of operation and may in some patients be related to a preexisting abnormality of the tricuspid valve, whereas in most it is related to right ventricular dysfunction. Although assessment of right ventricular contractility is difficult, the right ventricular pump function appears to be impaired before Mustard operation and does not return to normal after successful surgery.[496] It seems likely that the right ventricle can perform as a systemic pumping chamber for the duration of a normal life span.[492] In patients with significant pulmonary vascular obstructive disease, the risk associated with definitive repair (anatomical correction or intraatrial baffle and closure of the ventricular septal defect) is great. In this group of patients, a "palliative" Mustard or Senning procedure leaving the ventricular septal defect open often provides good,

short-term, symptomatic improvement by increasing arterial oxygen tension and reducing the stimulus to progressive polycythemia.[497] Congenitally Corrected Transposition of the Great Arteries (See also p. 1612 )

This term is applied to two distinctly different anomalies: anatomically corrected transposition or malposition of the great arteries and physiologically corrected levo- or L-transposition of the great arteries. DEFINITION.

Invariably, the term congenitally corrected l-transposition is applied to the heart in which a functional correction of the circulation exists by virtue of the relation between the ventricles and great arteries.[499] [500] Corrected or L-transposition occurs when the primitive cardiac tube loops to the left instead of to the right during embryogenesis. The anatomical right ventricle comes to lie on the left and receives oxygenated blood from the left atrium; this blood is ejected into an anteriorly placed, left-sided aorta. The anatomical left ventricle lies to the right and connects the right atrium to a posteriorly placed pulmonary artery. Thus, there are both ventriculoarterial and AV discordant connections, with ventricular inversion. This arrangement of the great arteries and ventricles (in contrast to the uncorrected, complete, or D-transposition) permits functional correction, so that systemic venous blood passes into the pulmonary trunk while arterialized pulmonary venous blood flows into the aorta. In a heart with congenitally corrected transposition, the venae cavae and coronary sinus drain into a right atrium that is normal in position and structure. MORPHOLOGY.

Anatomically corrected malposition of the great arteries is a rare form of congenital heart disease in which the great arteries are abnormally related to each other and to the ventricles but arise, nonetheless, above the anatomically correct ventricles.[498] Because of this, the term malposition rather than transposition is preferable. The anomaly results from either leftward looping of the ventricular segment of the embryonic heart tube in the situs solitus heart or from rightward looping in the situs inversus heart. In this unusual malformation, the aorta is anterior and to the left (levo- or L-malposition) and the pulmonary artery is posteromedial and to the right, presumably because of a subaortic conus that causes mitral-aortic discontinuity. When no other defect exists, the circulation proceeds normally. When an associated lesion prompts ochocardiographic examination, the diagnosis is indicated by the finding of AV concordance in association with wide mitral-aortic discontinuity with an anteriorly placed aorta. At cardiac catheterization, the diagnosis of the abnormal relation between the great arteries may be made by biplane angiocardiography. Anomalies commonly associated with anatomically corrected malposition of the great arteries include VSD, left juxtaposition of the atrial appendages, tricuspid atresia or stenosis, and valvular and subvalvular pulmonic stenosis.

PHYSIOLOGY.

Venous blood flows from the right atrium, designated as the "venous atrium," across an AV valve that has the structure of a normal mitral valve and into the right-sided "venous ventricle" (Fig. 44-22) (Figure Not Available) . The venous ventricle, however, has the morphological characteristics of a normal left ventricle; i.e., its interior lining is trabeculated, it has no crista supraventricularis, and the AV valve is in continuity with the posteriorly placed semilunar valve. It ejects blood into the pulmonary trunk, which arises posterior to the ascending aorta. Oxygenated blood returns from the lungs to the left atrium, which is normal in position and structure; from there it flows into the left-sided "arterial ventricle" across an AV valve that has the structure of a normal tricuspid valve. The interior lining of the arterial ventricle has the morphological characteristics of a normal right ventricle (i.e., it has coarse trabeculations and a crista supraventricularis), and the tricuspid AV valve is not in continuity with the anteriorly placed semilunar valve. The arterial ventricle ejects blood into the aorta, which arises anterior to the pulmonary trunk. In addition to inversion of the cardiac ventricles, there is inversion of the conduction system and coronary arteries. Commonly associated anatomical lesions include atrial and ventricular septal defects, often accompanied by valvular or subvalvular pulmonary stenosis; single ventricle with an outlet chamber with or without pulmonic stenosis; left AV valve regurgitation, usually because of an Ebstein's malformation of the left-sided tricuspid valve; and abnormalities of visceral and atrial situs.[499] CLINICAL MANIFESTATIONS.

The clinical presentation, course, and prognosis of patients with congenital functionally corrected transposition vary, depending on the nature and severity of the complicating intracardiac anomalies. [500] Patients in whom corrected transposition exists as an isolated anomaly present no functional alterations and have no symptoms.[501] Asymptomatic children with an increase in the size of the systemic ventricle, due to significant left-to-right shunting or tricuspid regurgitation, usually develop symptoms of systemic ventricular dysfunction by the third or fourth decade.[500] [501] [502] [503] The natural history of the anomaly and the ability of the right ventricle to perform systemic work are determined primarily by the nature and severity of the associated cardiac defects. [502] The physical findings in congenitally corrected transposition are those of the associated lesions with two exceptions: (1) a single accentuated second heart sound usually is present in the second left intercostal space, representing closure of the aortic valve lying lateral and anterior to the pulmonic valve; and (2) there is a high incidence of cardiac dysrhythmias. LABORATORY EXAMINATION.

Because of the inversion of the heart's conduction system, the ECG can provide important clues in the diagnosis. An abnormal direction of initial (septal) depolarization from right to left causes leftward, anterior, and superior orientation of the initial QRS

forces and reversal of the precordial Q wave pattern (Q waves are present in the right precordial leads and absent in the left). Two AV nodes, one posterior and one anterior, are present in some patients.[504] In addition to inversion of the conduction system, the His bundle is elongated because of the greater distance between the AV node and the base of the ventricular septum. The His bundle is located beneath

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the pulmonic valve in the position of mitral pulmonary continuity; thus, it is subject to significant excursions during mitral valve closure. The anterior "accessory" AV node may be connected directly with an aberrantly located penetrating portion of the His bundle. This arrangement may be a causal factor in the arrhythmias and AV conduction disturbances commonly observed in these patients. First-degree AV block occurs in about 50 percent and complete AV block occurs in 10 to 15 percent of patients. Other degrees of AV dissociation may be observed, as well as paroxysmal supraventricular tachycardia and ventricular extrasystoles. In some patients, Kent bundle connections provide the anatomical substrate for preexcitation.[504] Roentgenographic examination characteristically reveals absence of the normal pulmonary artery segment and a smooth convexity of the left supracardiac border produced by the displaced ascending aorta (see Chap. 8 ). The latter may be visualized by radionuclide scintillation scans of the central circulation. The main pulmonary trunk is medially displaced and absent from the cardiac silhouette; the right pulmonary hilus often is prominent and elevated compared with the left, producing a right-sided waterfall appearance. Two-dimensional echocardiography seeks to identify the morphology of each ventricle by defining the characteristics of the inflow and outflow tracts and papillary and trabecular muscle morphology, ventricular shape, and great artery position.[505] By tracing the great arteries back to their ventricles of origin in subxiphoid and parasternal short-axis planes, one would find that the anterior leftward great artery (the aorta) arises from the left-sided ventricle and is not in continuity with the left-sided AV valve. The great arteries exit the heart in parallel fashion; the position, origin, and branching pattern of the great arteries are observed in subxiphoid and suprasternal views, and the anteroposterior and right-left positions of the great arteries can be seen from the parasternal short-axis view. Because the ventricular septum lies in the anteroposterior plane parallel to the echo beam, it may not be visualized from a left parasternal view. In apical-basal or subxiphoid four-chamber echocardiographic views, the right and left ventricular morphology and the inverted position of the AV valves may be ascertained correctly. The latter views also demonstrate the level of attachment of the AV valves and allow detection of inferior displacement of the left-sided tricuspid valve when Ebstein's anomaly coexists. At cardiac catheterization, the diagnosis should be suspected when the venous catheter enters a posterior and midline main pulmonary trunk. Retrograde arterial catheter passage establishes the typical position of the ascending aorta at the upper left cardiac border. Hemodynamic abnormalities depend on the lesions associated with corrected

transposition. Selective angiocardiography allows visualization of the transposed great arteries and morphological differentiation of the two ventricles (Fig. 43-62) . The ventricles usually lie side by side, with the ventricular septum oriented in an anteroposterior direction. Selective aortography demonstrates the inverted coronary arterial pattern that is invariably present in corrected transposition. The competence of the left AV valve may be determined by injection of contrast material into the arterial ventricle.[506] When a left-sided Ebstein's malformation exists, the leaflets are displaced distal to the true valve annulus. The level of the annulus may be determined by visualization of the circumflex branch of the left coronary artery, which courses posteriorly in the AV groove. Specific problems have attended operative repair of the lesions associated with congenitally corrected transposition, owing primarily to the course of the conduction AV system and the coronary arterial pattern. [507] [508] The inversion of the coronary arterial system occasionally may limit and preclude an incision into the venous ventricle, thereby interfering with exposure of intracardiac defects in the usual manner. The disadvantage in approaching intracardiac anomalies using an incision in the morphological right ventricle is that this is the systemic ventricle. When significant pulmonary stenosis exists within a VSD, a valved extracardiac conduit often is a required part of the surgical repair. Surgical risks are especially high in patients in whom significant regurgitation exists from the arterial ventricle to the arterial atrium. In these patients, annuloplasty or, more usually, valve replacement is required. In all operative approaches, if complete heart block has been present intermittently or permanently preoperatively or intraoperatively, permanent epicardial atrial and ventricular pacemaker leads are implanted. The disappointing results with traditional techniques of repair have led to more anatomical forms of surgical correction in which the morphological left ventricle supports the systemic circulation, rather than leaving the morphological right ventricle and tricuspid valve in the systemic circulation. Thus, the so-called double-switch procedure promises to decrease the development and significance of tricuspid valve regurgitation as well as the incidence of surgical complete heart block. In this procedure, an arterial switch operation establishes ventriculoarterial concordance and the systemic and pulmonary venous returns are rerouted by either the Mustard or Senning technique. If a VSD is present, it can be closed in the usual manner. When pulmonary stenosis is present in association with a ventricular defect, the performance of an arterial switch procedure is precluded, but the left ventricle can be routed to the aorta via a prosthetic baffle within the right ventricle to channel the VSD to the aortic valve. The outflow tract of the right ventricle can then be reconstructed by placement of a conduit from the right ventricle to the pulmonary artery bifurcation, and a venous switch procedure completes the operation. Double-Outlet Right Ventricle MORPHOLOGY.

Other designations applied to this lesion include origin of both great arteries from the right ventricle, partial transposition, complete transposition of the aorta and levoposition

of the pulmonary artery, complete dextroposition of the aorta, and the Taussig-Bing complex. This is an extremely heterogeneous category of malformations in which an abnormal relation exists between the aorta and the pulmonary trunk, which arise wholly or in large part from the right ventricle.[509] DEFINITIONS.

A uniform definition or classification of double-outlet right ventricle does not exist. To some, double-outlet right ventricle means origin of one great artery and at least 50 percent of the other over the right ventricle; others require the presence of bilateral conus muscle between both great arteries and the AV annulus. One or both great arteries may arise from an infundibular chamber; there may be considerable variability in the amount of subarterial conus muscle. Thus, the semilunar valves may lie side by side, or with the pulmonary valve more anterior and superior, or with a more anterior and superior aortic valve. Commonly, neither semilunar valve is in fibrous continuity with either AV valve, and a VSD is usually present and represents the only outlet from the left ventricle. The VSD is of the malalignment type because the infundibular septum is positioned abnormally. When the amount of conus muscle beneath the two great arteries varies, the VSD commonly is positioned beneath the more posterior semilunar valve, which in fact usually overrides the interventricular septum through this VSD. The amount of conus muscle underneath the valve determines the position of the semilunar root in relation to the ventricles below. Thus, double-outlet right ventricle resides within the spectrum of conotruncal abnormalities ranging from tetralogy of Fallot to transposition of the great arteries. The VSD occasionally extends beneath both great arteries and is referred to as doubly committed. In some instances, the VSD is remote from both great arteries, or is considered uncommitted, in which case the defect often lies in the inlet or muscular portion of the interventricular septum. ASSOCIATED LESIONS.

More than half of patients with double-outlet right ventricle have associated anomalies of the right AV valves.[509] [510] Mitral atresia associated with a hypoplastic left ventricle is common; less often observed are tricuspid stenosis, Ebstein's anomaly of the tricuspid valve, complete AV septal defect, and overriding or straddling of either AV valve. Aortic coarctation may be associated with double-outlet right ventricle, particularly when the subaortic area is narrowed by malalignment of the infundibular septum. Double-outlet right ventricle also may be a component of the many cardiovascular anomalies of the splenic dysgenesis or heterotaxy syndromes. An increased incidence of the anomaly occurs in infants with the trisomy 18 syndrome. The pathological features in most patients include side-by-side pulmonic and aortic valves and discontinuity between the mitral and aortic valves. The latter exists because muscular infundibulum is usual beneath both semilunar valves. The VSD may be remote from or closely related to one or both semilunar valves (Fig. 43-63) . When the interventricular defect is subpulmonic, with or without a straddling pulmonary trunk, the complex is designated Taussig-Bing. In most patients, the interventricular septal defect

is below the crista supraventricularis and is subaortic in location. Least often, the defect either

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Figure 43-62 Congenitally corrected (levo-)transposition of the great arteries in a 4-year-old boy. A, Anteroposterior ventriculogram in left-sided ventricle with mesocardia. The morphological right ventricle (RV) is left sided, indicating an L-ventricular loop (inverted ventricles in situs solitus). The aorta (AO) originates above the morphological right ventricle and is thus transposed and in classic levo-transposition. B, Lateral ventriculogram in left-sided ventricle (same frame as A). The aorta originates anteriorly above the morphological right ventricle (RV). C, Anteroposterior ventriculogram in right-sided morphological left ventricle (LV). The transposed pulmonary artery (PA) arises from this ventricle, and the ventricular septum appears intact. Pulmonic valve thickening is also evident. The aorta (A) is to the left of the pulmonary artery. Note that the ventricular septum in the L-ventricular loop is visualized best in the anteroposterior views. D, Lateral ventriculogram in right-sided ventricle (same frame as C). The pulmonary artery is posterior to the aorta, and supravalvular pulmonic narrowing is seen. (From Freedom RM, Harrington DP, White RI Jr, et al: The differential diagnosis of levo-transposed or malposed aorta: An angiocardiographic study. Circulation 50:1040, 1974.)

is remote from both semilunar valves (uncommitted) or underlies both (doubly committed). CLINICAL MANIFESTATIONS.

The clinical and physiological picture is determined by the size and location of the VSD and the presence or absence of pulmonic stenosis. In the Taussig-Bing form of double-outlet right ventricle, the malformation resembles physiologically and clinically complete transposition with VSD and pulmonary hypertension. When the VSD is subaortic, the stream of blood from the left

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Figure 43-63 Double-outlet right ventricle with side-by-side relation of great arteries is illustrated in both panels. A, A subaortic ventricular septal defect below the crista supraventricularis favors delivery of left ventricular blood to the aorta. B, Subpulmonary location of the ventricular septal defect above the crista favors streaming to the pulmonary trunk. (From Castaneda A, Jonas RA, Mayer JE Jr, et al: Cardiac Surgery of the Neonate and Infant. Philadelphia, WB Saunders, 1994, p 446.)

ventricle is directed preferentially to the aorta. Thus, there may be little or no detectable cyanosis, and these patients usually clinically resemble those with an isolated large VSD and pulmonary hypertension. The most important determinant of the natural history in both these types of

double-outlet right ventricle is the progression of pulmonary vascular obstruction. In contrast, when there is pulmonary outflow tract obstruction, which often is severe and found commonly in these patients in whom the VSD is subaortic, clinical findings are similar to those of cyanotic tetralogy of Fallot. In some patients, especially without pulmonic stenosis, the ECG shows a superiorly oriented counterclockwise frontal plane QRS loop in addition to right ventricular hypertrophy.[511] The pattern appears to result from relative hypoplasia of the anterosuperior left bundle and preferential activation of the posteroinferior left ventricular wall. The presence of the latter ECG pattern in patients with double-outlet right ventricle should alert one to the possibility of a coexistent AV septal defect or abnormality of the mitral valve. DIAGNOSIS.

Two-dimensional echocardiography may reliably distinguish double-outlet right ventricle from other lesions causing cyanosis, such as tetralogy of Fallot and transposition of the great arteries.[512] [513] The three key imaging features are origin of both great arteries from the anterior right ventricle, mitral-semilunar valve discontinuity, and absence of left ventricular outflow other than the VSD. The relative anteroposterior positions of the great arteries can be determined from the parasternal short-axis view. The parasternal long-axis view shows the position of the more posterior semilunar root relative to the interventricular septum and anterior mitral leaflet and is the best view for demonstrating the presence of subarterial conus muscle. Subxiphoid views best demonstrate the position of both great arteries over the ventricles. Each great artery is displayed on longand short-axis subxiphoid sweeps. In reporting echocardiographic results, it is imperative to state each component's anatomical feature, i.e., the position of both great arteries, the presence and amount of infundibulum under each semilunar valve, the anatomy of both subpulmonary and subaortic outflow tracts, the position and size of the associated VSD, and the presence of all other associated lesions, particularly AV valve anomalies and coarctation of the aorta. In each of the different types of double-outlet right ventricle, precise delineation of the malformation also depends on careful angiocardiographic analysis. The diagnosis can be established with confidence when the angiographic findings include simultaneous opacification of both great vessels from the right ventricle, aortic and pulmonic valves at the same transverse level, and separation of the aortic valve from the aortic leaflet of the mitral valve by the crista supraventricularis (Fig. 43-64) . The position of the VSD and the relation between the great arteries must be defined to plan surgical procedures appropriately. Experience is growing with the application of transesophageal echocardiograpy in analyzing the complex anatomical and spatial relationships encountered in double-outlet right ventricle, requiring a biplane or multiplane format for adequate assessment. SURGICAL TREATMENT.

The goals of operative treatment are to establish left ventricle-to-aorta continuity, create adequate right ventricle-to-pulmonary continuity, and repair associated lesions.[510] Because of the complexity of intracardiac repair of these anomalies, many centers prefer to give palliation to infants, attempting reparative surgery after the age of 1 to 2 years. In double-outlet right ventricle with subaortic VSD, repair is accomplished by creating an intraventricular baffle that conducts left ventricular blood to the aorta. When the VSD is subpulmonic, repair is accomplished by closure of the VSD and arterial switch.[510] [514] When the VSD is doubly committed, i.e., both subaortic and subpulmonic, operation consists of creating an intraventricular baffle that conducts left ventricular blood to the aorta. The type of double-outlet right ventricle in which the VSD is remote and uncommitted to either semilunar orifice may be approached by a venous switch operation, permitting the right ventricle to eject into the aorta, followed by placement of a conduit between the left ventricle and the pulmonary trunk. Alternatively, some patients may be candidates for a cavopulmonary shunt or a modified Fontan procedure, particularly if additional findings include a common AV orifice, hypoplastic ventricles, a straddling tricuspid valve, or a straddling mitral valve.[515] Double-Outlet Left Ventricle

One of the rarest cardiac anomalies consists of the origin of both great arteries from the morphological left ventricle. Conal musculature or an infundibulum usually is absent or deficient beneath the orifices of both semilunar valves.[516] The spectrum of associated malformations is broad. VSD and valvular or subvalvular pulmonic stenosis has been present in most patients. Supportive diagnostic information is provided by magnetic resonance imaging. Echocardiographic[517] and angiocardiographic assessment of the spatial relations of the origins of the great arteries are essential to an accurate diagnosis and to evaluating the possibility of operative repair. In most patients, the latter consists of closure of the VSD and placement of a right ventricle-pulmonary artery conduit.

Figure 43-64 Simultaneous opacification of both great arteries from a right ventricular injection of contrast material in a patient with double-outlet right ventricle (RV). The aortic and pulmonic valves are at the same transverse level. AO = aorta; PA = pulmonary artery. (Courtesy of Dr. Robert White.)

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Total Anomalous Pulmonary Venous Connection

This anomaly has been estimated to account for 1 to 3 percent of all cases of congenital heart disease and 2 percent of deaths therefrom in the first year of life. [518] The anomaly is the result of persistence during embryogenesis of communications between the pulmonary portion of the foregut plexus and the cardinal or umbilicovitelline system of veins, resulting in the connection of all the pulmonary veins either to the right atrium directly or to the systemic veins and their tributaries. Because all venous blood returns

to the right atrium, an interatrial communication is an integral part of this malformation. Additional major cardiac malformations occur in about 30 percent of patients. Among these are common atrium, atrial isomerism, single ventricle, truncus arteriosus, and anomalies of the systemic veins. Extracardiac malformations, particularly of the alimentary, endocrine, and genitourinary systems, are present in 25 to 30 percent of cases. MORPHOLOGY.

The anatomical varieties of total anomalous pulmonary venous connection may be subdivided, depending on the level of the abnormal drainage (Fig. 43-65). Table 43-10 provides average figures of the distribution of the sites of anomalous connection. [578] The anomalous connection usually is supradiaphragmatic and to the left brachiocephalic vein, right atrium, coronary sinus, or superior vena cava. In about 13 percent, particularly in males, the distal site of connection is below the diaphragm. In this situation, a common trunk originates from the confluence of pulmonary veins and descends in front of the esophagus, penetrating the diaphragm through the esophageal hiatus. The anomalous trunk then connects into the portal vein or one of its tributaries, the ductus venosus, or, rarely, to one

Figure 43-65 Anatomical types of total anomalous pulmonary venous return: supracardiac, in which the pulmonary veins drain either via the vertical vein to the anomalous vein (A) or directly to the superior vena cava with the orifice close to the orifice of the azygos vein (B). C, Drainage directly into the right atrium or into the coronary sinus. D, Infracardiac drainage via a vertical vein into the portal vein or the inferior vena cava. (From Stark I, deLeval M: Surgery for Congenital Heart Defects. 2nd ed. Philadelphia, WB Saunders, 1994, p 330.)

TABLE 43-10 -- SITE OF CONNECTION IN TOTAL ANOMALOUS PULMONARY VENOUS CONNECTION Connection to right atrium 15% Connection to common cardinal system (Right) superior vena cava Azygos vein

11% 1%

Connection to left common cardinal system Left innominate vein

36%

Coronary sinus

16%

Connection to umbilicovitelline system Portal vein

6%

Ductus venosus

4%

Inferior vena cava

2%

Hepatic vein

1%

Multiple sites

7%

Unknown

1%

of the hepatic veins. In rare cases, various combinations of anomalous connection occur, with drainage to several levels. HEMODYNAMICS.

The physiological consequences and, accordingly, the clinical picture depend on the size of the interatrial communication and on the magnitude of the pulmonary vascular resistance. When the interatrial communication is small, systemic blood flow is markedly limited.[519] Right atrial and systemic venous pressures are elevated, and hepatic enlargement and peripheral edema are present. The size of the interatrial communication also is an important determinant in the development in utero and postnatally of the left atrium and left ventricle. Left atrial cavity size usually is somewhat reduced, whereas left ventricular volumes may be reduced or normal. The magnitude of pulmonary blood flow and therefore the ratio of oxygenated to unoxygenated blood that returns to the right atrium are a function of pulmonary vascular resistance. The arterial oxygen saturation, which ranges from markedly reduced to normal values, is inversely related to the pulmonary vascular resistance. In this regard, in most patients, the principal determinant of pulmonary pressures and resistance is related less to augmented pulmonary blood flow and pulmonary arteriolar vascular obstruction than to the presence and intensity of pulmonary venous obstruction.[520] [521] Obstruction to pulmonary venous return and pulmonary venous hypertension are invariably present in patients with infradiaphragmatic anomalous pulmonary venous connection and in many with a subdiaphragmatic pathway. In the former type, pulmonary venous obstruction results from the length and narrowness of the common pulmonary venous trunk, compression at the esophageal hiatus of the diaphragm, constriction at the subdiaphragmatic site of insertion, or pulmonary venous return that must pass first through the portal-hepatic circulation before returning to the right atrium. When venous obstruction occurs in supradiaphragmatic types of drainage, constriction may exist at the entrance site of the anomalous veins into the systemic venous circulation, and/or the anomalous venous channel may be kinked or situated abnormally and compressed between the left pulmonary artery and left bronchus.[520] The presence of a small, restrictive patent foramen ovale occasionally results in pulmonary venous obstruction. Pulmonary vascular obstructive disease is rare during infancy, although exceptions have been reported. In patients without pulmonary venous obstruction, the risk of developing Eisenmenger reaction is comparable with that in patients with an atrial septal defect. CLINICAL MANIFESTATIONS.

The majority of patients with total anomalous pulmonary venous connection have symptoms during the first year of life, and 80 percent die before age 1 year if left

untreated.[518] The few who remain asymptomatic have a relatively good prognosis; once the condition is detected, operation may be elected later in

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childhood. Symptomatic infants with total anomalous pulmonary venous connection present with signs of heart failure and/or cyanosis. Infants with pulmonary venous obstruction present with the early onset of severe dyspnea, pulmonary edema, cyanosis, and right heart failure. Cardiac murmurs often are not prominent. In the unobstructed forms of total anomalous pulmonary venous connection, the characteristic physical findings include right ventricular precordial overactivity and minimal cyanosis unless congestive heart failure intervenes. Multiple heart sounds often are audible, consisting of a first heart sound followed by an ejection sound; a fixed, widely split second heart sound with an accentuated pulmonic component; and a third and often a fourth heart sound. A soft systolic ejection murmur is usual along the left sternal border, and a mid-diastolic murmur of flow across the tricuspid valve commonly is audible at the lower left sternal border. LABORATORY FINDINGS.

The ECG shows right-axis deviation and right atrial and right ventricular hypertrophy. Roentgenograms of the chest reveal increased pulmonary blood flow; the right atrium and ventricle are dilated and hypertrophied, and the pulmonary artery segment is enlarged (Fig. 43-66) . In addition, the specific site of anomalous connection may cause a characteristic appearance of the cardiac silhouette. Thus, in patients with total anomalous pulmonary venous connection to the left brachiocephalic vein, the superior vena cava on the right, left brachiocephalic vein superiorly, and vertical vein on the left produce a cardiac shadow that resembles a snowman or figure eight. The upper right cardiac border may be prominent when the anomalous connection is to the right superior vena cava. Echocardiography demonstrates marked enlargement of the right ventricle and a small left atrium.[522] The objective of ultrasound imaging in these patients is to confirm the clinical diagnosis and to locate the site of connection of the common pulmonary vein. Doppler flow and color mapping enhance the capability of identifying all the pulmonary veins and their drainage sites and help to assess the presence of obstruction within individual pulmonary veins and along the vertical vein.[523] [524] An echo-free space representing the common pulmonary venous chamber may occasionally be seen to lie behind the left atrium on ultrasound examination. The use of echocardiography has supplanted cardiac catheterization in preoperative diagnosis in patients without atrial isomerism or single-ventricle hearts. Diagnostic echocardiographic findings include an absence of pulmonary

Figure 43-66 Chest roentgenogram in an infant with total anomalous pulmonary venous connection

below the diaphragm shows normal overall heart size but a diffuse pattern of pulmonary venous hypertension in both lung fields.

vein connections and a small left atrium in the presence of right-to-left bulging of the septum primum at the foramen ovale. Positive diagnosis is made by identifying pulmonary venous connection to the systemic veins, coronary sinus, or right atrium rather than to the left atrium. All four pulmonary veins and their connections must be identified to diagnose mixed types accurately. There is no standard echocardiographic method for tracing pulmonary venous pathways because of their diverse anatomical positions, although transesophageal studies can importantly assist in this regard.[524] An infradiaphragmatic total anomalous pulmonary venous connection usually connects to the portal venous system but can connect to the hepatic veins. Doppler is used to distinguish between the abdominal vessels. Thus, the flow pattern in the inferior vena cava is phasic, nearly continuous, and toward the heart, in contrast to flow in the descending aorta, which has a laminar profile in systole in a direction away from the heart. Flow in the common pulmonary vein resembles that of the inferior vena cava except that its direction is away from the heart. Although not often used, especially in infants, magnetic resonance imaging may also delineate the site of connections of the various types of total anomalous pulmonary venous return. At cardiac catheterization, those patients found to have systemic arterial saturations below 70 percent and pulmonary artery pressure at or above systemic levels are likely to have pulmonary venous obstruction. Variations in oxygen saturation in the systemic venous circulation may be helpful. In the subdiaphragmatic type, a step-up may not be apparent in inferior vena caval oxygen saturations obtained by way of femoral vein cannulation because of the contribution of highly oxygenated renal venous blood to the caval stream. In contrast, sampling of the hepatic or portal vein by way of a catheter inserted through the umbilical vein yields diagnostically higher oxygen saturations, indicating anomalous return to those vessels. If the cardiac catheter can be manipulated directly into the anomalous trunk through its site of connection, selective injection of contrast material into the common channel provides anatomical definition of the pulmonary venous tree. If the pulmonary veins cannot be entered directly, selective right and left main pulmonary artery injection of contrast material often is more helpful than is injection into a main pulmonary artery because many infants have a persistent patent ductus arteriosus through which the contrast agent flows right to left. Moreover, the drainage from both lungs must be outlined clearly to preclude a mixed type of anomalous venous drainage. Pulmonary venous obstruction may be detected by noting a pressure difference between the pulmonary artery wedge pressure and the right atrium. MANAGEMENT.

Corrective surgery for sick infants should be performed as soon as possible, usually on the basis of two-dimensional and Doppler echocardiography, avoiding the additional stress of invasive diagnostic study. Before age 1 month, survival greater than 75 percent is anticipated. Infants with the worst prognosis are those in whom individual pulmonary vein sizes are smallest, which are measurements that can be made

preoperatively by echocardiogram. Unless a child has pulmonary vascular disease, results of operation for total anomalous pulmonary venous connection in patients beyond infancy are generally good.[525] [526] The procedure consists of creating an anastomosis between the common pulmonary venous channel and left atrium and closing the atrial defect and the anomalous venous pathway. Improved results of operation in infancy require that postoperative pulmonary venous hypertension be averted by construction of a generally large anastomosis with or without enlargement of the left atrium. Normal hemodynamics and cardiac function have been demonstrated after surgical correction.

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Partial Anomalous Pulmonary Venous Connection

In this condition, one or more of the pulmonary veins, but not all, are connected to the right atrium or to one or more of its venous tributaries. An atrial septal defect, particularly one of the sinus venosus type, commonly accompanies this anomaly; the usual connection involves the veins of the right upper and middle lobes and the superior vena cava.[518] Exclusive of atrial septal defects, major additional cardiac malformations occur in about 20 percent of patients: these include VSD, tetralogy of Fallot, and various complex anomalies. In the absence of associated anomalies, the physiological disturbance is determined by the number of anomalous veins and their site of connection, the presence and size of an atrial septal defect, and the state of the pulmonary vascular bed.[527] In the usual patient with isolated partial pulmonary venous connection, the hemodynamic state and physical findings are similar to those in atrial septal defect. Rarely, venous drainage of the right lung is into the inferior vena cava. This condition often is associated with hypoplasia of the right lung, dextroposition of the heart, pulmonary parenchymal abnormalities, and anomalous system supply to the lower lobe of the right lung from the abdominal aorta or its main branches. This complex has been designated the scimitar syndrome because of the characteristic roentgenographic finding of a crescent-like shadow in the right lower lung field that is produced by the anomalous venous channel.[528] Transesophageal echocardiography is highly diagnostic of partial anomalous pulmonary venous connection and can obviate catheterization and angiography.[524] At cardiac catheterization, partial anomalous pulmonary venous connection to the coronary sinus, azygos vein, or superior vena cava may be identified by careful and frequent oximetry sampling. Oximetry is of limited value when the anomalous connection is to the inferior vena cava because of both reduced flow through the right lung and the contribution to the vena caval stream of highly oxygenated blood from the renal veins. Selective angiography is most helpful in cases in which the anomalous veins connect far away from the right atrium. Surgical repair offers definitive therapy at low risk if pulmonary vascular obliterative disease has not yet developed.

Malpositions of the Heart and Cardiac Apex

Positional anomalies of the heart are conditions in which the cardiac apex is located in the right side of the chest (dextrocardia) or is centrally located (mesocardia), or in which the heart is in its normal location in the left side of the chest but the position of the viscera is abnormal (isolated levocardia). Such hearts commonly are abnormal with respect to chamber localization and great artery attachments: associated complex intracardiac and extracardiac lesions are common. Problems of terminology abound in the literature describing these complex cardiac anomalies, although sensible and uniform systems of classification are available.[529] [530] ANATOMICAL FEATURES.

Defining the cardiac anatomy in instances of cardiac malposition requires a description of three cardiac segments--the visceroatrial situs, the ventricular loop, and the conotruncus (the atria, ventricles, and great arteries, respectively). In addition to defining positional interrelation, the description of the malposed heart also must include the connections of the ventricles to the atria and great arteries as well as chamber identification, both morphologically and functionally. DIAGNOSIS.

To accomplish accurate diagnosis may require a synthesis of findings from noninvasive tests such as two-dimensional echocardiography, CT, and magnetic resonance imaging,[531] as well as hemodynamic and cineangiographic findings obtained at cardiac catheterization. Expert echocardiographers analyze, separately and independently of adjacent segments, each cardiac segment (atria, AV canal, ventricles, infundibulum, and great arteries) in terms of both situs and alignments.[532] [533] In general, the determination of the body situs indicates the position of the atria. The visceral situs usually can be determined by the location of the stomach bubble and liver on a routine roentgenogram and of the inferior vena cava by means of echocardiography or the position of a cardiac catheter or by means of a CT or venous or radioisotope angiocardiogram. Atrial anatomy is best investigated noninvasively by using subxiphoid long- and short-axis and apical four-chamber echocardiographic views. Venous contrast injections may be useful to define systemic venous connections. Situs solitus is the normal arrangement of viscera and atria, with the right atrium right sided and the left atrium left sided. Situs solitus is further characterized by a trilobed right lung and eparterial bronchus (i.e., the right upper lobe bronchus passes above the right pulmonary artery), a bilobed left lung and hyparterial bronchus (i.e., the left bronchus passes below the left pulmonary artery), the major lobe of the liver on the right, a left-sided stomach and spleen, and right-sided venae cavae. Situs inversus is a mirror image of normal. Situs ambiguus or visceral heterotaxy refers to an anatomically uncertain or indeterminate body configuration. The latter often is seen in association

with congenital asplenia, which resembles bilateral right-sidedness (right isomerism), and congenital polysplenia, which resembles bilateral left-sidedness (left isomerism).[530] [531] [532] [533] [534] [535]

ASPLENIA (RIGHT ISOMERISM).

Cardiac anomalies commonly associated with asplenia include anomalous systemic venous connection, atrial septal or complete endocardial cushion defect, common ventricle, transposition of the great arteries, severe pulmonic stenosis or atresia, and anomalous pulmonary venous connection usually infradiaphragmatic or to the superior vena cava-atrium junction. Polysplenia (left isomerism) commonly is associated with absence of the hepatic portion of the inferior vena cava with azygos continuation, bilateral superior venae cavae, anomalous pulmonary venous connection, and atrial septal defect (either ostium secundum or endocardial cushion). Pulmonic stenosis and double-outlet right ventricle are each observed in about 25 percent of cases. It is important to recognize these complex syndromes to distinguish them from forms of cyanotic heart disease that may be more amenable to corrective surgical therapy. In many of these patients, improvement results from palliation by modifications of the Fontan procedure, despite anomalies of systemic and pulmonary venous return in association with single ventricle anatomy.[536] [537] Diagnosis is suggested by a symmetrical liver shadow roentgenographically and, in asplenia, by the presence of Howell-Jolly and Heinz bodies in red blood cells demonstrated on blood smear, and it is confirmed by a negative or abnormal radioactive spleen scan. Once the type of visceral situs is defined, it is necessary to describe the bulboventricular loop. The primitive cardiac tube normally bends to the right (D-loop), and thus the anatomical right ventricle is brought to the right of the anatomical left ventricle. An L-loop brings the morphological right ventricle left-sided relative to the morphological left ventricle. The L-loop is normal in the presence of situs inversus, but in situs solitus it is synonymous with inverted ventricles. VENTRICULAR MORPHOLOGY.

The number, morphology, and size of the ventricles can be ascertained by using various echocardiographic views. The morphological features of each ventricle also can be identified angiographically. The anatomical right ventricle is equipped with a tricuspid valve, is highly trabeculated, and contains the septal band of the single papillary muscle; its infundibulum lies anterior to and superiorly beyond the outlet of the left ventricle. The anatomical right ventricle usually connects with whichever of the two great arteries is the more anterior. The anatomical left ventricle is smooth walled and contains an outlet that lies posterior to the right ventricular infundibulum; its entrance is guarded by a bicuspid mitral valve, the anterior leaflet of which is normally in continuity with elements of the semilunar valve at its outlet. On echocardiographic examination, the insertion of the AV valves assists identification of the ventricle. The tricuspid valve is more apically situated than the mitral valve and is attached to the ventricular septum by papillary muscles, whereas the mitral valve is not. The right ventricular apical musculature is coarse and contains a moderator band of muscle.

GREAT ARTERIES.

The great arteries are described in terms of their positional interrelations and their ventricular connections. Each outflow tract and semilunar valve should be examined in both long- and short-axis echocardiographic views.[533] The ventriculoarterial alignments may be determined by direct visualization from the subxiphoid window. The relation between the great arteries can best be demonstrated noninvasively using parasternal short-axis echocardiographic views, which display the semilunar roots. The aortic arch and brachiocephalic arteries are seen well using suprasternal notch views. The pulmonary artery is seen from high parasternal or suprasternal notch short-axis sections. The ventricular attachments may be normal or may form the anomalies of double-outlet right or left ventricle or transposition. The arterial interrelations are described as D(dextro), in which the ascending aorta sweeps toward the right and lies to the right of the main pulmonary artery; L(levo), in which the ascending aorta sweeps toward the left and lies to the left of the main pulmonary artery; or A(antero), which is the rare situation in which the aorta lies directly in front of the pulmonary artery. The D, L, and Adescriptions of the aorticopulmonary artery interrelations should not be confused with the D- or L-loop designation of the ventricular interrelations.[530] Using segmental sets composed of descriptive units of visceroatrial situs/ventricular loop/great artery relations greatly simplifies expression of the type of cardiac anatomy present in cardiac malposition. For example, the normal heart in a patient with situs inversus and dextrocardia is referred to as inversus/Lloop/Lnormal; complete transposition of the great arteries in a patient with situs inversus is referred to as inversus/Lloop/Ltransposition; functionally corrected transposition in a patient with situs solitus is referred to as solitus/Lloop/Ltransposition; dextrocardia and functionally corrected transposition is designated solitus/Dloop/Dtransposition with dextrocardia. After the cardiac chambers are diagnosed functionally (arterial and venous), the positional and morphological relations are understood, and the presence of associated anomalies is established, the principles of medical and surgical treatment apply to these cardiac malpositions as they do to normally located hearts.[536]

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OTHER CONDITIONS Congenital Pericardial Defects

Isolated pericardial defects (see Chap. 50 ) are rare. They most commonly occur in males and usually are left sided, although they may be right sided, diaphragmatic, or total.[538] The anomaly is produced by deficient formation of the pleuropericardial membrane or, if diaphragmatic, defective formations of the septum transversum. Associated congenital anomalies of the heart and lungs occur in about 30 percent of cases. Most patients with the isolated defect are asymptomatic. Nonspecific anterior

chest pain may be the result of torsion of the great arteries due to absence of the stabilizing forces of the left pericardium. With complete absence of the left pericardium, a conspicuous apical impulse may be noted to be shifted leftward to the anterior or midaxillary line. ECG changes may be related to levoposition of the heart; a leftward displacement of the QRS transition in the precordial leads and vertical or right-axis deviation are usual. The diagnosis may be suggested by chest roentgenograms. With complete left pericardial absence, the heart is levo-posed, and the aortic knob, pulmonary artery, and ventricles form three prominent left heart border convexities. A partial left pericardial defect may be suspected on the basis of various degrees of prominence of the pulmonary artery and/or the left atrial appendage. Echocardiographic findings often mimic those observed in patients with right ventricular volume overload (enlarged right ventricle and abnormal ventricular septal motion), probably owing to the altered cardiac position and motion with the thorax.[539] Other echocardiographic clues include lateral extension of the left atrial appendage as it herniates through the pericardial defect; this is best seen in short-axis views. The anomaly can be definitively diagnosed by CT or magnetic resonance imaging.[540] Cardiac catheterization is of little diagnostic value. Complete absence of the left pericardium requires no treatment. Partial defects, however, may impose serious risks, including herniation and strangulation of the ventricles or left atrial appendage with left-sided defects or the possibility of a superior vena cava obstructive syndrome with right-sided defects. [541] In the diaphragmatic type, cardiac compression by abdominal contents requires surgical repair. Partial left or right defects may be closed with a patch of mediastinal pleura. Single Atrium

Single or common atrium is a rare, isolated defect. The anomaly consists of an absent atrial septum, usually with a cleft in the anteromedial leaflet of the mitral valve and, occasionally, with a cleft tricuspid valve as well. The lesion may be one component of the Ellis-van Creveld syndrome (see Table 43-2 (Table Not Available) ) or of the complex cardiac anomalies in patients with asplenia or polysplenia. Single atrium may be suspected clinically by the presence of cardiac murmurs of an atrial septal defect and mitral regurgitation associated with mild cyanosis, roentgenographic evidence of cardiac enlargement and increased pulmonary blood flow, and ECG features of AV septal defect. An absence of echoes from any part of the atrial septum is the essential feature of two-dimensional echocardiographic examination, which also may show a cleft anterior mitral leaflet, increased right ventricular end-diastolic dimension, paradoxical ventricular septal motion, and a dilated, pulsatile pulmonary trunk. Angiographically, the absence of the atrial septum produces a large, globe-shaped single atrial structure. Selective left ventricular angiocardiography shows the characteristic gooseneck appearance seen in the various forms of AV septal defect. In the absence of pulmonary vascular obstructive disease, surgical correction is

indicated by means of a prosthetic patch. Single Ventricle (Univentricular Atrioventricular Connection)

Hearts with univentricular AV connection constitute a family of complex lesions in which both AV valves or a common AV valve open into a single ventricular chamber.[542] Terminology is varied, and the anomaly often is referred to as a double-inlet, single, or common ventricle, which is imprecise but useful shorthand for the entity. The definition excludes examples of tricuspid or mitral atresia. Single ventricle is almost always accompanied by abnormal great artery positional relations; the incidence of L-malposition of the great arteries is about equal to that of D-malposition. Associated anomalies are common and include, in particular, pulmonic valvular or subvalvular stenosis, subaortic stenosis, total or partial anomalous pulmonary venous connection, and coarctation of the aorta. MORPHOLOGY.

In about 80 percent of patients, the single ventricle morphologically resembles a left ventricular chamber that is separated from an infundibular outlet chamber by a bulboventricular septum.[543] The opening is variously called the bulboventricular foramen and VSD. The infundibular chamber is considered to represent developmentally the outflow tract of the right ventricle. The usual AV connection is transposition; when the heart is left sided, the connection is usually L-transposition, whereas it is usually D-transposition when the heart is right sided. When the great arteries are malposed, the infundibulum lying anteriorly at the basal position of the single ventricle communicates with the aorta and may be in one of two positions: noninverted (D-malposition), when it is situated at the right basal aspect of the heart, or inverted (L-malposition), when it is located at the left base of the heart. In the unusual situation in which the great arteries are normally related, the infundibulum communicates with the pulmonary trunk.[542] Double-inlet left ventricle is a term used synonymously to describe the most frequently encountered single ventricular chamber that has the anatomical characteristics of the left ventricle. Less commonly, the single ventricular chamber resembles a right ventricle (double-inlet right ventricle) or contains features suggestive of both ventricles or neither one; the latter two situations occasionally have been designated common ventricle and single ventricle of the primitive type, respectively. CLINICAL FINDINGS.

Depending on the associated anomalies, the clinical presentation of single ventricle mimics other conditions in which cyanosis and decreased or increased pulmonary blood flow coexist, e.g., tetralogy of Fallot or tricuspid atresia in the former instance or complete transposition of the great arteries and double-outlet right ventricle in the latter. The ECG in double-inlet left ventricle without inversion of the infundibulum (D-malposition) usually shows features of left ventricular hypertrophy. with infundibular inversion (L-malposition) the electrical forces are directed anteriorly and rightward, as they are in ventricular inversion without associated defects. In patients with the more primitive types of common or single ventricle, a repetitious rS pattern is seen in all the

precordial ECG leads. Chest roentgenographic findings resemble those observed in patients with complete (dextro-) transposition of the great arteries or functionally corrected (levo-) transposition of the great arteries without features distinctive of single ventricle. ECHOCARDIOGRAPHY.

Two-dimensional and Doppler echocardiography are extremely important to demonstrate ventricular anatomy and to recognize associated intra- and extracardiac anomalies (Fig. 43-67) . A segmental approach should be used for accurate and complete echocardiographic evaluation. Thus, precise details are required of the basic anatomy of atrial and visceral situs, location of the cardiac apex, the extracardiac course of the great arteries, and systemic and pulmonary venous connections. In those patients in whom two separate AV valves communicate with the single ventricular chamber, echocardiography (see Chap. 7 ) suggests the correct diagnosis when echoes are visualized from the two valves without an intervening interventricular septum. In the absence of ventricular septal echoes when the two valves are not visualized simultaneously, they may be identified separately with a careful long-axis sweep of the ventricle. It is possible to detect the presence of a small outflow chamber anterior to the AV valves by using subcostal or parasternal short-axis views and a plane orthogonal to the long-axis plane (see Fig. 43-63 ). The single ventricle with a single AV valve is suspected when the excursion of echoes from the single valve located posteriorly in the

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Figure 43-67 Echo images of a double-inlet left ventricle type of univentricular heart. Top, Subcostal coronal view shows the right atrium (RA) giving rise to a tricuspid valve guarding entry into a main chamber (M CH) of left ventricular morphology from which the pulmonary artery (PA) arises. The arrow indicates the small ventricular septal defect (bulboventricular foramen) entering into an outflow chamber (O CH), which gives rise to the aorta (AO). Middle, Orthogonal subcostal sagittal equivalent to the top frame. The left atrium (LA) is seen above the main chamber of left ventricular morphology (V). The arrows indicate the origin of the left and right atrioventricular valves within the same ventricular chamber. The pulmonary artery (PA) arises from the main chamber, and the long narrow bulboventric ular foramen is shown to enter the outlet chamber (O Ch.), with its connection to the aorta. Bottom, Apical four-chamber view shows the right atrium (RA) and the left atrium (LA) with their corresponding valves (arrows) entering into the common large ventricle (V).

ventricular chamber is of large amplitude. Enhanced assessment of the AV valve in patients with single ventricle is provided by Doppler echocardiography.[544] Magnetic resonance imaging provides valuable information complementary to echocardiographic study. Selective ventriculography is necessary to delineate with certainty the anatomical type of single ventricle and to diagnose the associated great artery interrelations and the presence or absence of additional lesions.

SURGICAL TREATMENT.

Modifications of Fontan approach are generally applied to patients with all types of anatomical and functional single ventricle.[545] [546] [547] Surgical outcome is related to the creation of an unobstructed pathway from the systemic veins to the pulmonary arteries, low pulmonary vascular resistance, and a compliant, well-functioning ventricle. In most centers, Fontan procedure is divided into two stages, an initial superior vena cava-pulmonary artery anastomosis (bidirectional Glenn shunt or hemi-Fontan procedure: Fig. 43-68 ), followed later by completion of the Fontan procedure directing flow from the inferior vena cava to the amalgamation of the superior vena cava and the branch pulmonary arteries. At first-stage operation, prior systemic-pulmonary shunts are eliminated and any areas of distortion or narrowing of the pulmonary arteries are repaired, particularly if a prior pulmonary artery banding was performed to limit pulmonary blood flow. At our center, the complete Fontan procedure is accompanied by placement of a snare around the atrial septal defect to control its size postoperatively,[548] whereas in other centers, fenestrations in the atrial baffle may be used.[549] [550] [551] [552] These procedures appear to reduce significantly postoperative morbidity from pericardial effusions and significantly improve survival. Results of early bidirectional cavopulmonary shunting in young infants are encouraging. The objective of this approach early in life is to yield a more suitable Fontan candidate while reducing ventricular volume overload and repeated palliative procedures. Subaortic stenosis, a common occurrence in patients with univentricular heart and malposed great arteries, occurs as a result of a restrictive bulboventricular foramen (VSD) or as a consequence of ventricular hypertrophy from a previous pulmonary banding operation. The Damus-Kaye-Stansel operation, consisting of anastomosis of the pulmonary artery to the ascending aorta, is a generally successful approach to this problem.[552] After operation, all patients need continued close surveillance.[553] [554] [555] [556] Complications include thromboembolic phenomena and atrial arrhythmias. Survivors generally lead active lives with exercise levels less than normal but relevant to ordinary daily life. VASCULAR RINGS MORPHOLOGY.

The normal development of the aortic arch system is described earlier (see Fig. 43-3 ). The term vascular ring is used for those aortic arch or pulmonary artery malformations that exhibit an abnormal relation with the esophagus and trachea, causing compression, dysphagia, and/or respiratory symptoms.[557] The most common and serious vascular ring is produced by a double aortic arch in which both the right and left fourth embryonic aortic arches persist. In the most common type of double aortic arch, there is a left ligamentum arteriosum or ductus arteriosus and both arches are patent, the right being larger than the left. A right aortic arch with a left ductus or ligamentum arteriosum connecting the left pulmonary artery and the upper part of the descending aorta and

with an anomalous right subclavian artery arising from the left descending aorta are additional important vascular ring arrangements.

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Figure 43-68 A bidirectional cavopulmonary artery shunt with patch occlusion of the superior vena cava right atrial junction (hemi-Fontan procedure) using direct cannulation of the superior and inferior venae cavae and a single arterial cannula. The main pulmonary artery is shown divided and oversewn, but in some cases it may be allowed to remain patent. Connections are made between both ends of the divided superior vena cava and the pulmonary artery. A subsequent Fontan operation involves only removal of the patch at the junction of the superior vena cava and the right atrium and placement of the intraatrial baffle to divert the inferior vena caval blood up to the superior vena cava orifice. (From Castaneda A, Jonas RA, Mayer JE Jr, et al: Cardiac Surgery of the Neonate and Infant. Philadelphia, WB Saunders, 1994, p 263.)

The latter anomaly frequently exists in cases of tetralogy of Fallot and otherwise uncomplicated coarctation of the aorta. An unusual cause of tracheal compression is the vascular sling created by an anomalous left pulmonary artery that arises from a rightward, elongated pulmonary trunk and courses between the trachea and esophagus before it branches normally within the left lung.[558] This arrangement commonly is associated with other cardiac and extracardiac anomalies. CLINICAL FINDINGS.

The symptoms produced by vascular rings depend on the tightness of anatomical constriction of the trachea and esophagus and consist principally of respiratory difficulties, cyanosis (associated especially with feeding), stridor, and dysphagia. The ECG appears normal unless associated cardiovascular anomalies are present. The barium esophagogram is a useful screening procedure. Prominent posterior indentation of the esophagus is observed in the common vascular ring arrangements, although the pulmonary artery vascular sling produces an anterior indentation. Unusual and rare aortic arch anomalies may create rings that impinge on the trachea but do not compress the esophagus and are detected not by this simple radiographic procedure but rather by bronchoscopy. Selective contrast angiography delineates the anatomy of the aorta and its branches or the course of the main pulmonary arteries. CT and magnetic resonance imaging offer excellent imaging alternatives.[559] MANAGEMENT.

The severity of symptoms and the anatomy of the malformation are the most important factors in determining treatment. Patients, particularly infants, with respiratory obstruction require prompt surgical intervention. Operative repair of the double aortic arch requires division of the minor arch (usually the left).[560] A reported 10 to 20 percent operative mortality is related, in part, to problems in postoperative respiratory care, especially when there is coexistent residual anatomical tracheal narrowing. Patients with

a right aortic arch and a left ductus or ligamentum arteriosum require division of the ductus or ligamentum and/or ligation and division of the left subclavian artery, which is the posterior component of the ring. Video-assisted thoracoscopy holds promise as an alternative to open thoracotomy for management.[561] Operation seldom is indicated for patients with an aberrant right subclavian artery derived from a left aortic arch and left descending aorta. In patients with a pulmonary artery vascular sling, operation consists of detachment of the left pulmonary artery at its origin and anastomosis to the main pulmonary artery directly or by way of a conduit of its proximal end brought anterior to the trachea.[560] Some patients with persistent respiratory symptoms require postoperative evaluation of residual anatomical obstruction, tests of pulmonary function, and bronchodilator therapy.[562] CONGENITAL ARRHYTHMIAS This classification refers to arrhythmias that are present in infancy, whose causes, when known, relate to a structural malformation or defect of the conduction system or to an acquired prenatal condition such as myocarditis, hypoxia acidosis, or transplacental passage of a drug or substance from mother to fetus. In these latter examples, the substrate for the postnatal expression of the rhythm disturbance existed before birth and the arrhythmia is therefore designated congenital. Complete heart block and supraventricular and ventricular tachycardias are the most common important congenital arrhythmias.[563] The electrophysiological and ECG features of these arrhythmias are discussed elsewhere (see Chaps. 23 and 25 ). Congenital Complete Heart Block

The AV node and the His bundle originate during fetal development as separate structures and later join together. Anatomical studies have shown the basic lesion in congenital complete heart block to consist of discontinuity between the atrial musculature and the AV node or the His bundle, if the AV node is absent. The anatomical interruption occasionally can be situated between the AV node and the main His bundle or within the bundle itself.[564] No cause is known for the vast majority of cases of congenital heart block in infants, who usually have otherwise anatomically normal hearts. However, fetal myocarditis, idiopathic hemorrhage and necrosis involving conduction tissue, and degeneration and fibrosis related in some instances to the transplacental passage of anti-SSA/Ro-SSB/La antibodies and other immune complexes from mothers with systemic lupus erythematosus all are entities capable of causing congenital heart block.[565] It is not clear if medical treatment in high-risk pregnancies aimed at reducing antibody titers will modify immunopathologic damage to the fetus. Less often, congenital heart block can be associated with various forms of congenital heart disease, the most common malformation being congenitally corrected transposition of the great arteries.[566] Detection of consistent fetal bradycardia (heart rate 40 to 80 beats/min) by auscultation, fetal echocardiography (Fig. 43-69) , or electronic monitoring allows anticipation of the correct diagnosis. A newborn, especially with a ventricular

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Figure 43-69 M-mode recording taken from the four-chamber fetal reference image shown in the lower right corner. The image is inverted, with the M-mode reference from fetal left ventricle (LV) through to the right atrium. In the M-mode, the ventricle is seen above (V) and the atrium (A) is seen below. The ventricular rate is approximately 48 beats/min, whereas the atrial rate is approximately 150 beats/min. There were no structural cardiac abnormalities. The mother had lupus erythematosus.

rate less than 50 beats/min and atrial rate in excess of 150 beats/min, is at highest risk; the presence of an associated cardiovascular anomaly greatly lessens the chances of survival. Treatment is not required for asymptomatic infants. Digitalization is recommended for infants in congestive heart failure, irrespective of complete heart block. Isoproterenol and other sympathomimetic drugs and atropine do not have permanent or beneficial effect. Congestive heart failure and Stokes-Adams attacks require pacemaker treatment at any age, including transvenous or transatrial placement of endocardial leads in older children or permanent epicardial pacemaker insertion in infants and small children.[567] [568] Various problems can be anticipated after pacemaker implantation related to growth of the patient, which stresses the electrical lead system; the fragility of the lead system in a physically active young patient; and the limited life span of the pulse generator. Patients who have congenital complete heart block and who survive infancy usually remain asymptomatic until late in childhood or adolescence.[569] Supraventricular Tachycardia

Paroxysmal tachycardia of supraventricular origin can have its origin in utero or in the immediate postnatal period. The most frequent arrhythmias producing symptoms are paroxysmal supraventricular tachycardia with or without ventricular preexcitation, atrial flutter, and junctional tachycardia. The arrhythmia can cause intrauterine cardiac failure and hydrops fetalis[570] [571] ; its detection and persistence prenatally should prompt consideration of administration of digitalis or, if that fails, of propranolol, quinidine, flecainide, or amiodarone to the mother if amniocentesis indicates surfactant deficiency and fetal lung immaturity, because early delivery is not indicated if the baby will have hyaline membrane disease. Experience with antiarrhythmic drugs, delivered by umbilical venous infusion, is limited.[96] Cesarean delivery or induced labor may be indicated if the fetus is close to term. No cause is recognized for the disorder in the majority of infants. Transplacental passage of long-acting thyroid stimulators (LATSs) and immune gamma-2-globulin from hyperthyroid mothers, hypoglycemia, and Ebstein's anomaly of the tricuspid valve occasionally are causative. WPW syndrome (see Chaps. 23 and 25 ) is present in 10 to 50 percent of infants with supraventricular tachycardia.[572] Symptoms produced by the tachyarrhythmia after birth are subtle and often remain undetected until signs of heart failure have been present for 24 to 36 hours. Conversion to normal sinus rhythm usually is accomplished by administration of digitalis or adenosine, direct-current cardioversion, transesophageal atrial pacing, or a diving reflex elicited by covering the face with an ice-cold wet washcloth for 4 to 5 seconds. [573] [574] [575] [576] [577] Conversion should be followed by digitalization on a prophylactic basis. Common practice consists

of digitalis treatment for 9 to 12 recurrence-free months followed by its abrupt cessation.[578] Recurrence of tachycardia, particularly in those infants with ventricular preexcitation, is not uncommon; maintenance of normal rhythm may require administration, alone or in combination, of digitalis, phenytoin sodium, flecainide, sotalol, and amiodarone.[573] The rate of recurrence falls substantially between ages 2 and 10 years, with a slight rise during adolescence. In general, the prognosis is excellent. ELECTROPHYSIOLOGICAL STUDIES.

Beyond infancy, patients whose condition is refractory to medical treatment are candidates for electrophysiological catheter evaluation, which facilitates differentiation of a causative ectopic anatomical focus within the atria from accessory conduction pathways (see Chap. 23 ).[579] [580] If the tachyarrhythmia is refractory to pharmacological therapy, it should be treated definitively by radiofrequency catheter ablation of accessory pathways (see Chaps. 23 and 25 ). This procedure has become the primary treatment modality for most symptomatic rhythm disturbances in children. The results are excellent, with success exceeding 90% and very low complication rates.[576] [580] [581] Among the advantages of this approach is that successful ablation represents a cure; the heart is left structurally normal, and the cause of the arrhythmia is eliminated. Further, the need for antiarrhythmic agents with the concomitant risk of side effects or proarrhythmia is eliminated. ATRIAL FLUTTER (see Chaps. 23 and 25 ).

Uncommonly, atrial flutter is the cause of supraventricular tachycardia, [582] especially in newborn infants with hydrops fetalis, whose intrauterine tachyarrhythmia

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is an alternation between supraventricular tachycardia with WPW syndrome and atrial flutter. Another common clinical setting for atrial flutter is in infants younger than 6 months with an otherwise normal heart, who show frequent premature atrial complexes. In infants, classic flutter waves may not be present on a surface ECG or rhythm strip; detection may require recordings of transesophageal atrial electrograms. Acute treatment with electrical conversion or transesophageal overdrive pacing effectively terminates the rhythm disturbance.[583] If synchronized direct-current electrocardioversion is used, standby pacing should be available; if overdrive pacing is used, the same pacing catheter can be used to pace the heart in the event of asystole. Long-term drug treatment with digitalis, digitalis plus quinidine, or amiodarone may uncommonly be required. Junctional automatic tachycardia is characterized by a narrow QRS complex and AV dissociation, with the ventricular rate faster than the normal atrial rate. Ventricular dysfunction and congestive heart failure occur early, and the rhythm disturbance usually is not convertible to sinus rhythm by any medical treatment. When the latter falls and because sudden death is a risk, catheter ablation can be used to eliminate the

tachycardia focus. Pacemaker implantation may be necessary if heart block results (see Chap. 25 ). VENTRICULAR TACHYCARDIA.

Ventricular tachycardia is defined as three or more consecutive premature ventricular complexes (see Chap. 25 ). The definition, however, falls to identify a high-risk group. Infants or children who meet this criterion but seldom require treatment and seem to be at little risk have no symptoms and no evidence of anatomical heart disease. Potentially serious ventricular tachycardia in the newborn is associated with QT prolongation, mitral valve prolapse, and Marfan's syndrome. In these settings, the tachycardia is potentially life threatening and always merits treatment. [563] Numerous genes causing long QT syndrome have been identified, confirming that the defects occurs in a transmembrane ion channel in most patients (see Chaps. 23 and 25 ).[584] The two most effective treatments are beta blockade and high thoracic left sympathectomy, which reduce the incidence of syncope and sudden death without affecting the QT interval. Trials of gene-specific therapy directed at the involved ion channel may be anticipated in the future.[584] Implantable defibrillators can be life saving in patients at risk for torsades de pointes and ventricular fibrillation. The treatment of ventricular tachycardia (see Chap. 23 ) consists of intravenous administration of lidocaine, followed by direct-current electrical cardioversion. In the absence of QT prolongation but in the presence of mitral prolapse or other cardiac abnormalities, long-term treatment should be undertaken of multiform premature ventricular complexes, couplets, or ventricular tachycardia. In infants and children unresponsive to conventional or investigational antiarrhythmic drugs, consideration should be given to pacemaker implantation, cardiac sympathetic denervation, and perhaps implantation of a defibrilator.[585]




REFERENCES 1.

Hoffman JIE: Congenital heart disease. Pediatr Clin North Am 37:45, 1990.

Brickner ME, Hillis LD, Lange RA: Congenital heart disease in adults: I. N Engl J Med 342:256-263, 2000. 1A.

Brickner ME, Hillis LD, Lange RA: Congenital heart disease in adults: II. N Engl J Med 342:334-342, 2000. 1B.

Roberts WC: Anatomically isolated aortic valvular disease: The case against its being of rheumatic etiology. Am J Cardiol 49:151, 1970. 2.

Warth DC, King ME, Cohen JM, et al: Prevalence of mitral valve prolapse in normal children. J Am Coll Cardiol 5:1173, 1985. 3.

Fontana RS, Edwards JE: Congenital Cardiac Disease: A Review of 357 Cases Studied Pathologically. Philadelphia, WB Saunders, 1962. 4.

Bankl H: Congenital Malformations of the Heart and Great Vessels: Synopsis of Pathology, Embryology and Natural History. BaltimoreMunich, Urban & Schwarzenberg, 1977. 5.

Gerlis LM: Covert congenital cardiovascular malformations discovered in an autopsy series of nearly 5000 cases. Cardiovasc Pathol 5:11, 1996. 6.

Samanek M: Boy:girl ratio in children born with different forms of cardiac malformation: A population-based study. Pediatr Cardiol 15:53, 1994. 7.

8.

Clark EB, Gibson WT: Congenital cardiovascular malformations: An intersection of human genetics and

developmental biology. Prog Pediatr Cardiol 9:199, 1999. Goldmuntz E, Clark BJ, Mitchell LE, et al: Frequency of 22q11 deletions in patients with conotruncal defects. J Am Coll Cardiol 32:492, 1998. 9.

Greenwood RD: Cardiovascular malformations associated with extracardiac anomalies and malformation syndromes. Clin Pediatr 23:145, 1984. 10.

Ouelette EM, Rossett HL, Rossman MP, Wiener L: Adverse effects on offspring of maternal alcohol abuse during pregnancy. N Engl J Med 297:528, 1977. 11.

Farrell MJ, Stadt H, Wallis KT, et al: HIRA, a DiGeorge syndrome candidate gene, is required for cardiac outflow tracts septation. Circ Res 84:127, 1999. 12.

13.

Noonan J: Twins, conjoined twins, and cardiac defects. Am J Dis Child 132:17, 1978.

14.

Burn J: Consequences of chromosome 22q11.2 deletions. Circulation 90:II-ID, 1994.

Corone P, Bonaiti C, Feingold J, et al: Familial congenital heart disease: How are the various types related? Am J Cardiol 51:942, 1983. 15.

Whittemore R, Wells, JA, Castellsague X: A second-generation study of 427 probands with congenital heart defects and their 837 children. J Am Coll Cardiol 23:1459, 1994. 16.

Daubeney PEF, Sherland GK, Cook AC, et al: Pulmonary atresia with intact ventricular septum: Impact of fetal echocardiography on incidence at birth and postnatal outcome. Circulation 98:562, 1998. 17.

Kumar RK, Newburger JW, Gauvreau K, et al: Comparison of outcome when hypoplastic left heart syndrome and transposition of the great arteries are diagnosed prenatally versus when diagnosis of these two conditions is made only postnatally. Am J Cardiol 83:1649, 1999. 18.

19.

Angelini P: Embryology and congenital heart disease. Tex Heart Inst J 22:1, 1995.

Anderson RH, Ashley GT: Anatomic development of the cardiovascular system. In Davies J, Dobbing J (eds): Scientific Foundations of Paediatrics. London, Heinemann, 1974, p 165. 20.

Tworetzky W, McElhinney DB, Reddy VM, et al: Echocardiography as the definitive diagnostic modality for the preoperative evaluation of complex congenital heart defects. J Am Coll Cardiol 31(Suppl A):427A, 1998. 21.

22.

Rudolph AM: Congenital Diseases of the Heart. Chicago, Year Book Medical Publishers, 1974.

Hornberger LK, Sanders SP, Rein AJ, et al: Left heart obstructive lesions and left ventricular growth in the midtrimester fetus. A longitudinal study. Circulation 92:1531, 1995. 23.

Sheldon CA, Friedman WF, Sybers HD: Scanning electron microscopy of fetal and neonatal lamb cardiac cells. J Mol Cell Cardiol 8:853, 1976. 24.

McPherson RA, Kramer MF, Covell JW, Friedman WF: A comparison of the active stiffness of fetal and adult cardiac muscle. Pediatr Res 10:660, 1976. 25.

26.

Friedman WF: The intrinsic physiologic properties of the developing heart. Prog Cardiovasc Dis 15:87,

1972. Huynh TV, Wetzel GT, Friedman WF, Klitzner TS: Developmental changes in membrane Ca 2+ and K+ currents in fetal, neonatal, and adult heart cells. Circ Res 70:508, 1992. 27.

Chen F, Wetzel GT, Friedman WF, Klitzner TS: ATP sensitive potassium channels in isolated neonatal and adult rabbit ventricular myocytes. Pediatr Res 32:230, 1992. 28.

Ingwall JS, Kramer MF, Woodman D, Friedman WF: Maturation of energy metabolism in the lamb: Changes in myosin ATPase and creatine kinase activities. Pediatr Res 15:1128, 1981. 29.

Friedman WF: Physiological properties of the developing heart. In Paediatric Cardiology. Vol 6. New York, Churchill Livingstone, 1987, p 3. 30.

Geis WP, Tatooles CJ, Priola DV, Friedman WF: Factors influencing neurohumoral control of the heart and newborn. Am J Physiol 228:1685, 1975. 31.

Klitzner TS, Friedman WF: Excitation contraction coupling in developing mammalian myocardium. Pediatr Res 23:428, 1988. 32.

Klitzner TS, Friedman WF: A diminished role for the sarcoplasmic reticulum in newborn myocardial contraction. Pediatr Res 26:98, 1989. 33.

Romero TE, Friedman WF: Limited left ventricular response to volume overload in the neonatal period. Pediatr Res 33:910, 1979. 34.

Finer NN, Etches PC, Kamstra B, et al: Inhaled nitric oxide in infants referred for extracorporeal membrane oxygenation: Dose response. J Pediatr 124:302, 1994. 35.

Friedman WF, Printz MP, Kirkpatrick SE, Hoskins EJ: The vasoactivity of the fetal lamb ductus arteriosus studied in utero. Pediatr Res 17:331, 1983. 36.

PATHOLOGICAL CONSEQUENCES Friedman WF, George BL: Medical progress--treatment of congestive heart failure by altering loading conditions of the heart. J Pediatr 106:697, 1985. 37.

Artman M, Parrish MD, Graham TP Jr: Congestive heart failure in childhood and adolescence: Recognition and management. Am Heart J 105:471, 1983. 38.

Meijboom EJ, Van Engelen AD, Van de Beek EW, et al: Fetal arrhythmias. Curr Opin Cardiol 9:97, 1994. 39.

Milne MJ, Sung RYT, Fok TF, Crozier IG: Doppler echocardiographic assessment of shunting via the ductus arteriosus in newborn infants. Am J Cardiol 64:102, 1989. 40.

Sahn DJ, Friedman WF: Difficulties in distinguishing cardiac from pulmonary disease in the neonate. Pediatr Clin North Am 20:293, 1973. 41.

Stanger P, Lucas RV Jr, Edwards JE: Anatomic factors causing respiratory distress in acyanotic congenital cardiac disease: Special reference to bronchial obstruction. Pediatrics 43:760, 1969. 42.

DiSessa TG, Friedman WF: Echocardiographic evaluation of cardiac performance. In Friedman WF, Higgins CB (eds): Pediatric Cardiac Imaging. Philadelphia, WB Saunders, 1984, p 219. 43.

Mercier JC, DiSessa TG, Jarmakani J, Friedman WF: Two dimensional echocardiographic assessment of left ventricular volumes and ejection fraction. Circulation 65:962, 1982. 44.

Huwez FU, Houston AB, Watson J, et al: Age and body surface area related normal upper and lower limits of M mode echocardiographic measurements and left ventricular volume and mass from infancy to early adulthood. Br Heart J 72:276, 1994. 45.

1583

46.

Teitel D, Rudolph AM: Perinatal oxygen delivery and cardiac function. Adv Pediatr 32:321, 1985.

Rosenthal A, Nathan DG, Marty AT, et al: Acute hemodynamic effects of red cell volume reduction, polycythemia of cyanotic congenital heart disease. Circulation 42:297, 1970. 47.

48.

Voigt GC, Wright JR: Cyanotic congenital heart disease and sudden death. Am Heart J 87:773, 1974.

Fischbein CA, Rosenthal A, Fischer EG, et al: Risk factors for brain abscess in patients with congenital heart disease. Am J Cardiol 34:97, 1974. 49.

50.

Corrin C: Paradoxical embolism. Br Heart J 26:549, 1964.

Haroutunian LM, Neill CA: Pulmonary complications of congenital heart disease: Hemoptysis. Am Heart J 84:540, 1972. 51.

Guntheroth WG, Morgan BC, Mullens GL: Physiologic studies of paroxysmal hyperpnea in cyanotic congenital heart disease. Circulation 31:70, 1965. 52.

53.

Talmer NS: Congestive heart failure in the infant. Pediatr Clin North Am 18:1011, 1971.

Gingell RI, Hornung MG: Growth problems associated with congenital heart disease in infancy. In Lebenthal E (ed): Textbook of Gastroenterology and Nutrition in Infancy. New York, Raven Press, 1989, p 639. 54.

Salzer HR, Haschke F, Wimmer M, et al: Growth and nutritional intake of infants with congenital heart disease. Pediatr Cardiol 10:17, 1989. 55.

Friedman WF, Heiferman MF, Perloff JK: Late postoperative pulmonary vascular disease--clinical concerns. In Engle MA, Perloff JK (eds): Congenital Heart Disease After Surgery. New York, York Medical Publishers, 1983, p 151. 56.

Rabinovitch M: Structure and function of the pulmonary vascular bed: An update. Cardiol Clin 7:227, 1989. 57.

Rabinovitch M, Keane JF, Norwood WI: Vascular structure and lung biopsy tissue correlated with pulmonary hemodynamic findings after repair of congenital heart defects. Circulation 69:655, 1984. 58.

Heath D, Edwards JE: The pathology of hypertensive pulmonary vascular disease. Circulation 18:533, 1958. 59.

Burchenal JEB, Loscalzo J: Endothelial dysfunction and pulmonary hypertension. Primary Cardiol 20:28, 1994. 60.

Celermajer DS, Dollery C, Burch M, Deanfield JE: Role of endothelium in the maintenance of low pulmonary vascular tone in normal children. Circulation 89:2041, 1994. 61.

Niwa K, Perloff JK, Kaplan S, et al: Eisenmenger syndrome in adults: Ventricular septal defect, truncus arteriosus, univentricular heart. J Am Coll Cardiol 34:223, 1999. 62.

Rabinovitch M, Reid LM: Quantitative structural analysis of the pulmonary vascular bed in congenital heart defects. In Engle MA (ed): Pediatric Cardiovascular Disease. Philadelphia, FA Davis, 1981, p 149. 63.

Friedman WF: Proceedings of the National Heart, Lung and Blood Institute Pediatric Cardiology Workshop: Pulmonary Hypertension. Pediatr Res 20:8, 1986. 64.

Kovalchin JP, Mott AR, Rosen KL, et al: Nitric oxide for the evaluation and treatment of pulmonary hypertension in congenital heart disease. Tex Heart Inst J 24:308, 1997. 65.

Rabinovitch M, Keane JF, Fellows KE, et al: Quantitative analysis of the pulmonary wedge angiogram in congenital heart defects. Circulation 63:152, 1981. 66.

Rabinovitch M, Castaneda AR, Reid L: Lung biopsy with frozen section as a diagnostic aid in patients with congenital heart defects. Am J Cardiol 47:77, 1981. 67.

Yamaki S, Abe A, Tabayashi K, et al: Inoperable pulmonary vascular disease in infants with congenital heart disease. Ann Thorac Surg 66:1565, 1998. 68.

Rabinovitch M: Pathophysiology of pulmonary hypertension. In Emmanouilides GC, Riemenschneider TA, Allen HD, et al (eds): Moss and Adams' Heart Disease in Infants, Children, and Adolescents. 5th ed. Baltimore, Williams & Wilkins, 1995, p 1659. 69.

Rosenzweig EB, Kerstein D, Barst RJ: Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation 99:1858, 1999. 70.

Barst RJ: Recent advances in the treatment of pulmonary artery hypertension. Am Coll Cardiol Curr J Rev 7:60, 1998. 71.

Awadallah SM, Kavey RE, Byrum CJ, et al: The changing pattern of infective endocarditis in childhood. Am J Cardiol 68:90, 1991. 72.

73.

Roberts GJ, Holzel HS, Sury MRJ, et al: Dental bacteremia in children. Pediatr Cardiol 18:24, 1997.

Dajani AS, Taubert KA, Wilson W, et al: Prevention of bacterial endocarditis: Recommendations by the American Heart Association. Circulation 96:358, 1997. 74.

74A. Bayer

AS, Bolger AF, Taubert KA, et al: Diagnosis and management of infective endocarditis and its complications. Circulation 98:2936, 1998.

Selbst SM, Ruddy RM, Clark BJ, et al: Pediatric chest pain: A prospective study. Pediatrics 82:319, 1988. 75.

Driscoll DJ, Jacobsen SJ, Porter CJ, Wollan PC: Syncope in children and adolescents. J Am Coll Cardiol 29:1039, 1997. 76.

Grubb BP, Samoil D, Kosinski D, et al: Use of sertraline hydrochloride in the treatment of refractory neurocardiogenic syncope in children and adolescents. Am Coll Cardiol 24:490, 1994. 77.

78.

Gillette PC, Garson A: Sudden cardiac death in the pediatric population. Circulation 85:1, 1992.

Maron BJ, Gohman TE, Aeppli D: Prevalence of sudden cardiac death during competitive sports activities in Minnesota high school athletes. J Am Coll Cardiol 32:1881, 1998. 79.

Ackerman MJ: The long QT syndrome: Ion channel diseases of the heart. Mayo Clin Proc 73:250, 1998. 80.

APPROACH TO THE HIGH-RISK INFANT Friedman WF, George BL: New concepts and drugs in the treatment of congestive heart failure. Pediatr Clin North Am 31:1197, 1984. 81.

82.

Anderson PAW: Maturation in cardiac contractility. Cardiol Clin 7:209, 1989.

Park MK: Use of digoxin in infants and children, with specific emphasis on dosage. J Pediatr 108:871, 1986. 83.

84.

Hauptman PJ, Kelly RA: Digitalis. Circulation 99:1265, 1999.

Lewis AB, Freed MD, Heymann MA, et al: Diagnosis and management of infective endocarditis and its complications. Circulation 98:2936, 1998. 85.

Friedman WF, Kurlinski J, Jacob J, et al: Inhibition of prostaglandin and prostacyclin synthesis in clinical management of PDA. Semin Perinatol 4:125, 1980. 86.

Friedman WF: Patent ductus arteriosus in respiratory distress syndrome. Pediatr Cardiol 4(Suppl 2):3, 1983. 87.

Brunner-La Rocca HP, Vaddadi G, Esler MD: Recent insight into therapy of congestive heart failure: Focus on ACE inhibition and angiotensin-II antagonism. J Am Coll Cardiol 33:1163, 1999. 88.

Harada K, Tamura M, Ito T, et al: Effects of low-dose dobutamine on left ventricular diastolic filling in children. Pediatr Cardiol 17:220, 1996. 89.

Mendelsohn AM, Johnson CE, Brown CE, et al: Hemodynamic and clinical effects of oral levodopa in children with congestive heart failure. J Am Coll Cardiol 30:237, 1997. 90.

Colucci WS: Molecular and cellular mechanisms of myocardial failure. Am J Cardiol 80(11A):15L, 1997. 91.

Snyder JV: Assessment of systemic oxygen transport. In Snyder JV (ed): Oxygen Transport in the Clinically Ill. Chicago, Year Book, 1987, p 179. 92.

92A. Kleinman

CS, Donnerstein RL: Ultrasonic assessment of cardiac function in the intact human fetus. J Am Coll Cardiol 5:84S, 1985. Silverman NH, Kleinman CS, Rudolph AM, et al: Fetal atrioventricular valve insufficiency associated with nonimmune hydrops: A two-dimensional echocardiographic and pulsed Doppler ultrasound study. Circulation 72:825, 1985. 93.

Allan LD, Sharland GK, Millburn A, et al: Prospective diagnosis of 1,006 consecutive cases of congenital heart disease in the fetus. J Am Coll Cardiol 23:1452, 1994. 94.

Hornberger LK, Bromley B, Lichter E, Benacerraf BR: Development of severe aortic stenosis and left ventricular dysfunction with endocardial fibroelastosis in a second trimester fetus. J Ultrasound Med 15:651, 1996. 95.

Gembruch U, Manz M, Bald R, et al: Repeated intravascular treatment with amiodarone in a fetus with refractory supraventricular tachycardia and hydrops fetalis. Am Heart J 118:1335, 1989. 96.

Tworetzky W, McElhinney DB, Brook MM, et al: Echocardiographic diagnosis alone for the complete repair of major congenital heart defects. J Am Coll Cardiol 33:228, 1999. 97.

97A. Balestrini

L, Fleishman C, Lanzoni L, et al: Real-time 3-dimensional echocardiography evaluation of congenital heart disease. J Am Soc Echocardiogr 13:171-176, 2000. Silverman NH, Schmidt KG: The current role of Doppler echocardiography in the diagnosis of heart disease in children. Cardiol Clin 7:265, 1989. 98.

Cloez JL, Schmidt KG, Birk E, Silverman NH: Determination of pulmonary systemic blood flow ratio in children by simplified Doppler echocardiographic method. J Am Coll Cardiol 11:825, 1988. 99.

99A. de

Roos A, Roest AA: Evaluation of congenital heart disease by magnetic resonance imaging. Eur Radiol 10:2-6, 2000. Beekman RP, Filippini LHPM, Meijboom EJ: Evolving usage of pediatric cardiac catheterization. Curr Opin Cardiol 9:721, 1994. 100.

Stanger P, Heymann MA, Tarnoff H, et al: Complications of cardiac catheterization of neonates, infants and children. Circulation 50:595, 1974. 101.

Allen HD, Driscoll DJ, Fricker FJ, et al: Guidelines for pediatric therapeutic cardiac catheterization. Circulation 84:2248, 1991. 102.

Shim D, Lloyd TR, Crowley DC, Beekman RH: Neonatal cardiac catheterization: A 10-year transition from diagnosis to therapy. Pediatr Cardiol 20:131, 1999. 103.

Mullins CE: History of pediatric interventional catheterization: Pediatric therapeutic cardiac catheterizations. Pediatr Cardiol 19:3, 1998. 104.

105.

Moore JW: Advances in pediatric interventional catheterization. Prog Pediatr Cardiol 6:93, 1996.

Kugler JD, Danford DA, Deal BJ: Radiofrequency catheter ablation for tachyarrhythmias in children and adolescents. N Engl J Med 330:1481, 1994. 106.

Zipes DP, Akthar M, Denes P, et al: Guidelines for clinical intracardiac electrophysiologic studies: A report of the American College of Cardiology/AHA Task Force on assessment of diagnostic and therapeutic cardiovascular procedures. J Am Coll Cardiol 14:1827, 1989. 107.

Klitzner TS, Wetzel GT, Saxon LA, Stevenson WG: Radiofrequency ablation: A new era in the management of pediatric arrhythmias. Am J Dis Child 147:769, 1993. 108.

Van Hare GF, Lesh MD, Stanger P: Radiofrequency catheter ablation of supraventricular arrhythmias in patients with congenital heart disease: Results and technical considerations. J Am Coll Cardiol 22:883, 1993. 109.

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SPECIFIC CARDIAC DEFECTS 110.

Hunt CE, Lucas RV Jr: Symptomatic atrial septal defect in infancy. Circulation 42:1042, 1973.

Van Praagh S, Carrera ME, Sanders SP, et al: Sinus venosus defects: Unroofing of the right pulmonary veins--anatomic and echocardiographic findings and surgical treatment. Am Heart J 128:365, 1994. 111.

Bashi VV, Ravikumar E, Jairaj PS, et al: Coexistent mitral valve disease with left-to-right shunt at the atrial level: Clinical profile, hemodynamics, and surgical considerations in 67 consecutive patients. Am Heart J 114:1406, 1987. 112.

Leachman RD, Cokkinos DV, Cooley DA: Association of ostium secundum atrial septal defects with mitral valve prolapse. Am J Cardiol 38:167, 1976. 113.

Levin AR, Spach MS, Boineau JP et al: Atrial pressure flow dynamics and atrial septal defects (secundum type). Circulation 37:476, 1968. 114.

115.

Helgason H, Jonsdottir G: Spontaneous closure of atrial septal defects. Pediatr Cardiol 20:195, 1999.

O'Toole JD, Reddy I, Curtiss EI, Shaver JA: The mechanism of splitting the second heart sound in atrial septal defect. Circulation 41:1047, 1977. 116.

Heller J, Hagege AA, Besse B, et al: "Crochetage" (notch) on R wave in inferior limb leads: A new independent electrocardiographic sign of atrial septal defect. J Am Coll Cardiol 27:877, 1996. 117.

Konstantinides S, Kasper W, Geibel A, et al: Detection of left-to-right shunt in atrial septal defect by negative contrast echocardiography: A comparison of transthoracic and transesophageal approach. Am Heart J 126:909, 1993. 118.

Pascoe RD, Oh JK, Warnes CA, et al: Diagnosis of sinus venosus atrial septal defect with transesophageal echocardiography. Circulation 94:1049, 1996. 119.

120.

Shub C, Tajik AJ, Seward JB, et al: Surgical repair of uncomplicated atrial septal defect without

"routine" preoperative cardiac catheterization. J Am Coll Cardiol 6:49, 1985. Taketa RM, Sahn DJ, Simon AL, et al: Catheter positions in congenital cardiac malformations. Circulation 51:749, 1975. 121.

Brand A, Keren A, Branski D, et al: Natural course of atrial septal aneurysm in children and the potential for spontaneous closure of associated septal defect. Am J Cardiol 64:996, 1989. 122.

Black MD, Freedom RM: Minimally invasive repair of atrial septal defects. Ann Thorac Surg 65:765, 1998. 123.

Steele PM, Fuster V, Cohen M, et al: Isolated atrial septal defect with pulmonary vascular obstructive disease--long term follow up and prediction of outcome after surgical correction. Circulation 76:1037, 1987. 124.

Thanopoulos B, Laskari CV, Tsaousis GS, et al: Closure of atrial septal defects with the Amplatzer occlusion device: Preliminary results. J Am Coll Cardiol 31:1110, 1998. 125.

Formigari R, Santoro G, Rossetti L, et al: Comparison of three different atrial septal defect occlusion devices. Am J Cardiol 82:690, 1998. 126.

Rao PS: Transcatheter closure of atrial septal defect: Are we there yet? J Am Coll Cardiol 31:1117, 1998. 127.

Levin AR, Liebson PR, Ehlers KH, Daimant B: Assessment of left ventricular function in atrial septal defect. Pediatr Res 9:894, 1975. 128.

Epstein SE, Beiser GD, Goldstein RE, et al: Hemodynamic abnormalities in response to mild and intense upright exercise following operative correction of an atrial septal defect or tetralogy of Fallot. Circulation 42:1065, 1973. 129.

Murphy JG, Gersh BJ, McGoon MD, et al: Long term outcome after surgical repair of isolated atrial septal defect. N Engl J Med 323:1645, 1990. 130.

Bink-Boelkens MTE, Bergstra A, Landsman MLJ: Functional abnormalities of the conduction system in children with an atrial septal defect. Int J Cardiol 20:263, 1988. 131.

Bink-Boelkens MTE, Meuzelaar KJ, Eygelaar A: Arrhythmias after repair of secundum atrial septal defect: The influence of surgical modification. Am Heart J 115:629, 1988. 132.

Jacobsen JR, Gillette PC, Corbett BN, et al: Intracardiac electrography in endocardial cushion defects. Circulation 54:599, 1976. 133.

Minich LA, Snider AR, Bove EL, et al: Echocardiographic evaluation of atrioventricular orifice anatomy in children with atrioventricular septal defect. J Am Coll Cardiol 19:149, 1992. 134.

DeBia SEL, DiCommo V, Ballerini L, et al: Prevalence of left-sided obstructive lesions in patients with atrial ventricular canal without Down's syndrome. J Thorac Cardiovasc Surg 91:467, 1986. 135.

Suzuki K, Ho SY, Anderson RH, et al: Morphometric analysis of atrioventricular septal defect with common valve orifice. J Am Coll Cardiol 31:217, 1998. 136.

Elliott LP, Bargeron LM Jr, Green CE: Angled angiography: General approach and findings. In Friedman WF, Higgins CB (eds): Pediatric Cardiac Imaging. Philadelphia, WB Saunders, 1984, p 1. 137.

Najm HK, Williams WG, Chuaratanaphong S, et al: Primum atrial septal defect in children: Early results, risk factors, and freedom from reoperation. Ann Thorac Surg 66:829, 1998. 138.

139.

Meisner H, Guenther T: Atrioventricular septal defect. Pediatr Cardiol 19:276, 1998.

Najm HK, Coles JG, Endo M, et al: Complete atrioventricular septal defects: Results of repair, risk factors, and freedom from reoperation. Circulation 96(Suppl II):II-311, 1997. 140.

Michielon G, Stellin G, Rizzoli G, Casarotto DC: Repair of complete common atrioventricular canal defects in patients younger than four months of age. Circulation 96(Suppl II):II-316, 1997. 141.

Soto B, Ceballos R, Kirklin JW: Ventricular septal defects: A surgical viewpoint. J Am Coll Cardiol 14:1291, 1989. 142.

Hagler DJ, Edwards WD, Seward JB, Tajik AJ: Standardized nomenclature of the ventricular septum and venticular septal defects, with applications for two-dimensional echocardiography. Mayo Clin Proc 60:741, 1985. 143.

Baker EJ, Leung MP, Anderson RH, et al: The cross-sectional anatomy of ventricular septal defects: A reappraisal. Br Heart J 69:339, 1988. 144.

Helmcke F, Souza A, Nanda NC, et al: Two-dimensional and color Doppler assessment of ventricular septal defect of congenital origin. Am J Cardiol 63:1112, 1989. 145.

Pieroni DR, Nishimura RA, Bierman FZ, et al: Second natural history study of congenital heart defects: Ventricular septal defect: Echocardiography. Circulation 87:1, 1993. 146.

Sabry AF, Reller MD, Silberbach GM, et al: Comparison of four Doppler echocardiographic methods for calculating pulmonary-to-systemic shunt flow ratios in patients with ventricular septal defect. Am J Cardiol 75:611, 1995. 147.

Friedman WF, Pitlick PT: Ventricular septal defect in infancy--University of California, San Diego (Specialty Conference). West J Med 120:295, 1974. 148.

Van Den Heuvel F, Timmers T, Hess J: Morphological, haemodynamic, and clinical variables as predictors for management of isolated ventricular septal defect. Br Heart J 73:49, 1995. 149.

Kidd L, Driscoll DJ, Gersony WM, et al: Second natural history study of congenital heart defects: Results of treatment of patients with ventricular septal defects. Circulation 87:1, 1993. 150.

Friedman WF, Mehrizi A, Pusch AL: Multiple muscular ventricular septal defects. Circulation 32:35, 1964. 151.

152.

Krovetz LJ: Spontaneous closure of ventricular septal defect. Am J Cardiol 81:100, 1998.

Kirklin JW, Barrett-Boyes BJ (eds): Cardiac Surgery. 2nd ed. New York, Churchill Livingstone, 1993, p 798. 153.

154.

Carotti A, Marino B, Bevilacqua M, et al: Primary repair of isolated ventricular septal defect in infancy

guided by echocardiography. Am J Cardiol 79:1498, 1997. Neutze JM, Ishikawa T, Clarkson PM, et al: Assessment and follow up of patients with ventricular septal defect and elevated pulmonary vascular resistance. Am J Cardiol 63:327, 1989. 155.

Gheen KM, and Reeves JT: Effects of size of ventricular septal defect and age on pulmonary hemodynamics at sea level. Am J Cardiol 75:66, 1995. 156.

Hislop A, Haworth SG, Shinebourne EA, Reid L: Quantitative structural analysis of pulmonary vessels in isolated ventricular septal defect in infancy. Br Heart J 37:1014, 1975. 157.

DuShane JW, Kirklin JW: Late results of the repair of ventricular septal defect on pulmonary vascular disease. In Kirklin JW (ed): Advances in Cardiovascular Surgery. New York, Grune & Stratton, 1973, p 9. 158.

Rhodes LA, Keane JF, Keane JP, et al: Long-term follow up (up to 43 years) of ventricular septal defect with audible aortic regurgitation. Am J Cardiol 66:340, 1990. 159.

Wang JK, Lue HC, Wu MH, et al: Assessment of ventricular septal defect with aortic valvar prolapse by means of echocardiography and angiography. Cardiol Young 4:44, 1994. 160.

Tohyama K, Satomi G, Momma K: Aortic valve prolapse and aortic regurgitation association with subpulmonic ventricular septal defect. Am J Cardiol 79:1285, 1997. 161.

Leung MP, Mok CK, Lo RNS, Lau KC: An echocardiographic study of perimembranous ventricular septal defect with left ventricular to right atrial shunting. Br Heart J 55:45, 1986. 162.

Gersony WM, Hayes CJ: Bacterial endocarditis in patients with pulmonary stenosis, aortic stenosis, or ventricular septal defect: Natural history study. Circulation 56(Suppl):1, 1977. 163.

deLeval M: Ventricular septal defects. In Stark J, deLeval M (eds): Surgery for Congenital Heart Defects. New York, Grune & Stratton, 1983, p 271. 164.

165.

Waldman JD: Why not close a small ventricular septal defect? Ann Thorac Surg 56:1011, 1993.

Kumar K, Lock JE, Geva T: Apical muscular ventricular septal defects between the left ventricle and the right ventricular infundibulum: Diagnostic and interventional considerations. Circulation 95:1207, 1997. 166.

Tee SDC, Shiota T, Weintraub R, et al: Evaluation of ventricular septal defect by transesophageal echocardiography: Intraoperative assessment. Am Heart J 127:585, 1994. 167.

Rigby M, Redington AN: Primary transcatheter umbrella closure of perimembranous ventricular septal defect. Br Heart J 72:368, 1994. 168.

Sideris EB, Walsh KP, Haddad JL, et al: Occlusion of congenital ventricular septal defects by the buttoned device. Heart 77:276, 1997. 169.

Thanopoulos BD, Tsaousis GS, Konstadopoulou GN, et al: Transcatheter closure of muscular ventricular septal defects with the Amplatzer ventricular septal defect occluder: Initial clinical applications in children. J Am Coll Cardiol 33:1395, 1999. 170.

171.

Otterstad JE, Simonsen S, Erikssen J: Hemodynamic findings at rest and during mild supine exercise

in adults with isolated uncomplicated ventricular septal defects. Circulation 71:650, 1985. Graham TP Jr, Atwood GF, Boucek RJ Jr, et al: Right ventricular volume characteristics in ventricular septal defect. Circulation 54:800, 1976. 172.

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173.

Heymann MA, Rudolph AM: Control of the ductus arteriosus. Physiol Rev 55:62, 1975.

Friedman WF, Printz MP, Kirkpatrick SE, Hoskins EJ: The vasoactivity of the fetal lamb ductus arteriosus studied in utero. Pediatr Res 17:331, 1983. 174.

Skidgel RA, Friedman WF, Printz MP: Prostaglandin biosynthetic activities of the fetal lamb ductus arteriosus, other blood vessels and fetal lung. Pediatr Res 18:12, 1984. 175.

Printz MP, Skidgel RA, Friedman WF: Studies of pulmonary prostaglandin biosynthetic and catabolic enzymes as factors in ductus arteriosus patency and closure: Evidence for a shift in products with gestational age. Pediatr Res 18:19, 1984. 176.

Gittenberger-DeGroot AC: Persistent ductus arteriosus: Most probably a primary congenital malformation. Br Heart J 39:610, 1977. 177.

178.

Freed MD, Hegmann MA, Lewis AB, et al: Prostaglandin E1 in infants with ductus arteriosus

dependent congenital heart disease. Circulation 64:899, 1981. Friedman WF, Hirschklau MJ, Printz MP, et al: Pharmacologic closure of patent ductus arteriosus in the premature infant. N Engl J Med 295:526, 1976. 179.

Douidar SM, Richardson J, Snodgrass WR: Use of indomethacin in ductus closure: An updated evaluation. Dev Pharmacol Ther 11:196, 1988. 180.

Shimada S, Kasai T, Konishi M, et al: Effects of patent ductus arteriosus on left ventricular output and organ blood flows in preterm infants with respiratory distress syndrome treated with surfactant. J Pediatr 125:270, 1994. 181.

Hiraishi S, Horiguchi Y, Misawa H, et al: Noninvasive Doppler echocardiographic evaluation of shunt flow dynamics of the ductus arteriosus. Circulation 75:1146, 1987. 182.

Merritt TA, Harris JP, Roghmann K: Early closure of the patent ductus arteriosus in very low birth weight infants: A controlled trial. J Pediatr 99:281, 1981. 183.

Yeh TF, Achanti B, Patel H, Pildes RS: Indomethacin therapy in premature infants with patent ductus arteriosus--determination of therapeutic plasma levels. Dev Pharmacol Ther 12:169, 1989. 184.

Gersony WM, Peckham GJ, Ellison RC, et al: Effects of indomethacin in premature infants with patent ductus arteriosus: Results of a national collaborative study. J Pediatr 102:895, 1983. 185.

Wagner HR, Ellison RC, Zierler S, et al: Surgical closure of patent ductus arteriosus in 268 preterm infants. J Thorac Cardiovasc Surg 87:870, 1984. 186.

Jarmakini MM, Graham TP Jr, Canent RV Jr, et al: Effect of site of shunt on left heart volume characteristics in children with ventricular septal defect and patent ductus arteriosus. Circulation 40:411, 1969. 187.

Bessenger FB Jr, Blieden LC, Edwards JE: Hypertensive pulmonary vascular disease associated with patent ductus arteriosus. Circulation 52:157, 1975. 188.

Prieto LR, DeCamillo DM, Conrad DJ, et al: Comparison of cost and clinical outcome between transcatheter coil occlusion and surgical closure of isolated patent ductus arteriosus. Pediatrics 101:1020, 1998. 189.

Shim D, Beekman RH: Transcatheter management of patent ductus arteriosus. Pediatr Cardiol 19:67, 1998. 190.

Ing FF, Sommer RJ: The snare-assisted technique for transcatheter coil occlusion of moderate to large patent ductus arteriosus: Immediate and intermediate results. J Am Coll Cardiol 33:1710, 1999. 191.

Rao PS, Kim SH, Choi JY, et al: Follow-up results of transvenous occlusion of patent ductus arteriosus with the buttoned device. J Am Coll Cardiol 33:820, 1999. 192.

Gray DT, Walker AM, Fyler DC, et al: Examination of the early "learning curve" for transcatheter closure of patent ductus arteriosus using the Rashkind occluder. Circulation 90:36, 1994. 193.

Masura J, Walsh KP, Thanopoulus B, et al: Catheter closure of moderate to large-sized patent ductus arteriosus using the new Amplatzer duct occluder: Immediate and short-term results. J Am Coll Cardiol 31:878, 1998. 194.

Singh TP, Morrow WR, Walters HL, et al: Coil occlusion versus conventional surgical closure of patent ductus arteriosus. Am J Cardiol 79:1283, 1997. 195.

Hines MH, Bensky AS, Hammon JW, et al: Video-assisted thoracoscopic ligation of patent ductus arteriosus: Safe and outpatient. Ann Thorac Surg 66:853, 1998. 196.

Le Bret E, Folliguet TA, Laborde F: Videothoracoscopic surgical interruption of patent ductus arteriosus. Ann Thorac Surg 64:1492, 1997. 197.

Kutsche LM, Van Mierop LHS: Anatomy and pathogenesis of aorticopulmonary septal defect. Am J Cardiol 59:443, 1987. 198.

Tulloh RMR, Rigby ML: Transcatheter umbrella closure of aorto-pulmonary window. Heart 77:479, 1997. 199.

DiBella I, Gladstone DJ: Surgical management of aortopulmonary window. Ann Thorac Surg 65:768, 1998. 200.

McElhinney DB, Reddy VM, Tworetzky W, et al: Early and late result after repair of aortopulmonary septal defect and associated anomalies in infants 40 years old with "significant" ASDs is still disputed. For patients with pulmonary hypertension (pulmonary artery pressure [PAP] > two thirds of systemic arterial blood pressure [SABP], or pulmonary arteriolar resistance more than two thirds of systemic arteriolar resistance), closure can be recommended if there is a net left-to-right shunt of at least 1.5:1, evidence of pulmonary artery reactivity when challenged with a pulmonary vasodilator (e.g., oxygen or nitric oxide), or evidence on lung biopsy that pulmonary arterial changes are potentially reversible (see Chap. 53 ). Transvenous pacing should be avoided when possible in patients with ASDs, because paradoxical emboli can occur. For the same reason, venous thromboemboli from any site are potential sources of systemic emboli. If a source of paradoxical embolism is found, anticoagulation and/or ASD closure may be recommended. INTERVENTIONAL OPTIONS AND OUTCOMES

Device Closure.

The use of devices to close ASDs percutaneously under fluoroscopy and TEE guidance[16] is gaining popularity. Indications for device closure are the same as for surgical closure but selection criteria are stricter. This technique is available mainly for patients with single secundum ASD with a stretched diameter of less than 50 percent of the diameter of the biggest available device and with adequate septal margin for proper device support. Anomalous pulmonary venous drainage or proximity of the defect to the atrioventricular (AV) valves, coronary sinus, or systemic venous drainage precludes the use of this technique. It is a safe and effective procedure in experienced hands, with major complications (e.g., device embolization, atrial perforation) occurring in less than 1 percent of patients and echo closure achieved in 85 percent or more of patients. Using "older" devices, silent residual shunts, more than half of which are trivial or mild, are still seen in 19 to 53 percent of patients at 6 to 12 months' follow-up. [17] Long-term follow-up data are not available.[17] Notwithstanding, device closure can be attractive to a patient wishing to avoid the consequences of surgery (general anesthesia, pain, and a scar) or to a patient believed to be at high surgical risk (see Fig. 43-12 ). Surgery.

Surgical closure of ASDs can be performed by primary suture closure or using an autologous pericardial

Figure 44-2 Chest radiograph in an adult with ostium secundum atrial septal defect. Arrows point to the enlarged right and left pulmonary arteries. Note the increase in peripheral pulmonary perfusion.

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or synthetic patch. The procedure is usually performed through a midline sternotomy, but the availability of an inframammary or minithoracotomy approach to a typical secundum ASD should be made known to potentially interested patients. Surgical mortality in the adult without pulmonary hypertension should be less than 1 percent with a low morbidity related mainly to the development of perioperative arrhythmias (atrial flutter/fibrillation or junctional rhythm). [12] [18] Surgical closure of an ASD improves functional status and exercise capacity in symptomatic patients[12] and improves survival, especially when patients are operated on at an earlier age.[13] [15] The incidence of late congestive heart failure is probably also reduced.[13] However, surgical closure of ASD does not prevent atrial fibrillation/flutter or stroke[13] especially when patients are operated on after the age of 40 years.[12] The role of a concomitant Cox/Maze procedure (see Chaps. 23 and 25 ) in patients older than the age of 40 years with a prior history of atrial flutter/fibrillation is unclear.[19] Patients with persistent atrial fibrillation should undergo anticoagulation. Follow-Up.

Patients who have had surgical or device repair as adults, with or without elevated pulmonary artery pressures at the time of operation, patients with atrial arrhythmias preoperatively or postoperatively, and patients with ventricular dysfunction preoperatively should remain under long-term cardiology surveillance. Isolated Ventricular Septal Defect (see also Chap. 43 )

Ventricular septal defects (VSDs) are the second most common congenital malformation of the heart, accounting for approximately 20 percent of all congenital cardiac malformations. Surgical repair of large defects and spontaneous closure of smaller defects during childhood decrease the overall incidence of VSDs in adulthood. ANATOMY.

The ventricular septum is composed of a muscular septum that can be divided into three major components (inlet, trabecular, and outlet) and a small membranous septum lying just underneath the aortic valve. VSDs are classified into three main categories according to their location and margins. Muscular VSDs are bordered entirely by myocardium and can be trabecular, inlet, or outlet in location. Membranous VSDs often have inlet, outlet, or trabecular extension and are bordered in part by fibrous continuity between the leaflets of an AV valve and an arterial valve. Doubly committed subarterial or outlet VSDs are situated in the outlet septum and are bordered by fibrous continuity of the aortic and pulmonary valves (see Fig. 43-15 ). In this section, we will deal with VSDs occurring in isolation from major associated cardiac anomalies. NATURAL HISTORY OF THE UNOPERATED PATIENT.

A restrictive VSD is defined as a defect that produces a significant pressure gradient between the left ventricle and the right ventricle, is accompanied by a small ( 50 mm Hg; increased left ventricular and left atrial size, or deteriorating left ventricular function) in the absence of irreversible pulmonary hypertension warrants surgical closure. If severe pulmonary hypertension is present (defined as pulmonary arteriolar resistance

greater than two thirds of systemic arteriolar resistance), surgical closure can be safely undertaken if there is a net left-to-right shunt of at least 1.5/1.0, strong evidence of pulmonary reactivity when challenged with a pulmonary vasodilator (oxygen, nitric oxide), or lung biopsy evidence that pulmonary artery changes are reversible. Other relative indications for VSD closure include the presence of a perimembranous or outlet VSD with more than mild aortic regurgitation and a history of endocarditis, especially if recurrent.[22] INTERVENTIONAL OPTIONS

Surgery.

Surgical closure, by direct suture closure or with a Dacron patch, has been used for over 50 years with low perioperative mortality--even in adults--and a very high closure rate.[6] Device Closure.

Successful transcatheter device closure of trabecular (muscular) and perimembranous VSDs has been reported.[23] Trabecular VSDs have proven more amenable to this technique because of their relatively straightforward anatomy and muscular rim to which the device attaches

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well. The closure of perimembranous VSDs is technically more challenging and should be considered experimental. INTERVENTIONAL OUTCOMES.

For patients with good to excellent functional class and good left ventricular function before surgical closure, life expectancy after surgical correction is close to normal. The risk of progressive aortic regurgitation is markedly reduced after surgery, as is the risk of endocarditis, unless a residual VSD persists. Intraventricular conduction disturbances are slightly increased after surgical closure and may be responsible for the slight increase in risk of sudden death encountered in this patient population.[24] FOLLOW-UP.

Yearly cardiac evaluation is suggested for patients with associated cardiac lesions (RVOTO, LVOTO, aortic regurgitation) not undergoing surgical repair, Eisenmenger syndrome patients, and adults with significant atrial or ventricular arrhythmias. Cardiac surveillance is also recommended for patients who had late repair of moderate or large defects, which are often associated with left ventricular impairment and elevated

pulmonary artery pressure at the time of surgery. Residual patch or device leaks are seldom hemodynamically important but can predispose to endocarditis. Maintenance of good dental hygiene and antibiotic prophylaxis in these patients is very important. Atrioventricular Septal Defect (see also Chap. 43 )

Unlike secundum ASDs, unoperated atrioventricular septal defects (AVSDs) are seldom first diagnosed in adults. ANATOMY.

AVSDs comprise a spectrum of anomalies caused by abnormal development of the endocardial cushions, which may give rise to partial, intermediate, or complete AVSDs (Table 44-1) . In AVSD, the AV valves are fundamentally abnormal, being derived from five leaflets (a right anterosuperior leaflet, a right inferior leaflet, a superior bridging leaflet, an inferior bridging leaflet, and a left mural leaflet). This arrangement may result in separate but TABLE 44-1 -- DEFINITIONS OF TYPES OF ATRIOVENTRICULAR SEPTAL DEFECTS (AVSD) PARTIAL AVSD Ostium primum ASD Two separate AV valves "Cleft" left AV valve Intact ventricular septum Rarely, no ASD with only a "cleft" in the left AV valve Associated anomalies: Down syndrome (90%). ASD=Atrial septal defect; AV=atrioventricular; VSD=ventricular septal defect.

Figure 44-3 Right- and left-sided atrioventricular valve in normal heart (A), partial atrioventricular septal defect (B), and complete atrioventricular septal defect (C). Rastelli type A: Superior bridging leaflet (RSL and LSL) has a cleft with ventricular septal attachment. Rastelli type B: Superior bridging leaflet has a cleft with right papillary muscle attachment. Rastelli type C: Superior bridging leaflet has no cleft and no attachment. TV=tricuspid valve; MV=mitral valve; AL=anterior leaflet; PL=posterior leaflet; SL=septal leaflet; RSL=right superior (bridging) leaflet; RLL=right lateral (anterosuperior) leaflet; RIL=right inferior (bridging) leaflet; LSL=left superior (bridging) leaflet; LLL=left lateral (mural) leaflet; LIL=left inferior (bridging) leaflet. (From Kirklin JW, Barratt-Boyes BG: Cardiac Surgery. 2nd ed. New York, Churchill Livingstone, 1993.)

abnormal right and left AV valves (primum and intermediate AVSD) or a common valve (complete AVSD) (Fig. 44-3) . The left AV valve is invariably abnormal, having a "cleft" at the conjunction of the superior and inferior bridging leaflets. Rarely, a double orifice left (mitral) AV valve is also encountered. The "unwedged" anteriorly located aorta, coupled to an apically displaced left AV valve (at the same level as the right AV valve), gives rise to an elongated left ventricular outflow tract, often characterized as a "gooseneck deformity." AVSD may occur in association with Down syndrome, tetralogy of Fallot, and other forms of complex congenital heart disease, including univentricular hearts. NATURAL HISTORY OF THE UNOPERATED PATIENT

Partial and Intermediate AVSD.

Patients with partial and intermediate AVSDs have a course similar to that of patients with large secundum ASDs, with the caveat that symptoms may appear sooner when significant mitral regurgitation occurs through the cleft left AV valve. Patients are usually asymptomatic until their third or fourth decade, but progressive symptoms related to congestive heart failure, atrial arrhythmias, complete heart block, and variable degrees of pulmonary hypertension develop in virtually all of them by the fifth decade. Complete AVSD.

Most patients with complete defects have had surgical repair in infancy. Some patients may have had palliative surgery in the past with pulmonary artery bands and have variable degrees of pulmonary vascular obstructive disease. When presenting de novo, most adults have established pulmonary vascular disease (see Eisenmenger Syndrome). Patients with Down syndrome have a propensity to develop pulmonary hypertension at an even earlier age than do other patients with AVSD.

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Clinical Manifestations.

Clinical presentation depends on the presence and size of the ASD, on the VSD, and on the competence of the left AV valve. A large left-to-right shunt gives rise to symptoms of heart failure (dyspnea or fatigue on exertion) or, worse, pulmonary vascular disease (exertional syncope, cyanosis). Severe chronic left or right AV valve insufficiency leads to pulmonary congestion, hepatic congestion, and peripheral edema. Palpitations from atrial arrhythmias are very common. Down syndrome is seen in 35 percent of patients with AVSD. Almost all have the complete form. Cardiac findings on physical examination for patients with partial AVSD are similar to those of patients with secundum ASD, with the important addition of a prominent left ventricular apex and holosystolic murmur when significant left AV valve regurgitation is present. The murmur of left AV valve regurgitation can sometimes be heard radiating to the left sternal border if the regurgitant jet is directed into the right atrium (the Gerbode defect). Intermediate AVSDs resemble partial AVSD with the addition of a holosystolic VSD murmur heard best at the left sternal border, sometimes difficult to differentiate from a left AV valve regurgitant murmur. Complete AVSDs have a single first heart sound (S1 ) (common AV valve), a mid-diastolic murmur from augmented AV valve inflow, and findings of pulmonary hypertension and/or a right-to-left shunt. DIAGNOSTIC TESTING

Electrocardiogram.

Because of the posteriorly located AV node and hence the closer proximity of the left posterior fascicle, most patients have first-degree AV block and left-axis deviation from late left anterior fascicular depolarization. Complete AV block and/or atrial fibrillation/flutter can be present in older patients. Partial or complete right bundle branch block is usually associated with right ventricular dilation (Fig. 44-4) . Chest Radiography.

Cardiomegaly and pulmonary plethora are the rule with an enlarged left atrium commonly present. Echocardiography.

Echocardiography is essential to document the type of AVSD; assess the magnitude and direction of intracardiac shunting, the degree of AV valve regurgitation, the presence/absence of subaortic stenosis; and estimate pulmonary artery pressure (Fig. 43-13) . The lack of "offsetting" between the left and right AV valves (the right AV valve being apically displaced in normal hearts) is readily seen in the four-chamber view and is the echocardiographic hallmark of AVSD (Fig. 44-5) . TEE may be needed to further

define the underlying anatomy of the defect (Rastelli type, see Table 44-1 ) and associated lesions (e.g., double orifice mitral valve) if unclear after TTE. Cardiac Catheterization.

Heart catheterization to determine the severity of pulmonary vascular disease, the presence and magnitude of intracardiac shunts, and the severity of subaortic stenosis may be necessary. The typical "goose neck" deformity of the left ventricular outflow tract is readily demonstrated on angiography. Open-Lung Biopsy.

This should only be considered when the reversibility of the pulmonary hypertension is uncertain from the hemodynamic data (see Eisenmenger Syndrome, p. 1614 ). INDICATIONS FOR INTERVENTION.

The patient with an unoperated or newly diagnosed AVSD and significant hemodynamic defects, manifested by atrial arrhythmias and impaired ventricular function or right ventricular volume overload, requires surgical repair. Equally, patients with symptoms, reversible pulmonary hypertension, or significant

Figure 44-5 Transesophageal echocardiogram of intermediate atrioventricular septal defect illustrates the lack of offsetting between the left-sided and right-sided atrioventricular valves. Single arrow points at the primum atrial septal defect; double arrows point at the restrictive ventricular septal defect. RA\m4\right atrium; LA\m4\left atrium; RV\m4\right ventricle; LV\m4\left ventricle.

Figure 44-4 Typical electrocardiogram of partial atrioventricular septal defect shows first-degree atrioventricular block, left-axis deviation, and complete right bundle branch block.

subaortic obstruction (peak gradient of at least 50 mm Hg at rest) require surgical intervention. INTERVENTIONAL OPTIONS

Partial AVSD.

Pericardial patch closure of the primum ASD with concomitant suture (±annuloplasty) of the "cleft" left AV valve is usually performed. When "mitral" valve repair is not possible, "mitral" valve replacement may be necessary.

Intermediate/Complete AVSD.

The "staged approach" (pulmonary artery banding followed by intracardiac repair) has been supplanted by primary intracardiac repair. The goals of intracardiac repair are ventricular and atrial septation with adequate mitral and tricuspid reconstruction. Both "single" and "double" patch techniques to close atrial and ventricular septal defects have been described with comparable results.[25] "Tricuspidization" of the left AV "mitral" valve (making a trileaflet left AV valve) at the time of surgery has been advocated by some, [26] [27] but a bileaflet repair is preferred by most. [28] [29] Patch augmentation of the tissue-deficient "bridging leaflets" forming the mitral valve is sometimes performed.[30] Occasionally, left AV valve replacement is necessary when valve repair is not possible. In patients with complete heart block, endocardial transvenous pacing should be avoided when intraatrial or intraventricular communications are present, because paradoxical emboli may occur. INTERVENTIONAL OUTCOMES.

Surgical mortality in adults with partial AVSDs varies between 0 and 6 percent with 5and 10-year survivals of 87 percent and 72 percent, respectively.[31] [32] [32A] The worst outcome occurs in patients with pulmonary arterial hypertension, severe AV valve regurgitation,

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and an enlarged heart.[32B] Improvement in functional class after surgical repair is the rule.[31] [32] Postoperative complications include patch dehiscence or residual septal defects (1 percent), the development of complete heart block (3 percent), late atrial fibrillation/flutter, left AV valve dysfunction, and progressive or de novo subaortic stenosis. Recurrent left AV valve regurgitation is the principal cause of late morbidity after surgical repair of AVSDs, necessitating reoperation in at least 10 percent of patients.[28] [29] [31] [32] [32A] [32B] [33] Left AV stenosis from overly zealous cleft suturing may occur. The development or progression of subaortic stenosis after AVSD surgery occurs in about 5 percent of cases.[34] The morphological features of AVSD (the long, narrow left ventricular outflow tract) promote actual or potential subaortic stenosis. Subaortic stenosis can be discrete or tunnel-like, and surgical repair is often necessary. An operation tailored to the underlying cause of obstruction has been advocated because of the high risk of recurrence after surgical resection[34] (see Subaortic Stenosis, p. 1599 ). FOLLOW-UP.

All patients require periodic follow-up by a cardiologist because of the possibility of progressive AV valve regurgitation (or stenosis), the development of subaortic stenosis, significant atrial arrhythmias, or progression of the commonly present first-degree AV block. Particular attention should be paid to those patients with pulmonary hypertension,

severe AV valve regurgitation, and an enlarged heart. Patent Ductus Arteriosus (see also Chap. 43 )

The incidence of isolated persistent patency of the ductus arteriosus has been estimated at 1:2000 to 1:5000 births, or about 10 to 12 percent of all varieties of congenital heart disease. ANATOMY.

The ductus arteriosus derives from the left sixth primitive aortic arch and connects the proximal left pulmonary artery to the descending aorta, just distal to the left subclavian artery. Occasionally, the ductus fails to close at birth and presents as a potential clinical problem. NATURAL HISTORY OF THE UNOPERATED PATIENT.

Physiological consequences of a patent ductus arteriosus (PDA) depend on the degree of left-to-right shunting, which is determined by both the size of the duct and the difference between systemic and pulmonary vascular resistances.[35] A small ductus accompanied by a small shunt does not cause significant hemodynamic derangement but may predispose to endarteritis, especially if accompanied by an audible murmur.[2] A moderate-sized duct and shunt pose a volume load on the left atrium and ventricle with resultant left ventricular dilation and dysfunction and eventual atrial fibrillation. A large duct results initially in left ventricular volume overload, with a progressive rise in pulmonary artery pressure leading to high pulmonary vascular resistance and eventually irreversible pulmonary vascular changes and systemic pulmonary pressures (see Eisenmenger Syndrome, p. 1614 ). CLINICAL MANIFESTATIONS.

Patients with silent PDAs are asymptomatic, and the PDAs are detected by nonclinical means, usually echocardiography. A small audible duct usually causes no symptoms but may rarely present as an endovascular infection. Physical examination reveals a grade 1-2 continuous murmur, peaking in late systole, and best heard in the first or second left intercostal space. Patients with a moderate-sized duct may present with dyspnea or palpitations from atrial arrhythmias. A louder

Figure 44-6 Short-axis left parasternal transthoracic echocardiogram of systolic flow traveling toward the pulmonary valve (arrow) in the main pulmonary artery from a patent ductus arteriosus. RV\m4\right ventricle; RA\m4\right atrium; AV\m4\aortic valve; PV\m4\pulmonary valve; MPA\m4\main pulmonary artery; LPA\m4\left pulmonary artery; RPA\m4\right pulmonary artery.

continuous "machinery" murmur in the first or second left intercostal space is typically accompanied by a wide systemic pulse pressure from aortic diastolic runoff into the

pulmonary trunk and signs of left ventricular volume overload, such as a displaced left ventricular apex and sometimes a left-sided S3 . With a moderate degree of pulmonary hypertension, the diastolic component of the murmur disappears, leaving a systolic murmur. Adults with a large uncorrected PDA eventually present with Eisenmenger syndrome physiology (see p. 1614 ). DIAGNOSTIC TESTING

Electrocardiogram.

The ECG reflects the size and degree of shunting occurring through the duct. A small duct produces a normal ECG. A moderate-sized duct may show left ventricular volume overload with broad, notched P waves together with deep Q waves, tall R waves, and peaked T waves in V5 and V6 . A large duct produces findings of right ventricular hypertrophy (see Eisenmenger syndrome, p. 1614 ). Chest Radiography.

A small duct produces a normal chest radiograph. A moderate-sized duct causes moderate cardiomegaly with left-sided heart enlargement and increased pulmonary perfusion. A large duct produces right ventricular hypertrophy and enlarged central pulmonary arteries with peripheral pruning (see Eisenmenger syndrome, p. 1614 ). Echocardiography.

This will determine the presence, size, and degree of shunting and the physiological consequences of the shunt. Suprasternal and parasternal short-axis views will best identify the duct. In the absence of Eisenmenger physiology, color flow Doppler shows a jet that travels on the lateral wall of the main pulmonary artery toward the pulmonary valve in systole and diastole ( Fig. 44-6 ; see also Fig. 43-18 ). Direction and timing of the flow as well as the Doppler-derived gradient obtained from the jet provide estimates of the pulmonary artery pressure. INDICATIONS FOR INTERVENTION.

Closure of a clinically detectable PDA, in the absence of irreversible pulmonary hypertension, is usually recommended to avoid its associated morbidity and premature mortality. The risk of endarteritis in a patient with a silent PDA is considered negligible, and closure of such ducts is not recommended for that reason.[2] In the presence of pulmonary hypertension (PAP > two thirds of SAP, or pulmonary arteriolar resistance > two thirds of systemic arteriolar resistance), PDA closure should be carried out if there is a net pulmonary/systemic blood flow greater than 1.5/1.0, evidence of pulmonary artery reactivity when challenged with a pulmonary vasodilator (e.g., oxygen, nitric oxide), or lung biopsy evidence that pulmonary arterial changes are potentially reversible (Heath-Edwards grade II or less). Contraindications to ductal closure include irreversible

pulmonary hypertension or active endarteritis.[2] INTERVENTIONAL OPTIONS AND OUTCOMES

Transcatheter Treatment.

Over the past 20 years, the efficacy and safety of transcatheter device closure for ducts less than 8 mm has been established,[36] [37] [38] with complete ductal closure achieved in more than 85 percent of patients by 1 year after device placement at a mortality rate of less than 1 percent. The avoidance of general anesthesia, thoracotomy, postoperative pain, and prolonged convalescence makes transcatheter closure a very attractive modality. In centers with appropriate resources and experience, transcatheter device occlusion should be the method of choice for ductal closure (see Chap. 43 , Fig. 43-19 ). Surgical Treatment.

Surgical closure, by ductal ligation and/or division, has been performed for over 50 years with a marginally greater closure rate than device closure but somewhat greater morbidity and mortality. Immediate clinical closure (no shunt audible on physical examination) is achieved in more than 95 percent of patients.[39] Surgical mortality in adults is 1.0 to 3.5 percent and relates to the presence of pulmonary artery hypertension and the difficult

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ductal morphology (calcified or aneurysmal) often seen in adults. Surgical closure of a duct should be reserved for patients with larger ducts (> 8 mm diameter) or at centers without access to interventional expertise. Emerging procedures such as muscle-sparing minithoracotomy and video-assisted thoracoscopic surgery may further broaden therapeutic surgical choices in the future. FOLLOW-UP.

Patients with a silent PDA do not require follow-up. Patients with device occlusion or after surgical closure should be examined periodically for possible recanalization. Silent residual shunts may be found by TTE. The risk of late endarteritis from a clinically silent residual shunt after device implantation or surgical closure is unclear,[40] [41] and the clinical management of such patients remains problematic. Until long-term follow-up data become available, it may be prudent to continue antibiotic endocarditis prophylaxis in such patients.[36] [40] [41] Bicuspid Aortic Valve (see also Chap. 43 )

The bicuspid aortic valve remains the most common congenital malformation of the

heart (1-2 percent of the population). This lesion accounts for approximately half the cases of surgically important isolated aortic stenosis in adults. ANATOMY.

A bicuspid aortic valve consists of two cusps, often of unequal size, the larger usually containing a false raphe. There is a male preponderance of 4:1. It usually occurs in isolation but is associated with other abnormalities in 20 percent, the most common being coarctation of the aorta and PDA. There is also a high prevalence of aortic root enlargement in patients with bicuspid aortic valve that occurs irrespective of altered hemodynamics or age.[42] [42A] [42B] NATURAL HISTORY OF THE UNOPERATED PATIENT.

Patients with a bicuspid aortic valve may not experience any problems, although there is always the risk of endocarditis. Mild aortic stenosis from bicuspid aortic valve commonly progresses as the patient ages, but the rate is variable.[43] Late aortic stenosis from calcification of the valve in the sixth decade is common. Other patients can develop aortic regurgitation, aneurysmal aortic root dilation, and possibly aortic dissection.[44] DIAGNOSTIC TESTING

Electrocardiogram.

The ECG ranges from normal to showing marked left ventricular hypertrophy from severe aortic stenosis or regurgitation. (see Fig. 43-31 ). Chest Radiography.

Dilation of the ascending aorta is common. Valvar calcification can sometimes be detected. The left ventricle is enlarged in proportion to the degree of aortic regurgitation. Echocardiography.

This permits identification of the bileaflet aortic valve and quantification of the severity of obstruction and/or regurgitation. It also provides information on left ventricular size and function as well as aortic root size. Concomitant defects such as coarctation or dissection of the aorta should be sought (see Fig. 43-32 ). INDICATIONS FOR INTERVENTION.

Bicuspid aortic valves require intervention for stenosis when symptoms (exertional dyspnea, angina, presyncope or syncope) are present. Intervention for asymptomatic "critical" aortic stenosis (valve area 55 mm) seems better than waiting for the aorta to dissect or rupture, although there is no agreement on the diameter at which referral for surgery is appropriate. INTERVENTIONAL OPTIONS.

Bicuspid aortic stenosis can be treated with balloon valvuloplasty if the valve is noncalcified.[45] Other treatment options include open aortic valvotomy or valve replacement using a mechanical valve, a biological valve, or a pulmonary autograft. The pulmonary autograft (Ross procedure), introduced by Donald Ross in 1967, consists of replacing the aortic valve with the patient's pulmonary valve and implanting a homograft in the pulmonary position. The advantages of this procedure--avoidance of anticoagulation and much reduced risk of thromboembolism--need to be weighed against the greater technical complexity of the procedure, the risk of early and late autograft dysfunction, and homograft failure.[46] [47] The choice of intervention depends on the availability and skills of the team involved and the preference of the patient. Aortic valve repair has been reported for aortic regurgitation from a prolapsing aortic valve leaflet. Short-term results are promising, but long-term data are awaited.[48] FOLLOW-UP.

All patients, treated and untreated, require skilled follow-up, the frequency being determined by the severity of the pathology. Subaortic Stenosis (see also Chap. 43 ) ANATOMY.

Subvalvar LVOTO can be either discrete (most common) or tunnel shaped. Discrete obstruction is due to a membranous ridge or fibromuscular narrowing partially or completely encircling the left ventricular outflow tract beneath the base of the aortic valve.[49] Tunnel-like obstruction is produced by a fibromuscular channel that involves a long segment of the left ventricular outflow tract and is usually associated with a small aortic root. Rarely, abnormal insertion of the mitral valve or an accessory mitral leaflet will cause subvalvar obstruction. Subvalvar LVOTO can also be seen after repair of AVSD (see p. 1596 ). The concurrence of subvalvar LVOTO, coarctation, and mitral stenosis (parachute mitral valve and supramitral ring) is known as Shone syndrome. VSD is sometimes associated with subvalvar LVOTO. NATURAL HISTORY OF THE UNOPERATED PATIENT.

Subvalvar LVOTO, discrete or tunnel-like, usually progresses at variable rate, resulting in left ventricular hypertrophy and the development of symptoms.[50] It is often associated with progressive aortic regurgitation (up to 60 percent of cases) from a bicuspid aortic valve or an otherwise normal valve damaged by the subvalvar jet of blood. Aortic regurgitation in this setting is seldom more than moderate. These patients

are particularly vulnerable to endocarditis. CLINICAL MANIFESTATIONS.

Patients can be asymptomatic or can present with angina, syncope, or heart failure. On examination, the pulse pressure may be diminished if the obstruction is severe. A2 may be normal or diminished depending on the severity of the stenosis. A systolic ejection murmur may be heard at the mid-left sternal edge in cases of tubular stenosis and in the second right intercostal space in cases of discrete stenosis. A blowing diastolic murmur from concomitant aortic regurgitation is often present. A systolic ejection click is not present in subvalvar aortic stenosis, and the systolic murmur does not radiate to the carotid arteries.[51] DIAGNOSTIC TESTING

Electrocardiogram.

Left ventricular hypertrophy may be present. Chest Radiography.

An inconspicuous cardiac silhouette and ascending aorta are the rule unless LVOTO is associated with a bicuspid aortic valve (see bicuspid valve/ascending aortopathy) or significant aortic regurgitation. Echocardiography.

Two-dimensional echocardiography permits identification of the morphology of the obstruction and any associated anomalies (e.g., bicuspid aortic valve, VSD, coarctation, or mitral inflow obstruction).[52] The severity

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of LVOTO can be determined by continuous-wave Doppler and the severity of aortic regurgitation by Doppler and color flow imaging. Angiography.

An angiogram to assess the severity of obstruction may be needed when noninvasive means are not adequate. INDICATIONS FOR INTERVENTION.

Whereas patients with symptomatic subvalvar LVOTO require intervention, indications for intervention in asymptomatic patients are less well defined. A resting peak-to-peak angiographic gradient greater than 50 mm Hg as well as progressive or moderate to severe aortic regurgitation have been used as criteria for intervention.[6] Some advocate earlier relief of subvalvar obstruction to minimize early aortic valve damage and prevent progressive regurgitation.[53] INTERVENTIONAL OPTIONS

Surgical.

For discrete obstruction, membranectomy with concomitant myomectomy or myotomy is usually performed. For tunnel-like obstruction, the left ventricular outflow tract often requires surgical augmentation using the modified Konno procedure (aortoventriculoplasty with aortic valve sparing).[54] In patients with significant aortic stenosis or moderate/severe aortic regurgitation, the Konno procedure (aortoventriculoplasty with aortic valve replacement) or the Konno-Ross procedure (aortoventriculoplasty with pulmonary autograft)[55] for younger patients or those with a contraindication to anticoagulation should be performed. Left ventricular apex-to-aorta valved conduits, bypassing the LVOTO, have been used in the past, but the long-term durability is unacceptable and the procedure has largely been abandoned. Transcatheter.

Transluminal balloon dilation of discrete subaortic stenosis has been described with good short- and intermediate-term results, [56] but long-term data have not been reported. At present, a surgical approach is still recommended. INTERVENTIONAL OUTCOMES.

Complications related to surgery include complete AV block, creation of VSD, or mitral valve regurgitation from intraoperative damage to the mitral valve apparatus. Long-term complications include recurrence of fibromuscular subvalvar LVOTO (up to 20 percent), particularly with tunnel-like obstruction or following isolated membranectomy for discrete obstruction. Clinically important aortic regurgitation is also not uncommon (up to 25 percent of patients). FOLLOW-UP.

Particular attention should be paid to patients with recurrent subvalvar stenosis or patients with an associated bicuspid aortic valve or progressive aortic regurgitation because they are most likely to require eventual surgery. Patients with bioprosthetic aortic valves in the aortic position (after the Konno procedure) or the pulmonic position (after the Konno-Ross procedure) need close follow-up. Reoperation is required in up to 25 percent of patients in the 20 years [57] [58] after surgical repair. Endocarditis prophylaxis

should be used for prosthetic valves or in the presence of any residual lesions. Coarctation of the Aorta (see also Chap. 43 )

This left-sided obstructive lesion occurs most frequently in males, with a sex ratio approaching 3:1. ANATOMY.

Coarctation of the aorta is a narrowing usually in the region of the ligamentum arteriosum (see Fig. 43-27 ). It may be discrete or associated with hypoplasia of the aortic arch and isthmus. The specific anatomy, severity, and degree of hypoplasia proximal to the coarctation are highly variable. "Complex" coarctation is used to describe coarctation in the presence of other important intracardiac anomalies (e.g., VSD, LVOTO, and mitral stenosis) and is usually detected in infancy. "Simple" coarctation refers to coarctation in the absence of such lesions. It is the most common form detected de novo in adults. Associated abnormalities include bicuspid aortic valve in 50 to 85 percent of cases, intracranial aneurysms (most commonly of the circle of Willis), and acquired intercostal artery aneurysms. One definition of "significant" coarctation is one with a gradient greater than 20 mm Hg across the coarctation site at angiography with or without proximal systemic hypertension. A second definition of "significant" coarctation requires the presence of proximal hypertension in the company of echocardiographic or angiographic evidence of aortic coarctation. Of note, if there is an extensive collateral circulation, there may be minimal or no pressure gradient and acquired aortic atresia. NATURAL HISTORY OF THE UNOPERATED PATIENT.

A significant coarctation causes a pressure load proximally with consequent left ventricular hypertrophy and ultimately heart failure. Most patients will develop systemic hypertension, typically during childhood, and are at risk of premature coronary artery disease. The mean survival of patients with untreated coarctation is 35 years, with 75 percent mortality by 50 years of age.[59] Death in patients who do not undergo repair is usually due to heart failure (usually beyond 30 years of age), coronary artery disease, aortic rupture/dissection, concomitant aortic valve disease, infective endarteritis/endocarditis, or cerebral hemorrhage.[59] CLINICAL MANIFESTATIONS.

Patients may be asymptomatic or present with minimal symptoms of epistaxis, headache, leg weakness on exertion, or more serious symptoms of congestive heart failure, angina, aortic stenosis, aortic dissection, or unexplained intracerebral hemorrhage. Leg claudication is rare unless there is concomitant abdominal aortic coarctation (Somerville J, personal communication, 1998). A thorough clinical examination reveals upper limb systemic hypertension as well as a differential systolic blood pressure of at least 10 mm Hg (brachial > popliteal artery pressure). Radial-femoral pulse delay is evident unless significant aortic regurgitation coexists.

Auscultation may reveal an interscapular systolic murmur emanating from the coarctation site and a widespread crescendo-decrescendo systolic murmur throughout the chest wall from intercostal collateral arteries. Fundoscopic examination can reveal "corkscrew" tortuosity of retinal arterioles. [60] DIAGNOSTIC TESTING

Electrocardiogram.

Left ventricular hypertrophy is common. Concomitant left atrial enlargement may be present. Chest Radiography.

Prestentotic and poststenotic dilation of the aorta gives the "3 sign" appearance on a chest radiograph. Rib notching appearing as sclerotic scalloping on the inferior surface of ribs number 3 through 8 from dilated intercostal arteries may be present, usually bilaterally, unless the left or right subclavian artery arises aberrantly below the coarctation, giving rise to unilateral right-sided or left-sided rib notching, respectively. Echocardiography.

The coarctation site can be visualized from the suprasternal view and its severity assessed by Doppler mode (see Fig. 43-28 ). A peak gradient greater than 20 mm Hg, especially if accompanied by continuous forward flow during diastole in the descending or abdominal aorta, suggests significant aortic coarctation. In addition, the echocardiographer should evaluate other cardiac lesions--notably aortic, mitral, or subaortic abnormality and the status of left ventricular function. Angiography.

Angiography with hemodynamic measurements can be done to assess the location, type, and severity of coarctation and to determine the presence/absence of collaterals or aneurysm formation. Associated stenoses in other great vessels (carotids and subclavian arteries) can also be detected by this modality. Coronary angiography should be performed if surgery is planned because of the risk of premature coronary artery disease in these patients.

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Magnetic Resonance Imaging (MRI).

MRI (two-dimensional and velocity mapping) provides as good anatomical and hemodynamic details as angiography and may obviate the need for angiography, unless

coronary artery disease needs to be excluded. INDICATIONS FOR INTERVENTION.

All patients with significant coarctation or re-coarctation (arm > leg systolic pressure difference 10 mm Hg; radial-femoral pulse delay; peak transcoarctation gradient > 20 mm Hg at angiography) including those with long-standing hypertension (regardless of age), whether symptomatic or asymptomatic, warrant intervention to reduce or eliminate the gradient.[59] INTERVENTIONAL OPTIONS

Surgical.

Surgical techniques include end-to-end repair, subclavian flap plasty, patch repair, interposed graft, or bypass graft and varies according to the underlying anatomy of the coarctation.[61] Patients with significant aortic valve stenosis may also require valve surgery that may or may not be done at the same time as coarctation repair. If lesions are operated on separately, the more severe lesion should be dealt with first. Transcatheter.

Balloon dilation with or without stent insertion in patients with native coarctation and re-coarctation has been performed with good immediate and medium-term results in children and adolescents.[62] [63] [64] However, it should still be considered experimental in the adult population and should only be performed in centers and by individuals with expertise in this domain (Fig. 44-7) . INTERVENTIONAL OUTCOMES

Surgical.

After surgical repair of simple coarctation, the obstruction is usually relieved with minimal mortality ( 65 percent) are relative indications.[78] [81] INTERVENTIONAL OPTIONS.

Tricuspid valve repair when feasible is preferable to tricuspid valve replacement. The feasibility of tricuspid valve repair depends primarily on the experience and skill of the surgeon, as well as on the adequacy of the anterior leaflet of the tricuspid valve to form a monocusp valve.[81] [82] Tricuspid valve repair is possible when the edges of the anterior leaflet of the tricuspid valve are not severely tethered down to the myocardium and when the functional right ventricle is of adequate size (>35 percent of the total right ventricle). If the tricuspid valve cannot be repaired, valve replacement with either a bioprosthetic or mechanical tricuspid valve is necessary. It is controversial whether the atrialized portion of the right ventricle should be plicated at the time of surgery to reduce the risk of atrial arrhythmias. For "high-risk" patients (those with severe tricuspid regurgitation, an inadequate functional right ventricle [because of size or function], and/or chronic supraventricular arrhythmias), a bidirectional cavopulmonary connection can be added to reduce right ventricular preload (see Glen procedure, Chap. 43 ).[83] Occasionally, a Fontan operation may be the best option in patients with tricuspid stenosis and/or hypoplastic right ventricle (see Fontan operation, p. 1607 ). Concomitant right atrial maze procedure at the time of surgery should be considered in patients with chronic atrial flutter/fibrillation.[84] If an accessory pathway is present, it should be mapped and obliterated either at the time of surgical repair or preoperatively in the catheter laboratory (see Chaps. 23 and 25 ). An atrial communication, if present, should be closed. INTERVENTIONAL OUTCOMES.

With satisfactory valve repair, with or without plication of the atrialized right ventricle or bidirectional cavopulmonary connection, the medium-term prognosis is excellent.[81] [82] Late arrhythmias can occur. With valve replacement, results are less satisfactory. Valve re-replacement may be necessary because of a failing bioprosthesis or thrombosed mechanical valve. Long-term anticoagulation with mechanical valves is mandatory.

Complete heart block after tricuspid valve replacement can occur. FOLLOW-UP.

All patients with Ebstein anomaly should have regular follow-up, the frequency dictated by the severity of their disease. Particular attention should be paid to patients with cyanosis, cardiomegaly, worsening right ventricular function, and important atrial arrhythmias. Patients with tricuspid regurgitation after tricuspid valve repair need close follow-up, as do patients with recurrent atrial arrhythmias, degenerating bioprostheses, or dysfunctional mechanical valves.

Figure 44-10 Four-chamber view, transthoracic echocardiogram of Ebstein anomaly. Multiple arrows point at the apically displaced tricuspid valve. RA=right atrium; ARV=atrialized right ventricle; RV=functional right ventricle; LA=left atrium; MV=mitral valve; LV=left ventricle.

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Tetralogy of Fallot (see also Chap. 43 )

Tetralogy of Fallot is the most common form of cyanotic congenital heart disease after 1 year of age, with an incidence approaching 10 percent of all forms of congenital heart disease. ANATOMY.

The defect is due to anterocephalad deviation of the outlet septum resulting in four features: (1) nonrestrictive VSD; (2) overriding aorta (but 50 mm Hg or RV/LV pressure ratio >0.6) may require surgical or catheter augmentation of the right ventricular outflow tract. Myocardial ischemia from coronary artery obstruction may require coronary artery bypass grafting, preferably with arterial conduits. Significant neoaortic valve regurgitation[136] may warrant aortic valve replacement. In patients who have had the Rastelli operation, significant right ventricle-to-pulmonary artery conduit stenosis (peak gradient 1.5/1.0) may require surgical closure.[137] Patients with clinical deterioration and a palliative atrial switch should be considered for lung or heart-lung transplantation. INTERVENTIONAL OPTIONS

Medical Therapy.

The role of afterload reduction with ACE inhibitors to preserve systemic right ventricular function is as yet unknown. In light of the effects of these drugs on dysfunctional systemic left ventricles, it seems logical to assume that similar beneficial effects on systemic right ventricles may occur. Two-Stage Arterial Switch.

Patients with symptomatic, severe systemic (right) ventricular dysfunction with or without severe systemic (tricuspid) AV valve regurgitation, following an atrial switch procedure, may require consideration of a conversion procedure to an arterial switch ("two-stage arterial switch") or heart transplantation. The "two-stage arterial switch" or "switch-conversion" procedure consists of banding the pulmonary artery in the first stage, to induce morphological pulmonary left ventricular hypertrophy and "train" the left ventricle to support systemic pressure. Once left ventricular systolic pressure is more than 75 percent of systemic pressure and the left ventricular mass is considered adequate, in the second stage, the atrial baffles and the pulmonary band are taken down, the atrial septum is reconstructed, and the great arteries are switched, leaving the morphological left ventricle as the systemic ventricle. This procedure, however, is still experimental in adults, with little data available to assess its short- and long-term efficacy.[133] Cardiac Transplantation.

Heart transplantation should be considered as an alternative, given its relatively good 5to 10-year survival.[7] FOLLOW-UP.

Regular follow-up by physicians with special expertise in adult congenital heart disease is recommended. Atrial Switch.

Serial follow-up of systemic right ventricular function is warranted. Echocardiography, radionuclide angiography, and MRI can be used.[138] [139] ACE inhibitors are often recommended empirically for moderate to severe right ventricular dysfunction and may be helpful to all atrial switch patients. Asymptomatic baffle obstruction should be sought with echocardiography or MRI. Regular Holter monitoring is recommended to diagnose unacceptable bradyarrhythmias or tachyarrhythmias. Arterial Switch.

Regular follow-up with echocardiography is recommended. Rastelli Procedure.

Regular follow-up with echocardiography is warranted given the inevitability of conduit degeneration over time. Congenitally Corrected Transposition of the Great Arteries (see also Chap. 43 ) ANATOMY.

Congenitally corrected TGA is a rare condition, accounting for less than 1 percent of all congenital heart disease. In congenitally corrected TGA, the connections of both the atria to ventricles and of the ventricles to the great arteries are discordant. Systemic venous blood passes from the right atrium through a mitral valve to the left ventricle and then to the right-sided posteriorly located pulmonary artery. Pulmonary venous blood passes from the left atrium through a tricuspid valve to the right ventricle and then to an anterior, left-sided aorta (Fig. 44-22) (Figure Not Available) . The circulation is thus "physiologically" corrected but the morphological right ventricle supports the systemic circulation. Associated anomalies occur in up to 95 percent of patients and consist of VSD (75 percent), pulmonary or subpulmonary stenosis (75 percent), and left-sided (tricuspid and often "Ebstein-like") valve anomalies (>75 percent).[140] Because of the inherently abnormal conduction system (anterior origin of the AV node and anterior course of the His bundle [anterior to the pulmonary artery and down the morphological left ventricular side of the septum]), 5 percent of patients with congenitally corrected TGA are born with congenital complete heart block. Congenitally corrected transposition may exist in the setting of univentricular heart. NATURAL HISTORY OF THE UNOPERATED PATIENT.

Patients with no associated abnormalities ("isolated" congenitally corrected TGA) can survive until the seventh or eighth Figure 44-22 (Figure Not Available) Diagrammatic representation of congenitally corrected transposition of the great arteries. AV and VA discordance (1). Note intact ventricular septum (2). RA=right atrium; RV=right ventricle; LA=left atrium; LV=left ventricle; Ao=aorta; PA=pulmonary artery. (From Mullins CE, Mayer DC: Congenital Heart Disease: A Diagrammatic Atlas. New York, Wiley-Liss, 1988.)

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decade and can go unrecognized until cardiac problems arise.[141] Progressive systemic (tricuspid) AV valve regurgitation and systemic (right) ventricular dysfunction tend to occur from the fourth decade onward, whereas atrial tachyarrhythmias are more

common from the fifth decade onward.[142] In addition to those born with congenital complete heart block, acquired complete AV block continues to develop at a rate of 2 percent per year. Patients with associated anomalies (VSD, pulmonary stenosis, left-sided [tricuspid] valve anomaly) often have undergone surgical palliation (systemic-to-pulmonary artery shunt for cyanosis) or repair of the associated anomalies (see surgical procedures). SURGICAL PROCEDURES

"Classic" Repair.

VSD patch closure for hemodynamically significant VSD, left ventricular to pulmonary artery valved conduit insertion for significant pulmonary valvar or subvalvar stenosis, and systemic tricuspid valve replacement for significant regurgitation may have been performed. VSD patch closure is carried out with a particular attention to avoid the anterior conduction system (coursing anterior to the VSD). In isolated pulmonary/subpulmonary stenosis, direct enlargement of the outflow tract and valve is seldom possible and a pulmonary (morphological left) ventricle to pulmonary artery conduit is required. Patients who have undergone this "classic" repair continue to have a morphological right ventricle supporting the systemic circulation. CLINICAL MANIFESTATIONS

Unoperated.

Patients with no associated defects (1 percent of all such patients) can be asymptomatic until late adulthood. Dyspnea, exercise intolerance from developing congestive heart failure, and palpitations from supraventricular arrhythmias may arise in the fifth or sixth decade. Patients with well-balanced VSD/pulmonary stenosis can present with paradoxical emboli or cyanosis, especially if pulmonary stenosis is severe. Physical examination of a patient whose condition is otherwise uncomplicated reveals a somewhat more medial apex due to the side-by-side orientation of the two ventricles. The A2 is often palpable in the second left intercostal space due to the anterior and leftward location of the aorta. A single S2 (A2 ) is heard, with P2 being silent due to its posterior location. The murmur of an associated VSD or of left AV valve regurgitation may be heard. The murmur of pulmonary stenosis will radiate upward and to the right given the rightward direction of the main pulmonary artery. If there is complete heart block, cannon a waves with an S1 of variable intensity are present. "Classic" Repair.

The majority of patients are in functional Class I at 5 to 10 years after surgery [143] [144] despite the common development of tricuspid regurgitation and systemic right ventricular dysfunction after surgical repair (>30 percent of patients at 3 years after surgery).[143] [145] [146] Dyspnea, exercise intolerance, and palpitations from supraventricular arrhythmia can occur in the fourth decade. [147] Complete heart block may complicate surgery in an additional 25 percent.[6] [7] [8] [144] [145] [146] Physical

examination reflects the basic cardiac malformation with or without residual coexisting anomalies. DIAGNOSTIC TESTING

Electrocardiogram.

Complete AV block can be present in up to 40 percent of adults. A delta wave from a left-sided accessory bypass tract (associated with "Ebstein-like" anomaly of the left-sided AV valve) can be seen. The presence of Q wave in leads V1 and V2 combined with an absent Q wave in leads V5 and V6 is typical and reflects the initial right-to-left septal depolarization occurring in the setting of "ventricular inversion" (Fig. 44-23) . This should not be mistaken for evidence of previous anterior myocardial infarction. Chest Radiography.

Because of the unusual position of the great vessels (pulmonary artery to the right and aorta to the left), the pulmonary trunk is inconspicuous and an abnormal

Figure 44-23 Electrocardiogram of a patient with congenitally corrected transposition of the great arteries. Note the presence of Q wave in V 1 and the absence of Q wave in V 5-6 . Low atrial rhythm and left-axis deviation are also present.

bulge along the left side of the cardiac contour reflects the left-sided ascending aorta rising to the aortic knuckle. A shallow indentation or "septal notch" can be seen above the left hemidiaphragm reflecting the apical portion of the interventricular groove (Fig. 44-24) . Echocardiography.

Echocardiography permits the identification of the basic malformation as well as any associated anomalies. The morphological pulmonary left ventricle is characterized by its smooth endocardial surface and is guarded by a bileaflet AV (mitral) valve with no direct septal attachment. The morphological systemic right ventricle is recognized by its apical trabeculation and moderator band and is guarded by a trileaflet apically displaced AV valve (tricuspid valve) with direct attachment to the septum (Fig. 44-25) . "Ebstein-like" malformation of the left (tricuspid) AV valve is defined by excessive (>8 mm/m2 ) apical displacement of the left (tricuspid) AV valve, with or without dysplastic features. Diagnostic Cardiac Catheterization.

This may be required to assess the hemodynamic significance or consequences of associated anomalies.

INDICATION FOR INTERVENTION OR RE-INTERVENTION.

If moderate or severe systemic (tricuspid) AV valve regurgitation develops, valve replacement is usually required. Left AV valve replacement should be performed before systemic right ventricular function deteriorates, namely at an ejection fraction of 45 percent or more.[148] When tricuspid regurgitation is associated with poor systemic (right) ventricular function, the "double switch" procedure (see Double Switch Procedure) should perhaps be considered.[131] [149] [150] [151] [152]

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Patients with end-stage symptomatic heart failure should be referred for cardiac transplantation. The presence of a hemodynamically significant VSD (Qp/Qs > 1.5:1.0) or residual VSD with significant native or postsurgical (conduit) pulmonary outflow tract stenosis (peak gradient >50 mm Hg) may require surgical correction. Left AV valve replacement at the time of VSD and pulmonary stenosis surgery should be considered if concomitant left AV valve regurgitation is present.[153] Complete AV block may require pacemaker implantation for symptoms, progressive or profound bradycardia, poor exercise heart rate response, or cardiac enlargement. The optimal pacing modality is DDD. Active fixation electrodes are required, owing to the lack of apical trabeculation in the morphological pulmonary left ventricle. Transvenous pacing should be avoided if there are intracardiac shunts because paradoxical emboli may occur. Epicardial leads are preferred under these circumstances. [154] INTERVENTIONAL OPTIONS

Medical Therapy.

ACE inhibitor therapy for patients with systemic ventricular dysfunction is recommended. The role of afterload reduction with an ACE inhibitor to preserve systemic right ventricular function is as yet unknown. The results of clinical trials are awaited. Classic Repair.

Tricuspid valve replacement for significant regurgitation is preferable to tricuspid valve repair. Valve repair is usually unsuccessful because of the abnormal, often "Ebstein-like" anatomy of the valve. Double Switch Procedure.

This procedure has been successfully performed in children. It should be considered for patients with severe tricuspid regurgitation and systemic ventricular dysfunction. Its purpose is to relocate the left ventricle into the systemic circulation and the right

ventricle into the pulmonary circulation, achieving "anatomical" correction. An atrial switch procedure (Mustard or Senning) together with either an arterial switch procedure (when pulmonary stenosis is not present, see Chap. 43 ) or a Rastelli-type repair, the so-called Ilbawi procedure (left ventricle tunneled to aorta and right ventricular to pulmonary artery valved conduit when VSD and pulmonary stenosis are present), can be performed after adequate left ventricular

Figure 44-24 Chest radiograph of a patient with congenitally corrected transposition of the great arteries. Note the left-sided ascending aorta (AO), transvenous pacemaker and mechanical left-sided (tricuspid) atrioventricular valve, and enlarged right atrium.

Figure 44-25 Transthoracic echocardiographic picture of a patient with congenitally corrected transposition of the great arteries. A, Single arrow points to the normally apically displaced left-sided tricuspid valve. Double arrows point to the left-sided right ventricular trabeculations. RA=right atrium; MV=mitral valve; LV=right-sided morphologic left ventricle; LA=left atrium; TV=tricuspid valve; TR=tricuspid regurgitation; RV=left-sided morphologic right ventricle.

retraining, leaving the regurgitant tricuspid valve and failing right ventricle on the pulmonary side. Cardiac Transplantation.

Patients with deteriorating systemic (right) ventricular function should be treated aggressively with medical therapy but may need to be considered for transplantation. INTERVENTIONAL OUTCOMES

"Classic" Repair.

After "classic" surgical repair, median survival of patients reaching adulthood is 40 years.[143] [144] [145] [147] [155] Usual causes of death are sudden (presumed arrhythmic) or, more commonly, progressive systemic right ventricular dysfunction with systemic (tricuspid) AV valve regurgitation. The major predictor of poor outcome is the presence of left AV (tricuspid) valve regurgitation.[155] Reoperation is common (15-25 percent), with left AV valve replacement usually being the primary reason.[143] [144] [146] [147] Double Switch Procedure.

Data in adults using the "double switch" procedure is lacking, and this procedure should be considered experimental in this patient population. FOLLOW-UP.

All patients should have at least annual cardiology follow-up with an expert in the care of adult patients with congenital cardiac defects. Regular assessment of systemic (tricuspid) AV valve regurgitation by serial echocardiographic studies and systemic ventricular function by echocardiography, MRI, or radionuclide angiography should be done. Holter recording may be useful if paroxysmal atrial arrhythmias or transient complete AV block is suspected. Eisenmenger Syndrome (see also Chaps. 43 and 53 ) DEFINITION.

Eisenmenger syndrome, a term coined by Paul Wood, is defined as pulmonary vascular obstructive disease that develops as a consequence of a large preexisting left-to-right shunt such that pulmonary artery pressures

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approach systemic levels and the direction of the flow becomes bidirectional or right to left. Congenital heart defects that can result in Eisenmenger syndrome include "simple" defects such as ASD, VSD, and PDA as well as more "complex" defects such as AVSD, truncus arteriosus, aortopulmonary window, and univentricular heart. The high pulmonary vascular resistance is usually established in infancy (by age 2 years, except in ASD) and sometimes is present from birth. NATURAL HISTORY OF THE UNOPERATED PATIENT.

Patients with defects that allow free communication between the pulmonary and systemic circuits at the aortic or ventricular levels usually have a fairly healthy childhood and gradually become progressively cyanotic during their second or third decade. Exercise intolerance (dyspnea and fatigue) is proportional to the degree of hypoxemia or cyanosis. In the absence of complications, these patients generally have an excellent to good functional capacity up to their third decade[156] [157] and thereafter usually experience a slowly progressive decline in their physical abilities. Most patients survive to adulthood,[157] [158] with a reported 77 percent and 42 percent survival rate at 15 and 25 years of age.[157] Complications from Eisenmenger syndrome tend to occur from the third decade onward. Congestive heart failure, the most serious complication, usually occurs after age 40.[156] The most common modes of death are sudden death (30 percent), congestive heart failure (25 percent), and hemoptysis (15 percent). Pregnancy, perioperative mortality after noncardiac surgery, and infectious causes (brain abscesses and endocarditis) account for most of the remainder.[156] [157]

CLINICAL MANIFESTATIONS.

Patients can present with the following complications: those related to their cyanotic state (see p. 1617 ); palpitations in nearly half the patients (atrial fibrillation/flutter--35 percent, ventricular tachycardia--10 percent); hemoptysis in about 20 percent; pulmonary thromboembolism, angina, syncope, and endocarditis in about 10 percent; and congestive heart failure.[156] Hemoptysis is usually due to bleeding bronchial vessels or pulmonary infarction. Physical examination reveals central cyanosis and clubbing of the nail beds. Patients with Eisenmenger PDA can have pink nail beds on the right (± left) hand and cyanosis and clubbing of both feet (± the left hand), so-called "differential cyanosis." This occurs because venous blood shunts through the ductus and enters the aorta distal to the right subclavian artery. The jugular venous pressure in Eisenmenger syndrome patients can be normal or elevated--especially with prominent v waves when tricuspid regurgitation is present. Signs of pulmonary hypertension--a right ventricular heave, palpable and loud P2 , and a right-sided S4 --are typically present. In many patients, a pulmonary ejection click and a soft and scratchy systolic ejection murmur, attributable to dilation of the pulmonary trunk, and a high-pitched decrescendo diastolic murmur of pulmonary regurgitation (Graham Steelle) are audible. Peripheral edema is absent until right-sided heart failure ensues. DIAGNOSTIC TESTING

Electrocardiogram.

Peaked P waves consistent with right atrial overload and evidence of right ventricular hypertrophy with right axis deviation are the rule. Atrial arrhythmias can be present (Fig. 44-26) . Chest Radiography.

Dilated central pulmonary arteries with "pruning" of the peripheral pulmonary vasculature are the radiographic hallmarks of Eisenmenger syndrome (Fig. 44-27) . Pulmonary artery calcification may be seen and is diagnostic of long-standing pulmonary hypertension. Eisenmenger syndrome due to VSD or PDA usually has a normal or slightly increased cardiothoracic ratio. Eisenmenger syndrome due to an ASD typically has a large cardiothoracic ratio due to right atrial and ventricular dilation, along with

Figure 44-26 ECG of a patient with Eisenmenger syndrome due to a VSD. Note the peaked P wave in lead II, right ventricular hypertrophy, and right-axis deviation.

an inconspicuous aorta. Calcification of the duct may be seen in Eisenmenger PDA.

Echocardiography.

The intracardiac defect should be seen readily along with bidirectional shunting. Evidence of pulmonary hypertension will be found. Assessment of pulmonary right ventricular function adds prognostic value. Catheterization.

Cardiac catheterization not only provides direct measurement of the pulmonary artery pressure, documenting the existence of severe pulmonary hypertension, but also may allow assessment of reactivity of the pulmonary vasculature. Administration of pulmonary arterial vasodilators (O2 , nitric oxide, prostaglandin I2 ) can discriminate between patients in whom surgical repair is contraindicated and those with reversible pulmonary hypertension who may benefit from surgical repair. Radiographic contrast material may cause hypotension and worsening cyanosis and should be used cautiously. Open-Lung Biopsy.

Open-lung biopsy should only be considered when the reversibility of the pulmonary hypertension is uncertain from the hemodynamic data. An expert opinion will determine the severity of the changes, usually using the Heath-Edwards classification. INDICATIONS FOR INTERVENTION.

The underlying principle of clinical management in patients with Eisenmenger syndrome is to avoid any factors that may destabilize the delicately balanced physiology. In general, an approach of nonintervention is recommended. The main interventions, therefore, are directed toward preventing complications (e.g., flu shots to reduce the morbidity of respiratory infections) or to restore the physiological balance (e.g., iron replacement for iron deficiency; antiarrhythmic management of atrial arrhythmias; digoxin and diuretics for right-sided

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Figure 44-27 Typical chest radiograph of a patient with Eisenmenger syndrome due to a ventricular septal defect. Note the enlarged central pulmonary arteries and the peripheral pruning of the pulmonary vasculature. A, Posteroanterior view. LPA=left pulmonary artery; RPA=right pulmonary artery.

heart failure). As a general rule, the first episode of hemoptysis should be considered an indication for hospital admission and investigation. Bed rest should be implemented; and, although usually self-limiting, each such episode should be regarded as potentially

life threatening, and a treatable cause sought. When patients are severely incapacitated from severe hypoxemia or congestive heart failure, the main intervention available is lung (plus repair of the cardiac defect) or heart-lung transplantation. This is generally reserved for individuals without contraindications who are thought to have a 1-year survival of less than 50 percent. Such assessment is fraught with difficulty because of the unpredictability of the time course of the disease and the risk of sudden death. Noncardiac surgery should be performed only when absolutely necessary because of its high associated mortality.[156] [159] Eisenmenger syndrome patients are particularly vulnerable to alterations in hemodynamics induced by anesthesia or surgery, such as minor decrease in systemic vascular resistance that can increase right-to-left shunting and possibly potentiate cardiovascular collapse. Local anesthesia should be used whenever possible. Avoidance of prolonged fasting and especially dehydration, the use of antibiotic prophylaxis when appropriate,[160] and careful intraoperative monitoring (sometimes with an arterial line ± a central venous line to allow early detection of sudden pressure and volume changes during surgery) are recommended. [159] [161] The choice of general versus epidural-spinal anesthesia is controversial. An experienced cardiac anesthetist with an understanding of Eisenmenger syndrome physiology should administer anesthesia. Additional risks of surgery include excessive bleeding, postoperative arrhythmias, and deep venous thrombosis with paradoxic emboli. An "air filter" or "bubble trap" should be used for any intravenous lines. Early ambulation is recommended.[159] [161] Postoperative care in an intensive care unit setting is optimal. INTERVENTIONAL OPTIONS AND OUTCOMES

Oxygen.

In a small prospective nonrandomized study of 15 children with pulmonary vascular disease, chronic administration of oxygen (12 hours a day for up to 5 years) resulted in an increased survival in the treatment group (n=9). [162] The impact of supplemental oxygen on survival in adult patients with Eisenmenger syndrome has never been studied, and its role is unclear. Chronic oxygen therapy can perhaps help raise oxygen saturation and reduce symptoms, but this should be counterbalanced with the potential effect of mucosal dehydration and increased incidence of epistaxis. Supplemental oxygen during commercial air travel is often recommended, but the scientific basis for this recommendation is lacking.[163] Transplantation.

Lung transplant may be undertaken in association with repair of existing cardiovascular defect(s). Alternatively, heart-lung transplantation may be required if the intracardiac anatomy is not correctable. The outcome of transplantation in these patients is generally less satisfactory than for transplant recipients without Eisenmenger syndrome. The 1-year survival rate for adults undergoing lung transplantation with primary intracardiac repair is 70 to 80 percent, and less than 50 percent of patients are alive 4 years after transplantation.[164] [165] The outcome after heart-lung transplantation is not better, with a 1-year survival rate of 60 to 80 percent and a 10-year survival rate of less than 30 percent.[164] These options, however sobering, may be relatively attractive to individuals

who are confronting death and have an intolerable quality of life. INVESTIGATIONAL THERAPY

Calcium Channel Blockers.

The chronic use of nifedipine in a small group of patients with Eisenmenger syndrome demonstrated a small but significant increase in exercise tolerance[166] and a decrease in pulmonary vascular resistance, especially in children.[167] This therapy is still considered investigational and should only be prescribed in a clinical research setting. ACE Inhibitors.

Data available on a highly selected group of 10 patients with cyanotic congenital heart disease showed no change in oxygen saturation despite a subjective improvement in functional capacity.[168] Proponents of the use of ACE inhibitors in these patients argue that, by decreasing systemic vascular resistance, one improves the cardiac output and thus oxygen delivery. The counter argument is that these agents are potentially dangerous because they lower systemic vascular resistance without changing pulmonary vascular resistance and lead to an increase in right-to-left shunting. The use of this medication remains highly experimental and again should only be administered within the boundaries of a study trial guided by rigorous monitoring. Prostacyclin.

A recent study of chronic prostacyclin administration in such patients showed improvement in hemodynamics (lower pulmonary vascular resistance and increased cardiac output) and a somewhat increased exercise capacity.[169] Further research in this field is needed before recommendations on the use of prostaglandins in these patients can be made. Pulmonary Artery Banding.

Pulmonary artery banding in one patient with biopsy-proven irreversible pulmonary vascular changes led to regression of pulmonary vascular changes, which made surgical closure of the defects possible.[170] Further data regarding this revolutionary practice are awaited. FOLLOW-UP.

Patient education is critical. Avoidance of over-the-counter medications, dehydration, smoking, high-altitude exposure, and excessive physical activity should be stressed. Avoidance of pregnancy is of paramount importance (see Chap. 65 ). Annual flu shots and use of endocarditis prophylaxis together with proper skin hygiene (avoidance of nail biting) are recommended. A yearly assessment of complete blood cell count and uric acid, creatinine, and ferritin levels should be done to monitor treatable causes of

deterioration.

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Medical Management of Cyanotic Congenital Heart Disease PATHOPHYSIOLOGY OF CYANOSIS.

Patients with cyanotic congenital heart lesions, either unoperated or palliated, have chronic hypoxemia as a result of persistent systemic venous to arterial shunting. Ensuing physiological adaptive mechanisms to enhance oxygen delivery include, among others, an increase in red blood cell mass to improve systemic oxygen transport. Erythropoietin production is stimulated as a result of exposure of renal oxygen sensors to hypoxemia. Red blood cell production is enhanced, oxygen content (hemoglobin×O2 saturation) increases, and oxygen delivery (cardiac output×O2 saturation) is reestablished, albeit at the cost of a higher hematocrit. Erythrocytosis, in the setting of chronic cyanotic congenital heart disease, is thus an adaptive physiological mechanism.[171] HYPERVISCOSITY SYNDROME.

Symptoms of hyperviscosity include headaches, altered mentation, visual disturbances, tinnitus, paresthesias, fatigue, dizziness, and myalgias.[171] These symptoms can be mild, moderate, or severe. They usually present in patients with an elevated hematocrit (>65 percent) or can present at a hematocrit less than 65 percent if the patient is iron deficient. The patient usually experiences the same hyperviscosity symptoms each time (e.g., headache, visual disturbances, fatigue), and they must be relieved by phlebotomy to qualify as hyperviscosity symptoms. An increased hematocrit level, in the absence of symptoms, does not constitute an indication for phlebotomy. Repeated phlebotomy under these circumstances will lead to iron deficiency, and perhaps cerebral arterial events. Dehydration secondary to excessive heat, illness, fever, diarrhea, or vomiting can be the cause of hyperviscosity symptoms and should be managed appropriately with volume replacement. If dehydration or iron deficiency is not the cause of hyperviscosity symptoms, phlebotomy becomes the treatment of choice. Removal of 500 ml of blood over 30 to 45 minutes preceded by or simultaneous with a 500- to 1000-ml volume replacement with normal saline (or dextran for patients with congestive heart failure) can usually be performed in an outpatient setting. The goal of phlebotomy is symptom control. The patient having phlebotomy is at risk of iron deficiency. As a rule, iron supplementation should be prescribed. IRON DEFICIENCY AND REPLACEMENT.

Iron deficiency is an important and common finding in cyanotic adults. The etiology can be multifactorial and includes excessive bleeding from hemoptysis, epistaxis, or excessive menses, but by far the most distressing cause is inappropriate phlebotomy. Microcytosis from iron deficiency results in an increase in whole blood viscosity because microspheres are much less deformable than the normal biconcave disc-shaped iron-replete red blood cell. In contrast to normocytic erythrocytosis, which seldom causes symptoms at hematocrit levels less than 65 percent, iron deficiency can present as hyperviscosity symptoms at hematocrit levels well below 65 percent. The treatment of choice in this case is iron repletion and not phlebotomy. If iron deficiency is confirmed, supplemental iron should be administered until a rise in hematocrit is registered, or until the iron-replete state has been achieved. Intravenous iron preparations are an alternative for patients intolerant of oral iron supplementation.[171] HEMOSTATIC ABNORMALITIES.

Hemostatic abnormalities have been documented in cyanotic patients with erythrocytosis.[171] Any bleeding tendency is usually mild and superficial, leading to easy bruising, petechiae, or mucosal bleeding. However, at times, bleeding can be moderate, with epistaxis or hemoptysis, or can even be life threatening, particularly in the postoperative setting. An increase in prothrombin time (PT) and partial thromboplastin time (PTT) from decreased levels of factors V, VII, VIII, and X, from quantitative and qualitative platelet disorders, and from increased fibrinolytic activity have all been described. The management of a bleeding diathesis can be subdivided into two clinical categories: spontaneous bleeding and perioperative prevention. Spontaneous, superficial bleeding usually is self-limited. Avoidance of aspirin, nonsteroidal antiinflammatory drugs, and heparin is an important prophylactic measure. The treatment of severe spontaneous bleeding is dictated by the specific hemostatic disturbances. Platelet transfusions, fresh-frozen plasma, vitamin K, and cryoprecipitate have all been used. It is recommended that cyanotic patients facing major surgery undergo prophylactic phlebotomy if the hematocrit level is greater than 65 percent to minimize hemostatic abnormalities intraoperatively and postoperatively. Isovolumetric phlebotomy of 500 ml can be performed every 24 hours until the hematocrit levels decrease below 65 percent. Blood that has been withdrawn should be kept for autologous transfusion if needed. CEREBROVASCULAR EVENTS.

Cerebrovascular events including stroke secondary to thrombosis or embolus have been recognized as a complication of cyanosis in adults with congenital heart disease. The risk of stroke caused by cerebral arterial thrombosis has usually been seen in patients with iron deficiency and not iron-replete erythrocytosis.[172] [173] Cerebral hemorrhage can occur due to hemostatic defects and is most often observed after the

use of often dangerous anticoagulant therapy. Patients with right-to-left shunts can also be at risk for paradoxical emboli. Focal brain injury can provide a nidus for brain abscess if bacteremia supervenes. Brain abscess patients can present with headaches with fever and focal neurological findings or seizures.[174] It follows from the previous discussion that prophylactic phlebotomy has no place in the prevention of cerebral arterial thrombosis. Avoidance of microcytosis is of paramount importance.[172] [173] Meticulous attention should be paid to the use of air filters in peripheral intravenous lines to avoid paradoxical emboli through a right-to-left shunt.[174] Anticoagulants should usually be avoided in chronically cyanotic cardiac patients. In the uncommon patient with atrial fibrillation or a mechanical prosthesis, a risk-benefit dilemma must be addressed. RENAL DYSFUNCTION.

Renal dysfunction can present as proteinuria, hyperuricemia, and, rarely, overt renal failure.[175] Hyperuricemia, commonly observed in patients with cyanotic congenital heart disease, is caused mainly by increased reabsorption of uric acid rather than by overproduction from erythrocytosis. Fortunately, urate nephropathy, uric acid nephrolithiasis, and gouty arthritis are rare. Asymptomatic hyperuricemia need not be treated. Acute gouty arthritis responds to intravenous colchicine. Corticosteroid therapy is a viable alternative. Nonsteroidal antiinflammatory drugs should be avoided, given the baseline hemostatic anomalies in these patients. Symptomatic hyperuricemia and chronic gouty arthritis can be treated with probenecid or sulfinpyrazone, which are uricosuric agents, or with allopurinol, which decreases uric acid production. Most diuretics are relatively contraindicated because they reduce renal tubular secretion of uric acid and may aggravate existing hyperuricemia. ARTHRALGIA.

Hypertrophic osteoarthropathy is thought to be the mechanism responsible for the arthralgias affecting up to one third of patients with cyanotic congenital heart disease. In patients with right-to-left shunting, megakaryocytes released from the bone marrow can bypass the lung. The entrapment of megakaryocytes in the systemic arterioles and capillaries induces the release of platelet-derived growth factor, promoting local cell proliferation.

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New osseous formation with periostitis ensues and gives rise to arthralgia and bony pain.[175] Arthralgias can be managed with salsalate, a nonacetylated analog of aspirin. This medication does not appear to interfere with platelet function and, therefore, is an ideal antiinflammatory medication for patients with bleeding tendencies. FOLLOW-UP.

Patients with cyanotic congenital heart disease should be followed regularly by experts.

Hemoglobin levels, mean corpuscular volume, ferritin, renal function, and uric acid should be checked at least annually to avoid treatable causes of deterioration. Annual flu shots are recommended. Avoidance of unnecessary phlebotomies and anticoagulant therapy is key. Smoking is to be strongly discouraged because it impairs oxygen-carrying capacity and worsens oxygen delivery.

REFERENCES Perloff JK: Congenital heart disease in adults: A new cardiovascular subspecialty. Circulation 84:1881-1890, 1991. 1.

Brickner ME, Hillis LD, Lange RA: Congenital heart disease in adults [first of two parts]. N Engl J Med 342:256-263, 2000. 1A.

Brickner ME, Hillis LD, Lange RA: Congenital heart disease in adults [second of two parts]. N Engl J Med 342:334-342, 2000. 1B.

Connelly MS, Webb GD, Somerville J, et al: Canadian Consensus Conference on Adult Congenital Heart Disease 1996. Can J Cardiol 14:395-452, 1998. 2.

Taylor AM, Thorne SA, Rubens MB, et al: Coronary artery imaging in grown up congenital heart disease: Complementary role of magnetic resonance and x-ray coronary angiography. Circulation 101:1670-1678, 2000. 2A.

Weiss BM, Zemp L, Seifert B, Hess OM: Outcome of pulmonary vascular disease in pregnancy: A systematic overview from 1978 through 1996. J Am Coll Cardiol 31:1650-1657, 1998. 3.

Chung T: Assessment of cardiovascular anatomy in patients with congenital heart disease by magnetic resonance imaging. Pediatr Cardiol 21:18-26, 2000. 3A.

Horner T, Liberthson R, Jellinek MS: Psychosocial profile of adults with complex congenital heart disease. Mayo Clin Proc 75:31-36, 2000. 3B.

MEDICAL MANAGEMENT OF CYANOTIC CONGENITAL HEART DISEASE Siu SC, Sermer M, Harrison DA, et al: Risk and predictors for pregnancy-related complications in women with heart disease. Circulation 96:2789-2794, 1997. 4.

Siu S, Chitayat D, Webb G: Pregnancy in women with congenital heart defects: What are the risks? Heart 81:225-226, 1999. 5.

Burn J, Brennan P, Little J, et al: Recurrence risks in offspring of adults with major heart defects: Results from first cohort of British collaborative study. Lancet 351:311-316, 1998. 6.

Lamour JM, Addonizio LJ Mancini DM, et al: Outcome after orthotopic heart transplantation in adults with congenital heart disease. Circulation 100[suppl I]:I-97, 1999. 7.

Gewillig M, Cullen S, Mertens B, et al: Risk factors for arrhythmia and death after Mustard operation for simple transposition of the great arteries. Circulation 84:187-192, 1991. 8.

Gelatt M, Hamilton RM, McCrindle BW, et al: Arrhythmia and mortality after the Mustard procedure: A 30-year single-center experience. J Am Coll Cardiol 29:194-201, 1997. 9.

ATRIAL SEPTAL DEFECT Ward C: Secundum atrial septal defect: Routine surgical treatment is not of proven benefit. Br Heart J 71:219-223, 1994. 10.

Di Tullio M, Sacco RL, Gopal A, et al: Patent foramen ovale as a risk factor for cryptogenic stroke. Ann Intern Med 117:461-465, 1992. 11.

Gatzoulis MA, Freeman MA, Siu SC, et al: Atrial arrhythmia after surgical closure of atrial septal defects in adults. N Engl J Med 340:839-846, 1999. 12.

Konstantinides S, Geibel A, Olschewski M, et al: A comparison of surgical and medical therapy for atrial septal defect in adults. N Engl J Med 333:469-473, 1995. 13.

Helber U, Baumann R, Seboldt H, et al: Atrial septal defect in adults: Cardiopulmonary exercise capacity before and 4 months and 10 years after defect closure. J Am Coll Cardiol 29:1345-1350, 1997. 14.

Shah D, Azhar M, Oakley CM, et al: Natural history of secundum atrial septal defect in adults after medical or surgical treatment: A historical prospective study. Br Heart J 71:224-228, 1994. 15.

Rao PS, Sideris EB, Hausdorf G, et al: International experience with secundum atrial septal defect occlusion by the buttoned device. Am Heart J 128:1022-1035, 1994. 16.

Boutin C, Musewe NN, Smallhorn JF, et al: Echocardiographic follow-up of atrial septal defect after catheter closure by double-umbrella device. Circulation 88:621-627, 1993. 17.

Horvath KA, Burke RP, Collins JJ Jr, Cohn LH: Surgical treatment of adult atrial septal defect: Early and long-term results. J Am Coll Cardiol 20:1156-1159, 1992. 18.

Sandoval N, Velasco VM, Orjuela H, et al: Concomitant mitral valve or atrial septal defect surgery and the modified Cox-maze procedure. Am J Cardiol 77:591-596, 1996. 19.

ISOLATED VENTRICULAR SEPTAL DEFECT Freed MD: Infective endocarditis in the adult with congenital heart disease. Cardiol Clin 11:589-602, 1993. 20.

Neumayer U, Stone S, Somerville J: Small ventricular septal defects in adults. Eur Heart J 19:1573-1582, 1998. 21.

Trusler GA, Williams WG, Smallhorn JF, Freedom RM: Late results after repair of aortic insufficiency associated with ventricular septal defect. J Thorac Cardiovasc Surg 103:276-281, 1992. 22.

Sideris EB, Walsh KP, Haddad JL, et al: Occlusion of congenital ventricular septal defects by the buttoned device. "Buttoned device" Clinical Trials International Register. Heart 77:276-279, 1997. 23.

Kidd L, Driscoll DJ, Gersony WM, et al: Second natural history study of congenital heart defects: Results of treatment of patients with ventricular septal defects. Circulation 87:38-51, 1993. 24.

ATRIOVENTRICULAR SEPTAL DEFECT Mavroudis C, Backer CL: The two-patch technique for complete atrioventricular canal. Semin Thorac Cardiovasc Surg 9:35-43, 1997. 25.

Ashraf MH, Amin Z, Sharma R, Subramanian S: Atrioventricular canal defect: Two-patch repair and tricuspidization of the mitral valve. Ann Thorac Surg 55:347-350; discussion 350-351, 1993. 26.

Carpentier A: Surgical anatomy and management of mitral component of atrioventricular canal defects. In Paediatric Cardiology. Edinburgh, Churchill Livingstone, 1978, pp 477-490. 27.

Pearl JM, Laks H: Intermediate and complete forms of atrioventricular canal. Semin Thorac Cardiovasc Surg 9:8-20, 1997. 28.

Michielon G, Stellin G, Rizzoli G, et al: Left atrioventricular valve incompetence after repair of common atrioventricular canal defects. Ann Thorac Surg 60:s604-s609, 1995. 29.

van Son JA, Van Praagh R, Falk V, Mohr FW: Pericardial patch augmentation of the tissue-deficient mitral valve in common atrioventricular canal. J Thorac Cardiovasc Surg 112:1117-1119, 1996. 30.

Burke RP, Horvath K, Landzberg M, et al: Long-term follow-up after surgical repair of ostium primum atrial septal defects in adults. J Am Coll Cardiol 27:696-699, 1996. 31.

Bergin ML, Warnes CA, Tajik AJ, Danielson GK: Partial atrioventricular canal defect: Long-term follow-up after initial repair in patients > or=40 years old. J Am Coll Cardiol 25:1189-1194, 1995. 32.

32A. Gatzoulis

MA, Hechter S, Webb GD, Williams WG: Surgery for partial atrioventricular septal defect in the adult. Ann Thorac Surg 67:504-510, 1999. 32B. Kameyama

T, Ando F, Okamoto F, et al: Long term follow up of atrioventricular valve function after repair of atrioventricular septal defect. Ann Thorac Cardiovasc Surg. 5:101-106, 1999. Bando K, Turrentine MW, Sun K, et al: Surgical management of complete atrioventricular septal defects: A twenty-year experience. J Thorac Cardiovasc Surg 110:1543-1552, 1995. 33.

Van Arsdell GS, Williams WG, Boutin C, et al: Subaortic stenosis in the spectrum of atrioventricular septal defects: Solutions may be complex and palliative. J Thorac Cardiovasc Surg 110:1534-1541, 1995. 34.

PATENT DUCTUS ARTERIOSUS Perloff JK: Patent ductus arteriosus. In The Clinical Recognition of Congenital Heart Disease. Philadelphia, WB Saunders, 1999, pp 467-489. 35.

Harrison DA, Benson LN, Lazzam C, et al: Percutaneous catheter closure of the persistently patent ductus arteriosus in the adult. Am J Cardiol 77:1094-1097, 1996. 36.

Landzberg MJ, Bridges ND, Perry SB, et al: Transcatheter occlusion: The treatment of choice for the adult with a patent ductus arteriosus. Circulation 84(Suppl II):67. 1999. 37.

38.

Sievert H, Ensslen R, Fach A, et al: Transcatheter closure of patent ductus arteriosus with the

Rashkind occluder: Acute results and angiographic follow-up in adults. Eur Heart J 18:1014-1018, 1997. Sorensen KE, Kristensen B, Hansen OK: Frequency of occurrence of residual ductal flow after surgical ligation by color-flow mapping. Am J Cardiol 67:653-654, 1991. 39.

Houston AB, Gnanapragasam JP, Lim MK, et al: Doppler ultrasound and the silent ductus arteriosus. Br Heart J 65:97-99, 1991. 40.

Hosking MC, Benson LN, Musewe N, et al: Transcatheter occlusion of the persistently patent ductus arteriosus: Forty-month follow-up and prevalence of residual shunting. Circulation 84:2313-2317, 1991. 41.

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BICUSPID AORTIC VALVE Hahn RT, Roman MJ, Mogtader AH, Devereux RB: Association of aortic dilation with regurgitant, stenotic and functionally normal bicuspid aortic valves. J Am Coll Cardiol 19:283-288, 1992. 42.

42A. De

Sa M, Moshkovitz Y, Butany J, David TE: Histologic abnormalities of the ascending aorta and pulmonary trunk in patients with bicuspid aortic valve disease: Clinical relevance to the Ross procedure. J Thorac Cardiovasc Surg 118:588-594, 1999. 42B. Nistri

S, Sorbo MD, Marin M, et al: Aortic root dilatation in young men with normally functioning bicuspid aortic valves. Heart 82:19-22, 1999. Kitchiner D, Jackson M, Walsh K, et al: The progression of mild congenital aortic valve stenosis from childhood into adult life. Int J Cardiol 42:217-223, 1993. 43.

Burks JM, Illes RW, Keating EC, Lubbe WJ: Ascending aortic aneurysm and dissection in young adults with bicuspid aortic valve: Implications for echocardiographic surveillance. Clin Cardiol 21:439-443, 1998. 44.

Bahl VK, Chandra S, Goswami KC, Manchanda SC: Balloon aortic valvuloplasty in young adults by antegrade, transseptal approach using Inoue balloon. Cathet Cardiovasc Diagn 44:297-301, 1998. 45.

Elkins RC, Lane MM, McCue C: Pulmonary autograft reoperation: Incidence and management. Ann Thorac Surg 62:450-455, 1996. 46.

Niwaya K, Knott-Craig CJ, Lane MM, et al: Cryopreserved homograft valves in the pulmonary position: Risk analysis for intermediate-term failure. J Thorac Cardiovasc Surg 117:141-146, 1999. 47.

Cosgrove DM, Rosenkranz ER, Hendren WG, et al: Valvuloplasty for aortic insufficiency. J Thorac Cardiovasc Surg 102:571-576, 1991. 48.

SUBAORTIC STENOSIS 49.

Somerville J: Fixed subaortic stenosis--a frequent misunderstood lesion. Int J Cardiol 8:145-148, 1999.

Choi JY, Sullivan ID: Fixed subaortic stenosis: Anatomical spectrum and nature of progression. Br Heart J 65:280-286, 1991. 50.

Perloff JK: Congenital aortic stenosis; congenital aortic regurgitation. In The Clinical Recognition of Congenital Heart Disease. Philadelphia, WB Saunders, 1999, pp 91-131. 51.

Cabrera A, Galdeano JM, Zumalde J, et al: Fixed subaortic stenosis: The value of cross-sectional echocardiography in evaluating different anatomical patterns. Int J Cardiol 24:151-157, 1989. 52.

Brauner R, Laks H, Drinkwater DCJ, et al: Benefits of early surgical repair in fixed subaortic stenosis. J Am Coll Cardiol 30:1835-1842, 1997. 53.

Vouhe PR, Ouaknine R, Poulain H, et al: Diffuse subaortic stenosis: Modified Konno procedures with aortic valve preservation. Eur J Cardiothor Surg 7:132-136, 1999. 54.

Reddy VM, Rajasinghe HA, Teitel DF, et al: Aortoventriculoplasty with the pulmonary autograft: The "Ross-Konno" procedure. J Thorac Cardiovasc Surg 111:158-165, 1996. 55.

Suarez dL, Pan M, Medina A, et al: Immediate and follow-up results of transluminal balloon dilation for discrete subaortic stenosis. J Am Coll Cardiol 18:1309-1315, 1991. 56.

Delius RE, Samyn MM, Behrendt DM: Should a bicuspid aortic valve be replaced in the presence of subvalvar or supravalvar aortic stenosis? Ann Thorac Surg 66:1337-1342, 1998. 57.

Brauner R, Laks H, Drinkwater DCJ, et al: Benefits of early surgical repair in fixed subaortic stenosis. J Am Coll Cardiol 30:1835-1842, 1997. 58.

COARCTATION OF THE AORTA 59.

Campbell M: Natural history of coarctation of the aorta. Br Heart J 32:633-640, 1970.

Perloff JK: Coarctation of the aorta. In The Clinical Recognition of Congenital Heart Disease. Philadelphia: WB Saunders, 1999, pp 132-169. 60.

Messmer BJ, Minale C, Muhler E, von Bernuth G: Surgical correction of coarctation in early infancy: Does surgical technique influence the result? Ann Thorac Surg 52:594-600, 1991. 61.

Ebeid MR, Prieto LR, Latson LA: Use of balloon-expandable stents for coarctation of the aorta: Initial results and intermediate-term follow-up. J Am Coll Cardiol 30:1847-1852, 1997. 62.

Yetman AT, Nykanen D, McCrindle BW, et al: Balloon angioplasty of recurrent coarctation: A 12-year review. J Am Coll Cardiol 30:811-816, 1997. 63.

McCrindle BW, Jones TK, Morrow WR, et al: Acute results of balloon angioplasty of native coarctation versus recurrent aortic obstruction are equivalent. Valvuloplasty and Angioplasty of Congenital Anomalies (VACA) Registry Investigators. J Am Coll Cardiol 28:1810-1817, 1996. 64.

Behl PR, Sante P, Blesovsky A: Isolated coarctation of the aorta: surgical treatment and late results: Eighteen years' experience. J Cardiovasc Surg 29:509-517, 1988. 65.

66.

Trinquet F, Vouhe PR, Vernant F, et al: Coarctation of the aorta in infants: Which operation? Ann

Thorac Surg 45:186-191, 1988. Hehrlein FW, Mulch J, Rautenburg HW, et al: Incidence and pathogenesis of late aneurysms after patch graft aortoplasty for coarctation. J Thorac Cardiovasc Surg 92:226-230, 1986. 67.

Shaddy RE, Boucek MM, Sturtevant JE, et al: Comparison of angioplasty and surgery for unoperated coarctation of the aorta. Circulation 87:793-799, 1993. 68.

68A. Therrien

J, Thorne SA, Wright A, et al: Repaired coarctation: A "cost-effective" approach to identify complications in adults. J Am Coll Cardiol 35:997-1002, 2000. Ross RD, Clapp SK, Gunther S, et al: Augmented norepinephrine and renin output in response to maximal exercise in hypertensive coarctectomy patients. Am Heart J 123:1293-1299, 1992. 69.

Guenthard J, Zumsteg U, Wyler F: Arm-leg pressure gradients on late follow-up after coarctation repair: Possible causes and implications. Eur Heart J 17:1572-1575, 1996. 70.

RIGHT VENTRICULAR OUTFLOW TRACT OBSTRUCTION Hayes CJ, Gersony WM, Driscoll DJ, et al: Second natural history study of congenital heart defects: Results of treatment of patients with pulmonary valvar stenosis. Circulation 87:28-37, 1993. 71.

Lock JE, Perry S, Beane JF: Profiles in congenital heart disease. In Cardiac Catheterisation, Angiography and Intervention. Philadelphia, Lea & Febiger, 1999, pp 654-675. 72.

Teupe CH, Burger W, Schrader R, Zeiher AM: Late (five to nine years) follow-up after balloon dilation of valvular pulmonary stenosis in adults. Am J Cardiol 80:240-242, 1997. 73.

McCrindle BW: Independent predictors of long-term results after balloon pulmonary valvuloplasty. Valvuloplasty and Angioplasty of Congenital Anomalies (VACA) Registry Investigators. Circulation 89:1751-1759, 1994. 74.

O'Connor BK, Beekman RH, Lindauer A, Rocchini A: Intermediate-term outcome after pulmonary balloon valvuloplasty: Comparison with a matched surgical control group. J Am Coll Cardiol 20:169-173, 1992. 75.

Fawzy ME, Galal O, Dunn B, et al: Regression of infundibular pulmonary stenosis after successful balloon pulmonary valvuloplasty in adults. Cathet Cardiovasc Diagn 21:77-81, 1990. 76.

EBSTEIN ANOMALY Celermajer DS, Bull C, Till JA, et al: Ebstein's anomaly: Presentation and outcome from fetus to adult. J Am Coll Cardiol 23:170-176, 1994. 77.

Gentles TL, Calder AL, Clarkson PM, Neutze JM: Predictors of long-term survival with Ebstein's anomaly of the tricuspid valve. Am J Cardiol 69:377-381, 1992. 78.

Perloff JK: Ebstein's anomaly of the tricuspid valve. In The Clinical Recognition of Congenital Heart Disease. Philadelphia, WB Saunders, 1999, pp 467-489. 79.

Ammash NM, Warnes CA, Connolly HM, et al: Mimics of Ebstein's anomaly. Am Heart J 134:508-513, 1997. 80.

Augustin N, Schmidt-Habelmann P, Wottke M, et al: Results after surgical repair of Ebstein's anomaly. Ann Thorac Surg 63:1650-1656, 1997. 81.

Hetzer R, Nagdyman N, Ewert P, et al: A modified repair technique for tricuspid incompetence in Ebstein's anomaly. J Thorac Cardiovasc Surg 115:857-868, 1998. 82.

Chauvaud S, Fuzellier JF, Berrebi A, et al: Bi-directional cavopulmonary shunt associated with ventriculo and valvuloplasty in Ebstein's anomaly: Benefits in high risk patients. Eur J Cardiothorac Surg 13:514-519, 1998. 83.

Theodoro DA, Danielson GK, Porter CJ, Warnes CA: Right-sided maze procedure for right atrial arrhythmias in congenital heart disease. Ann Thorac Surg 65:149-153, 1998. 84.

TETRALOGY OF FALLOT Perloff JK: Ventricular septal defect with pulmonary stenosis. In The Clinical Recognition of Congenital Heart Disease. Philadelphia, WB Saunders, 1999, pp 467-489. 85.

Oechslin EN, Harrison DA, Harris L, et al: Reoperation in adults with repair of Tetralogy of Fallot: Indications and outcomes. J Thorac Cardiovasc Surg 118:245-251, 1999. 86.

Gatzoulis MA, Till JA, Somerville J, Redington AN: Mechanoelectrical interaction in tetralogy of Fallot: QRS prolongation relates to right ventricular size and predicts malignant ventricular arrhythmias and sudden death. Circulation 92:231-237, 1995. 87.

Nollert G, Fischlein T, Bouterwek S, et al: Long-term results of total repair of tetralogy of Fallot in adulthood: 35 years follow-up in 104 patients corrected at the age of 18 or older. Thorac Cardiovasc Surg 45:178-181, 1997. 88.

Bonow RO, Lakatos E, Maron BJ, Epstein SE: Serial long-term assessment of the natural history of asymptomatic patients with chronic aortic regurgitation and normal left ventricular systolic function. Circulation 84:1625-1635, 1991. 89.

Downar E, Harris L, Kimber S, et al: Ventricular tachycardia after surgical repair of tetralogy of Fallot: Results of intraoperative mapping studies. J Am Coll Cardiol 20:648-655, 1992. 90.

Nollert G, Fischlein T, Bouterwek S, et al: Long-term survival in patients with repair of tetralogy of Fallot: 36-year follow-up of 490 survivors of the first year after surgical repair. J Am Coll Cardiol 30:1374-1383, 1997. 91.

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Yemets IM, Williams WG, Webb GD, et al: Pulmonary valve replacement late after repair of tetralogy of Fallot. Ann Thorac Surg 64:526-530, 1997. 92.

d'Udekem Y, Rubay J, Shango-Lody P, et al: Late homograft valve insertion after transannular patch repair of tetralogy of Fallot. J Heart Valve Dis 7:450-454, 1998. 93.

93A. Therrien

J, Sui CS, McLaughlin PR, et al: Pulmonary valve replacement in adults late after repair of tetralogy of Fallot: Are we operating too late? J Am Coll Cardiol 35(Suppl A):509A, 1999. Berul CI, Hill SL, Geggel RL, et al: Electrocardiographic markers of late sudden death risk in postoperative tetralogy of Fallot children. J Cardiovasc Electrophysiol 8:1349-1356, 1997. 94.

Murphy JG, Gersh BJ, Mair DD, et al: Long-term outcome in patients undergoing surgical repair of tetralogy of Fallot. N Engl J Med 329:593-599, 1993. 95.

Rosenthal A: Adults with tetralogy of Fallot--repaired, yes; cured, no (editorial; comment). N Engl J Med 329:655-656, 1993. 96.

Waien SA, Liu PP, Ross BL, et al: Serial follow-up of adults with repaired tetralogy of Fallot. J Am Coll Cardiol 20:295-300, 1992. 97.

POST-FONTAN PROCEDURE Choussat A, Fontan F, Besse P, et al: Selection criteria for Fontan's procedure. In Paediatric Cardiology. New York, Churchill-Livingstone, 1999, pp 559-566. 98.

Fontan F, Kirklin JW, Fernandez G, et al: Outcome after a "perfect" Fontan operation. Circulation 81:1520-1536, 1990. 99.

Gentles TL, Mayer JEJ, Gauvreau K, et al: Fontan operation in five hundred consecutive patients: Factors influencing early and late outcome. J Thorac Cardiovasc Surg 114:376-391, 1997. 100.

Gates RN, Laks H, Drinkwater DC Jr, et al: The Fontan procedure in adults. Ann Thorac Surg 63:1085-1090, 1997. 101.

Stumper O, Sutherland GR, Geuskens R, et al: Transesophageal echocardiography in evaluation and management after a Fontan procedure. J Am Coll Cardiol 17:1152-1160, 1991. 102.

Fishberger SB, Wernovsky G, Gentles TL, et al: Factors that influence the development of atrial flutter after the Fontan operation. J Thorac Cardiovasc Surg 113:80-86, 1997. 103.

Durongpisitkul K, Porter CJ, Cetta F, et al: Predictors of early- and late-onset supraventricular tachyarrhythmias after Fontan operation. Circulation 98:1099-1107, 1998. 104.

105.

Peters NS, Somerville J: Arrhythmias after the Fontan procedure. Br Heart J 68:199-204, 1992.

Amodeo A, Galletti L, Marianeschi S, et al: Extracardiac Fontan operation for complex cardiac anomalies: Seven years' experience. J Thorac Cardiovasc Surg 114:1020-1030, 1997. 106.

Shirai LK, Rosenthal DN, Reitz BA, et al: Arrhythmias and thromboembolic complications after the extracardiac Fontan operation. J Thorac Cardiovasc Surg 115:499-505, 1998. 107.

Kaulitz R, Luhmer I, Bergmann F, et al: Sequelae after modified Fontan operation: Postoperative haemodynamic data and organ function. Heart 78:154-159, 1997. 108.

Jahangiri M, Shore D, Kakkar V, et al: Coagulation factor abnormalities after the Fontan procedure and its modifications. J Thorac Cardiovasc Surg 113:989-992; discussion 992-993. 1997. 109.

Mertens L, Hagler DJ, Sauer U, et al: Protein-losing enteropathy after the Fontan operation: An international multicenter study. PLE study group. J Thorac Cardiovasc Surg 115:1063-1073, 1998. 110.

Balaji S, Johnson TB, Sade RM, et al: Management of atrial flutter after the Fontan procedure. J Am Coll Cardiol 23:1209-1215, 1994. 111.

Mavroudis C, Backer CL, Deal BJ, Johnsrude CL: Fontan conversion to cavopulmonary connection and arrhythmia circuit cryoblation. J Thorac Cardiovasc Surg 115:547-556, 1998. 112.

Deal BJ, Mavroudis C, Backer CL, et al: Impact of arrhythmia circuit cryoablation during Fontan conversion for refractory atrial tachycardia. Am J Cardiol 83:563-568, 1999. 112A.

Fishberger SB, Wernovsky G, Gentles TL, et al: Long-term outcome in patients with pacemakers following the Fontan operation. Am J Cardiol 77:887-889, 1996. 113.

Monagle P, Cochrane A, McCrindle B, et al: Thromboembolic complications after Fontan procedures--the role of prophylactic anticoagulation. J Thorac Cardiovasc Surg 115:493-498, 1998. 114.

Rychik J, Rome JJ, Jacobs ML: Late surgical fenestration for complications after the Fontan operation. Circulation 96:33-36, 1997. 115.

Sierra C, Calleja F, Picazo B, Martinez-Valverde A: Protein-losing enteropathy secondary to Fontan procedure resolved after cardiac transplantation. J Pediatr Gastroenterol Nutr 24:229-230, 1997. 116.

Kelly AM, Feldt RH, Driscoll DJ, Danielson GK: Use of heparin in the treatment of protein-losing enteropathy after Fontan operation for complex congenital heart disease. Mayo Clin Proc 73:777-779, 1998. 117.

Bac DJ, Van Hagen PM, Postema PT, et al: Octreotide for protein-losing enteropathy with intestinal lymphangiectasia (letter). Lancet 345:1639, 1995. 118.

Therrien J, Webb GD, Gatzoulis MA: Reversal of protein losing enteropathy with prednisone therapy in adult patients with modified Fontan operations: Long-term palliation or bridge to cardiac transplantation? Heart 82:241-243, 1999. 119.

McElhinney DB, Reddy VM, Moore P, Hanley FL: Revision of previous Fontan connections to extracardiac or intraatrial conduit cavopulmonary anastomosis. Ann Thorac Surg 62:1276-1282, 1996. 120.

Kreutzer J, Keane JF, Lock JE, et al: Conversion of modified Fontan procedure to lateral atrial tunnel cavopulmonary anastomosis. J Thorac Cardiovasc Surg 111:1169-1176, 1996. 121.

Kouatli AA, Garcia JA, Zellers TM, et al: Enalapril does not enhance exercise capacity in patients after Fontan procedure. Circulation 96:1507-1512, 1997. 122.

Shah MJ, Rychik J, Fogel MA, et al: Pulmonary AV malformations after superior cavopulmonary connection: Resolution after inclusion of hepatic veins in the pulmonary circulation. Ann Thorac Surg 63:960-963, 1997. 123.

COMPLETE TRANSPOSITION OF THE GREAT ARTERIES Wilson NJ, Clarkson PM, Barratt-Boyes BG, et al: Long-term outcome after the Mustard repair for simple transposition of the great arteries: 28-year follow-up. J Am Coll Cardiol 32:758-765, 1998. 124.

Puley G, Siu S, Connelly M, et al: Arrhythmia and survival in patients > 18 years of age after the Mustard procedure for complete transposition of the great arteries. Am J Cardiol 83:1080-1084, 1999. 125.

Myridakis DJ, Ehlers KH, Engle MA: Late follow-up after venous switch operation (Mustard procedure) for simple and complex transposition of the great arteries. Am J Cardiol 74:1030-1036, 1994. 126.

Ing FF, Mullins CE, Rose M, et al: Transcatheter closure of the patient ductus arteriosus in adults using the Gianturco coil. Clin Cardiol 19:875-879, 1996. 127.

Warnes CA, Somerville J: Transposition of the great arteries: late results in adolescents and adults after the Mustard procedure. Br Heart J 58:148-155, 1987. 128.

Rhodes LA, Wernovsky G, Keane JF, et al: Arrhythmias and intracardiac conduction after the arterial switch operation. J Thorac Cardiovasc Surg 109:303-310, 1995. 129.

Haas F, Wottke M, Popper H, Meisner H: Long-term survival and functional follow-up in patients after the arterial switch operation. Ann Thorac Surg 68:1692-1697, 1999. 129A.

Mahoney LT, Knoedel DL, Skorton DJ: Echocardiographic postoperative assessment of patients with transposition of the great arteries. Echocardiography 12:545-557. 1999. 130.

Helvind MH, McCarthy JF, Imamura M, et al: Ventriculo-arterial discordance: Switching the morphologically left ventricle into the systemic circulation after 3 months of age. Eur J Cardiothorac Surg 14:173-178, 1998. 131.

Cochrane AD, Karl TR, Mee RB: Staged conversion to arterial switch for late failure of the systemic right ventricle. Ann Thorac Surg 56:854-862, 1993. 132.

van Son JA, Reddy VM, Silverman NH, Hanley FL: Regression of tricuspid regurgitation after two-stage arterial switch operation for failing systemic ventricle after atrial inversion operation. J Thorac Cardiovasc Surg 111:342-347, 1996. 133.

De Jong PL, Bogers AJ, Witsenburg M, Bos E: Arterial switch for pulmonary venous obstruction complicating Mustard procedure. Ann Thorac Surg 59:1005-1007, 1995. 134.

Cetta F, Bonilla JJ, Lichtenberg RC, et al: Anatomic correction of dextrotransposition of the great arteries in a 36-year-old patient. Mayo Clin Proc 72:245-247, 1997. 135.

Jenkins KJ, Hanley FL, Colan SD, et al: Function of the anatomic pulmonary valve in the systemic circulation. Circulation 84(Suppl III):III173-III179, 1991. 136.

Vouhe PR, Tamisier D, Leca F, et al: Transposition of the great arteries, ventricular septal defect, and pulmonary outflow tract obstruction: Rastelli or Lecompte procedure? J Thorac Cardiovasc Surg 103:428-436, 1992. 137.

Lorenz CH, Walker ES, Graham TP Jr, Powers TA: Right ventricular performance and mass by use of cine MRI late after atrial repair of transposition of the great arteries. Circulation 92(Suppl II):II233-II239, 1995. 138.

Wilson NJ, Neutze JM, Rutland MD, Ramage MC: Transthoracic echocardiography for right ventricular function late after the Mustard operation. Am Heart J 131:360-367, 1996. 139.

CONGENITALLY CORRECTED TRANSPOSITION OF THE GREAT ARTERIES Van Praagh R, Papagiannis J, Grunenfelder J, et al: Pathologic anatomy of corrected transposition of the great arteries: Medical and surgical implications. Am Heart J 135:772-785, 1998. 140.

Ikeda U, Kimura K, Suzuki O, et al: Long-term survival in "corrected transposition." Lancet 337:180-181, 1991. 141.

Presbitero P, Somerville J, Rabajoli F, et al: Corrected transposition of the great arteries without associated defects in adult patients: Clinical profile and follow up. Br Heart J 74:57-59, 1995. 142.

Sano T, Riesenfeld T, Karl TR, Wilkinson JL: Intermediate-term outcome after intracardiac repair of associated cardiac defects in patients with atrioventricular and ventriculoarterial discordance. Circulation 92(Suppl II):II272-II278, 1995. 143.

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Szufladowicz M, Horvath P, de Leval M, et al: Intracardiac repair of lesions associated with atrioventricular discordance. Eur J Cadiothorac Surg 10:443-448, 1996. 144.

Voskuil M, Hazekamp MG, Kroft LJ, et al: Postsurgical course of patients with congenitally corrected transposition of the great arteries. Am J Cardiol 83:558-562, 1999. 145.

Termignon JL, Leca F, Vouhe PR, et al: "Classic" repair of congenitally corrected transposition and ventricular septal defect. Ann Thorac Surg 62:199-206, 1996. 146.

Connelly MS, Liu PP, Williams WG, et al: Congenitally corrected transposition of the great arteries in the adult: Functional status and complications [see comments]. J Am Coll Cardiol 27:1238-1243, 1996. 147.

van Son JA, Danielson GK, Huhta JC, et al: Late results of systemic atrioventricular valve replacement in corrected transposition. J Thorac Cardiovasc Surg 109:642-652, 1995. 148.

Imai Y: Double-switch operation for congenitally corrected transposition. Adv Cardiac Surg 9:65-86, 1997. 149.

Karl TR, Weintraub RG, Brizard CP, et al: Senning plus arterial switch operation for discordant (congenitally corrected) transposition. Ann Thorac Surg 64:495-502, 1997. 150.

Yagihara T, Kishimoto H, Isobe F, et al: Double switch operation in cardiac anomalies with atrioventricular and ventriculoarterial discordance. J Thorac Cardiovasc Surg 107:351-358, 1994. 151.

Stumper O, Wright JG, De Giovanni JV, et al: Combined atrial and arterial switch procedure for congenital corrected transposition with ventricular septal defect. Br Heart J 73:479-482, 1995. 152.

Horvath P, Szufladowicz M, de Leval MR, et al: Tricuspid valve abnormalities in patients with atrioventricular discordance: Surgical implications. Ann Thorac Surg 57:941-945, 1994. 153.

154.

Silka MJ, Rice MJ: Paradoxic embolism due to altered hemodynamic sequencing following

transvenous pacing. Pacing Clin Electrophysiol 14:499-503, 1991. Prieto LR, Hordof AJ, Secic M, et al: Progressive tricuspid valve disease in patients with congenitally corrected transposition of the great arteries. Circulation 98:997-1005, 1998. 155.

EISENMENGER SYNDROME Daliento L, Somerville J, Presbitero P, et al: Eisenmenger syndrome: Factors relating to deterioration and death. Eur Heart J 19:1845-1855, 1998. 156.

Saha A, Balakrishnan KG, Jaiswal PK, et al: Prognosis for patients with Eisenmenger syndrome of various aetiology. Int J Cardiol 45:199-207, 1994. 157.

Vongpatanasin W, Brickner ME, Hillis LD, Lange RA: The Eisenmenger syndrome in adults. Ann Intern Med 128:745-755, 1998. 158.

Ammash NM, Connolly HM, Abel MD, Warnes CA: Noncardiac surgery in Eisenmenger syndrome. J Am Coll Cardiol 33:222-227, 1999. 159.

Dajani AS, Taubert KA, Wilson W, et al: Prevention of bacterial endocarditis: Recommendations by the American Heart Association. JAMA 277:1794-1801, 1997. 160.

O'Kelly SW, Hayden-Smith J: Eisenmenger's syndrome: Surgical perspectives and anaesthetic implications. Br J Hosp Med 51:150-153, 1994. 161.

Bowyer JJ, Busst CM, Denison DM, Shinebourne EA: Effect of long term oxygen treatment at home in children with pulmonary vascular disease. Br Heart J 55:385-390, 1986. 162.

Harinck E, Hutter PA, Hoorntje TM, et al: Air travel and adults with cyanotic congenital heart disease. Circulation 93:272-276, 1996. 163.

Hosenpud JD, Novick RJ, Bennett LE, et al: The Registry of the International Society for Heart and Lung Transplantation: Thirteenth official report--1996. J Heart Lung Transplant 15:655-674, 1996. 164.

Bridges ND, Mallory GB Jr, Huddleston CB, et al: Lung transplantation in children and young adults with cardiovascular disease. Ann Thorac Surg 59:813-820; discussion 820-821, 1995. 165.

Wong CK, Yeung DW, Lau CP, et al: Improvement of exercise capacity after nifedipine in patients with Eisenmenger syndrome complicating ventricular septal defect. Clin Cardiol 14:957-961, 1991. 166.

Wimmer M, Schlemmer M: Long-term hemodynamic effects of nifedipine on congenital heart disease with Eisenmenger's mechanism in children. Cardiovasc Drugs Ther 6:183-186, 1992. 167.

Hopkins WE, Kelly DP: Angiotensin-converting enzyme inhibitors in adults with cyanotic congenital heart disease. Am J Cardiol 77:439-440, 1996. 168.

Rosenzweig EB, Kerstein D, Barst RJ: Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation 99:1858-1865, 1999. 169.

Batista RJ, Santos JL, Takeshita N, et al: Successful reversal of pulmonary hypertension in Eisenmenger complex. Arq Bras Cardiol 68:279-280, 1997. 170.

Perloff JK, Rosove MH, Child JS, Wright GB: Adults with cyanotic congenital heart disease: Hematologic management. Ann Intern Med 109:406-413, 1988. 171.

Perloff JK, Marelli AJ, Miner PD: Risk of stroke in adults with cyanotic congenital heart disease. Circulation 87:1954-1959, 1993. 172.

Ammash N, Warnes CA: Cerebrovascular events in adult patients with cyanotic congenital heart disease. J Am Coll Cardiol 28:768-772, 1999. 173.

Perloff JK, Marelli A: Neurological and psychosocial disorders in adults with congenital heart disease. Heart Dis Stroke 1:218-224, 1992. 174.

Perloff JK: Systemic complications of cyanosis in adults with congenital heart disease: Hematologic derangements, renal function, and urate metabolism. Cardiol Clin 11:689-699, 1993. 175.




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Chapter 45 - Acquired Heart Disease in Children STEVEN D. COLAN JANE W. NEWBURGER

The purpose of this chapter is to review cardiac diseases acquired in childhood. Congenital cardiac defects are discussed in Chapters 43 and 44 , while neurological diseases that affect the heart are described in Chapter 71 . Here we focus on cardiomyopathies, Kawasaki disease, hypertension, and hyperlipidemias. CARDIOMYOPATHIES (see also Chap. 48) This diverse group of disorders has historically been understood to represent "heart muscle diseases of unknown etiology,"[1] clearly excluding secondary processes such as hypertension, ischemic heart disease, and valvar and congenital heart disease. In addition, the World Health Organization definition also specifically excluded myocardial disease related to a known systemic disorder. Clinical practice does not concur with these exclusions, and secondary forms of cardiomyopathy are referred to as "anthracycline cardiomyopathy," "infectious cardiomyopathy," and other descriptive terms. Even etiologies that were intended to be specifically excluded have been incorporated under names such as "ischemic cardiomyopathy" and "cardiomyopathy of overload," a term that embodies the clinically familiar concept of load-induced myocyte

dysfunction. Cardiomyopathy is now more familiarly taken to imply a disease process involving the heart muscle that results in intrinsic myocardial dysfunction, subcategorized as primary and secondary forms. Classification of the cardiomyopathies as dilated, hypertrophic, and restrictive has fared the test of time somewhat better, although this terminology clearly has problems as well. The mixture of morphology and physiology inherent within this classification is unquestionably problematic because many overlapping cases are encountered. Furthermore, it is clear that the same etiology can be manifested as dilated cardiomyopathy (DCM) in some patients and as hypertrophic cardiomyopathy (HCM) in others and that individual patients can transition between the two. Although this effort at categorization is merely a general, descriptive approach that cannot be relied on for unambiguous classification, it nonetheless provides a clinically useful framework and will be used in this presentation. Dilated Cardiomyopathy (see also Chap. 48)

DCM has numerous etiologies, clinical manifestations, and outcomes that vary depending on both the pathogenesis and host response. Multiple associations have been described in children, but most cases remain idiopathic. Although the true frequency of the various causes of DCM is currently unknown, improved methods of diagnosis have enabled determination of the cause for a progressively larger proportion of the previously idiopathic cases. Between one-third and one-half of cases are thought to be familial.[2] Inflammatory heart disease caused by viral myocarditis or an abnormal immunologic response to viral infection is believed to be a common cause, but problems in confirming this diagnosis beyond the acute stage have hampered determination of the true incidence. Progress in molecular identification of viral presence in diseased human heart tissue[3] has created new opportunities to define the relationship between viral infections and myocarditis. It is generally assumed clinically that the primary functional change at the myofiber level in DCM is depression of contractile function. Despite how commonly this assumption is believed, several groups have shown that isolated cardiac muscle harvested from patients with end-stage heart failure is capable of normal force-generating capacity under ideal conditions and low stimulation frequencies,[4] even when force generation deteriorates at higher stimulation frequencies.[5] In contrast, diastolic abnormalities are a constant property of failing heart muscle.[6] The molecular event or events that account for myocardial failure remain elusive, although many metabolic abnormalities have been described. Numerous abnormalities often coexist, and their relative importance is not known. Although most investigators have sought a single final pathway to contractile dysfunction, this approach may not be correct. Since DCM appears as the end result of many quite different processes, it is likely that numerous metabolic disturbances may have contractile dysfunction as the final common manifestation. Clarification of the disease-specific pathogenesis of contractile failure has no doubt been hampered by our very limited ability to determine etiology. Clinical Features and Diagnostic Evaluation

Regardless of the underlying cause of the ventricular dysfunction, the congestive cardiomyopathies have a similar mode of expression. Older children experience

exercise intolerance, dyspnea on exertion, tachycardia, palpitations, abdominal distention, syncope or near-syncope, and occasionally, cardiovascular collapse and sudden death. Although many symptoms parallel those seen in adults, primary complaints of peripheral edema and paroxysmal nocturnal dyspnea are uncommon in children. Infants are generally recognized on the basis of respiratory distress, abdominal distention, and poor feeding, but occasionally the process is subacute and failure to thrive is present at the time of diagnosis. Secondary cardiomyopathies can manifest a broad spectrum of noncardiac abnormalities, depending on the nature of the primary disorder. PHYSICAL FINDINGS.

Physical findings depend on the severity of clinical compromise. Patients with mild ventricular dysfunction can have reduced exercise capacity but no

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abnormal physical findings. Congestive heart failure is nearly always accompanied by tachypnea and tachycardia. Peripheral cyanosis is noted only in the presence of severe compromise. Peripheral pulses are often weak and can be difficult to palpate because of narrow pulse pressure and occasionally hypotension. Cool extremities and poor capillary refill can be noted, particularly in infants. Intercostal retractions are a common finding in infants and young children, but in contrast to adults, pulmonary auscultation rarely reveals rales, even when frank pulmonary edema is present on chest radiographs. Wheezing can be heard at all ages because of attenuated airway relaxation, a process that appears to result from the generalized desensitization of beta-adrenergic receptors that is characteristic of congestive heart failure.[7] Hepatomegaly is a seminal finding and can be massive in infants but changes rapidly in response to therapy. Neck vein distention and peripheral edema are almost never observed in infants but become more common with age. The cardiac impulse is often displaced laterally and is frequently diffuse. Gallop rhythm with a third heart sound is common, as is a murmur of mitral regurgitation. LABORATORY DATA.

Cardiomegaly, pulmonary venous congestion, pulmonary edema, atelectasis, and pleural effusions are common radiographic findings. The electrocardiogram (ECG) shows sinus tachycardia in most patients. Nonspecific ST-T wave changes and left ventricular hypertrophy are noted in about half of patients,[8] with atrial and right ventricular hypertrophy in 25%. Just under 50% of patients have arrhythmias on initial evaluation, including atrial fibrillation and flutter, ventricular ectopic beats, and nonsustained ventricular tachycardia on Holter recording. DCM must be differentiated from tachycardia-induced cardiomyopathy, a process that can have similar features but responds to arrhythmia control with complete recovery. [9]

Echocardiography.

Diagnostic findings on echocardiography are a dilated left ventricle with diminished systolic performance. Dysfunction is global, although moderate regional variation in wall motion is usually present. Quantitative assessment of systolic and diastolic functional parameters and ventricular morphology is diagnostically and prognostically useful. Pericardial effusions are frequent. Intracardiac thrombi have been reported in as many as 23% of children, although rarely in infants.[10] Color flow and spectral Doppler examinations are useful for assessment of mitral regurgitation, as well as diastolic function. The echocardiogram is equally critical for excluding valvar and structural cardiac disease. Anomalous origin of the left main coronary artery from the pulmonary artery can be reliably recognized through the combined use of imaging and color flow Doppler.[11] Cardiac Catheterization.

This procedure is performed primarily for endomyocardial biopsy. Occasionally, the possibility of a coronary anomaly remains in doubt, in which case coronary arteriography is mandatory. Assessment of hemodynamics is rarely useful for patient management unless the clinical findings are discrepant from the echocardiographic findings, but hemodynamic evaluation has important prognostic implications and is needed if organ transplantation is considered. Biopsy findings in idiopathic DCM are nonspecific and demonstrate myocyte hypertrophy and variable amounts of fibrosis without evidence of inflammatory infiltrates. The primary importance of biopsy is detection of known causes of DCM, including histological or polymerase chain reaction evidence of myocarditis, infiltrative or mitochondrial disorders, cytoskeletal protein defects,[12] and endocardial fibroelastosis (EFE).[10] Numerous rare disorders can be diagnosed only by tissue analysis. A finding of inflammatory heart disease justifies a delay in consideration of transplantation because myocarditis in children is generally associated with a more favorable prognosis,[10] including the potential for complete recovery. The safety of transvenous biopsy has been amply demonstrated, and extensive experience in its use has been gained through routine application in cardiac transplant recipients. The highest risk is noted in infants,[13] in whom perforation by the stiff biopsy catheters is a recognized complication. However, this patient group is exactly the one in which the results can be most helpful, with the risk-benefit ratio shifted in favor of the test, even in this age group. DIFFERENTIAL DIAGNOSIS.

In children and infants with DCM the differential diagnosis is complex because of the imposing array of possible rare disorders. An ordered and logical algorithm for diagnostic evaluation based on standard and widely available laboratory screening tests has been published[14] and has led to targeted specific testing for particular disorders of metabolism. This field is rapidly evolving as new enzymatic disorders are recognized and must be incorporated within this algorithm.[14A] [14C] Certain disorders, such as the mitochondrial disorders,[15A] [15C] can be particularly difficult to diagnose because of tissue-selective and heterogeneous expression related to either tissue-specific

isoenzyme or to unbalanced segregation of mutated and wild-type mitochondrial DNA. The defect is biochemically manifested when a certain threshold of mutated mitochondrial DNA is reached. The situation is rendered even more complex by the age-dependent accumulation of mitochondrial DNA deletions that appear to have no causal relation to DCM.[16] Treatment

In the absence of an identifiable cause, treatment is supportive, nonspecific, and targeted at controlling the symptoms of congestive heart failure. The severity of clinical compromise determines the level of support needed. Critically ill children will generally require mechanical ventilation and inotropic support. Management at centers that have extracorporeal membrane oxygenator and ventricular assist device support available is advised for these patients. Some patients can experience sufficient recovery within a period of days to permit withdrawal of mechanical myocardial support, and the method can at times be used as a bridge to transplantation.[17] Once the patient is stabilized, or in patients who are not critically compromised at the time of initial assessment, oral therapy with digoxin, angiotensin-converting enzyme (ACE) inhibitors, and diuretics remains the mainstay of treatment. Recent data in adults indicate a 30% reduction in deaths when spironolactone is included in the diuretic scheme.[18] This medication is well tolerated in children, and despite the absence of specific data in this age group, these results are fairly compelling for its use. No consensus has been reached regarding which of these agents to institute first in children who do not require multidrug therapy, but asymptomatic ventricular dysfunction is often managed with ACE inhibitors alone because of the absence of significant reported risk. Arrhythmias are common in children with DCM,[8] and their management is not substantially different from that of adults. Data concerning the utility of ventricular stimulation protocols are rare in children, but the available data suggest that it is useful in risk stratification but not clearly effective in guiding therapy.[19] Intermittent infusion of inotropes such as dobutamine, a common practice in the management of children with severe chronic congestive heart failure, has been based on practice in adult clinics. Although the results in adult studies are mixed, with some trials reporting that survival can be adversely affected, most studies continue to note symptomatic improvement.[20] Intermittent inotrope infusion appears to be a reasonable alternative to achieve stabilization and symptom control in patients awaiting transplantation. Carnitine deficiency and disorders of carnitine transport can result in DCM and HCM, and in some cases, dietary carnitine supplementation can lead to dramatic cardiac and clinical improvement. In an attempt to avoid delays in ther

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apy, it is not uncommon for clinicians to initiate empirical carnitine supplementation prior to biochemical confirmation of this disorder. In fact, cardiomyopathy is not a prominent feature of myopathic carnitine deficiency, in which skeletal muscle weakness and

recurrent metabolic crises dominate. In addition to potentially obscuring diagnostic evaluation, other inborn errors of metabolism have been described that are manifested as DCM but deteriorate rapidly in response to carnitine supplementation.[21] Plasma carnitine concentrations and fatty acid metabolism byproducts should be evaluated in all infants with cardiomyopathy of unknown etiology, but empirical therapy is not advised. Children with DCM are at risk for intracardiac thrombus formation and systemic embolization. Intracardiac thrombi were seen in 46 to 84 percent of children at autopsy, but their relationship to premorbid findings is unclear since one of these studies documented no intracardiac thrombi during life.[22] Clinical series report the presence of intracardiac thrombi in 0 to 23 percent.[10] [22] [23] Comparison of these studies indicates an age-related trend toward a higher incidence, but none of the series have been large enough to draw firm conclusions. Guidelines for antithrombotic therapy are derived from and parallel those in adults. Mitral valve regurgitation is common in DCM and in some instances can be moderate or more pronounced in severity. Clinical improvement in symptoms, ventricular function, and survival after mitral valvuloplasty has, however, been reported in patients with DCM.[24] [25] The repair represents a form of afterload reduction, with a fall in wall stress consequent to ventricular remodeling. In patients with moderate to severe mitral regurgitation associated with DCM, valve repair should be seriously considered, but valve replacement generally entails excessive risk. Several forms of therapy are currently investigational in children. Two recent large and favorable experiences with beta blockers in adults with congestive heart failure[26] [26A] have not been adequately replicated in children. There is ample theoretical justification for their use, and preliminary results in children have been reported, [27] but data on risk-benefit analysis, appropriate dosing schedule, and patient selection criteria are limited. The combination of an ACE inhibitor and beta blocker has been found to result in a synergistic effect in adult patients with asymptomatic dysfunction,[28] an issue that has not been addressed in children. Trials of angiotensin II receptor antagonist[29] use in children have not been reported. Early reports of potential benefits of growth hormone therapy in adults with DCM[30] have not been confirmed in children. Patients with DCM often have markedly asynchronous ventricular activation resulting in a diminished peak force of contraction.[30A] Biventricular DDD pacing with optimized atrioventricular synchrony can improve ventricular performance and has been tried as a therapeutic modality in several small series of adult patients.[31] [31A] Again, no data are available in children. The recent advent of ventricular volume reduction surgery as a means of afterload reduction in patients with end-stage DCM has been attempted in a few children,[32] but the numbers are too few to draw any conclusions. This procedure improves systolic function at the expense of further impairing diastolic function,[33] [33A] with an unpredictable net impact on overall cardiac function. Infants and children with DCM have a marked dominance of systolic dysfunction with less evidence of diastolic dysfunction than is generally noted in adult studies, thus suggesting that they might indeed benefit from this procedure. Predictors of Outcome

Negative predictors of outcome in children with DCM include the severity of dysfunction, spherical ventricular shape, coexistence of right ventricular dysfunction, familial cardiomyopathy, tissue diagnosis of EFE, persistent cardiomegaly, and persistent congestive heart failure. Tissue diagnosis of myocarditis has been associated with a better outcome. Ventricular size and mass at initial evaluation have not been found to be predictive of outcome. Younger age at diagnosis has been reported to be associated with a better outcome by some groups,[34] has been associated with a worse outcome by other groups,[35] and in other series has not been found to be a significant factor. [36] One motivation for defining factors predictive of outcome is to facilitate early recommendation for cardiac transplantation. It is therefore disturbing that so little agreement has been found in the many studies to date. Given the heterogeneity of the disorder itself and the small number of patients included in many series, it is likely that the patient samples are quite dissimilar. Entry criteria have also varied substantially among these studies, with specific inclusion of myocarditis in some but exclusion in others. Many of the variables are likely to have a real association with outcome, but the relationship is weak. The fact that commonly used measures of ventricular performance are only weakly predictive of survival severely limits their utility in decisions concerning transplantation. OUTCOME.

Survival statistics for infants (Fig. 45-1) and older children ( Fig. 45-2 ) with idiopathic DCM have varied, with 1-, 2-, 5-, and 10-year survival rates of 41 to 94 percent, 20 to 88 percent, 34 to 86 percent, and 52 to 84 percent, respectively, having been reported. In those who survive, nearly half have full normalization of ventricular function, 25 percent have improved but abnormal function, and 25percent have persistently severely depressed function.[37] Recovery of function is generally complete within the first year, but occasional patients experience continued late improvement.[10] [38] Infective Myocarditis (see also Chap. 48)

Myocardial inflammatory diseases are an important cause of DCM in children. Myocarditis cannot be reliably distinguished from other forms of DCM on clinical grounds alone because both the acute and chronic forms have symptoms and functional consequences related to the severity of ventricular dysfunction. A significant number of cases of myocarditis have manifestations that are subclinical and associated with ECG changes or arrhythmias, and in a significant number the myocarditis can be occult or cause sudden death.[39] Nearly all the organisms that cause common infectious illnesses in children can also cause myocarditis,[40] although fewer have been associated with the manifestations of DCM. In addition, myocarditis can occur as a hypersensitivity or toxic reaction and is associated with a number of important systemic diseases such as rheumatic fever. Management of myocarditis is similar to management of other forms of DCM in that etiology-specific therapy is not generally available. Considerable evidence indicates that the immune response and autoimmunity may play a central role in the acute and chronic myocardial damage,[41] thus suggesting a role for immunosuppressive therapy. Small,

uncontrolled trials of corticosteroid therapy in children with evidence of myocarditis[42] [43] have reported favorable outcomes. Similar to trials of these and other immunosuppressive agents in adults, these uncontrolled studies in a disease with a high rate of spontaneous resolution are impossible to interpret. In some centers, administration of high-dose intravenous gamma globulin to children with findings indicative of acute myocarditis has led to improved survival and more rapid recovery of function.[44] Endocardial Fibroelastosis (see also Chap. 48)

Diffuse thickening of the left ventricular endocardium secondary to proliferation of fibrous and elastic tissue is an

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Figure 45-1 Survival in infants with idiopathic dilated cardiomyopathy. Chen (1990): Chen S, Nouri S, Balfour I, et al: Clinical profile of congestive cardiomyopathy in children. J Am Coll Cardiol 15:189, 1990; Griffin (1988): Griffin ML, Hernandez A, Martin TC, et al: Dilated cardiomyopathy in infants and children. J Am Coll Cardiol 11:139, 1988; Matitiau (1994): Matitiau A, Perez-Atayde A, Sanders SP, et al: Infantile dilated cardiomyopathy: Relation of outcome to left ventricular mechanics, hemodynamics, and histology at the time of presentation. Circulation 90:1310, 1994.

uncommon but nonspecific response to a variety of inciting agents. The finding was at one time thought to represent a specific disease, but as emphasized by Lurie, [45] it is now clear that EFE represents a final common pathway for many different myocardial stressors. An association with mumps virus infection has been suspected for many years, a theory supported by detection of the mumps virus genome in the myocardium of infants and children.[46] This proposed etiology for a significant proportion of cases is further supported by the observed fall in EFE incidence coincident with implementation of widespread vaccination. Despite the reduction in frequency, this histological finding continues to be reported in association with a wide variety of cardiac diseases, including prenatal and postnatal left ventricular outflow tract obstruction, numerous other forms of congenital heart disease, and many forms of DCM and HCM, as well as being a focal finding in adults with various cardiac disorders.[47] Among the various associations, no single theme emerges, which supports the interpretation that EFE represents a nonspecific tissue response. The pathophysiology of the response is of interest inasmuch as it can provide clues to pathways of injury shared by various diseases.

Figure 45-2 Survival in children with idiopathic dilated cardiomyopathy. Akagi (1991): Akagi T, Benson LN, Lightfoot NE, et al: Natural history of dilated cardiomyopathy in children. Am Heart J 121:1502, 1991; Arola (1998): Arola A, Tuominen J, Ruuskanen O, et al: Idiopathic dilated cardiomyopathy in children: Prognostic indicators and outcome. Pediatrics 101:369, 1998; Burch (1994): Burch M, Siddiqi SA, Celermajer DS, et al: Dilated cardiomyopathy in children: Determinants of outcome. Br Heart J 72:246, 1994; Chen (1990): Chen S, Nouri S, Balfour I, et al: Clinical profile of congestive cardiomyopathy in

children. J Am Coll Cardiol 15:189, 1990; Friedman (1991): Friedman RA, Moak JP, Garson A Jr: Clinical course of idiopathic dilated cardiomyopathy in children. J Am Coll Cardiol 18:152, 1991; Griffin (1988): Griffin ML, Hernandez A, Martin TC, et al: Dilated cardiomyopathy in infants and children. J Am Coll Cardiol 11:139, 1988; Taliercio (1985): Taliercio CP, Seward JB, Driscoll DJ, et al: Idiopathic dilated cardiomyopathy in the young: Clinical profile and natural history. J Am Coll Cardiol 6:1126, 1985; Wiles (1991): Wiles HB, McArthur PD, Taylor AB, et al: Prognostic features of children with idiopathic dilated cardiomyopathy. Am J Cardiol 68:1372, 1991.

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Clinically, more than 80 percent of cases occur in the first year of life, with features dependent on which form of the disease is manifested. Most patients have a dilated ventricle with increased wall thickness and depressed systolic function. The clinical manifestations of the dilated form are similar to findings in other types of DCM. Rarely, patients have a contracted form characterized by a small left ventricle and a clinical picture of restrictive cardiomyopathy. The diagnosis of EFE is most commonly made at autopsy. Although EFE is often suspected on echocardiography (see Chap. 7) when the ultrasound signal from the endocardial surface is unusually strong, echocardiography has not been found to be a reliable diagnostic technique.[48] EFE can be recognized on endomyocardial biopsy, and despite greater involvement of the left ventricle in many patients, the diagnosis can frequently be confirmed on right ventricular biopsy. An autopsy series found that most patients with EFE had right ventricular involvement, although to a lesser extent than on the left,[49] but the diagnostic accuracy of endomyocardial biopsy of the right ventricle has not been systematically tested. The purpose of the diagnosis is primarily for prognosis since in some clinical situations the finding of EFE has been associated with a poor outcome. For example, in case series of DCM, EFE is often identified as one of the risk factors for death.[10] [23] Nevertheless, in a group of patients with idiopathic EFE, the 4-year survival rate was 77 percent, which is not worse than rates reported in other forms of DCM. Doxorubicin Cardiomyopathy (see Chaps. 48 and 69)

The anthracycline antibiotics include a number of valuable antitumor agents, with doxorubicin (Adriamycin) in particular having the broadest spectrum of antitumor activity of the available cancer chemotherapeutic agents. Thousands of children have received doxorubicin over the past 30 years for several of the most common pediatric oncological disorders, including acute lymphocytic leukemia. A dramatic improvement in long-term survival after childhood cancer has occurred during the same time interval. As a result, late residua from therapy often represent the most important clinical problem for these patients. Among these residua is doxorubicin-associated cardiomyopathy, the consequences of which continue to unfold as the length of follow-up increases. The magnitude of this problem has escalated to the point that for many pediatric centers, doxorubicin cardiomyopathy accounts for the majority of cases of DCM. CLINICAL FEATURES.

Clinically, the most significant problems relate to a chronic, dose-related

cardiomyopathy. Historically, cardiomyopathy was manifested by left ventricular dysfunction, elevated filling pressure, and reduced cardiac output 2 to 4 months after completion of therapy. The myocardial insult is often delayed for a period after the last dose of the drug because of a time delay in the full cytotoxic effect of the drug, with a mean latency between 3 and 8 weeks. More recently, new onset of congestive heart failure has been described in patients years after completion of therapy.[50] As a group, these patients manifest a low incidence of depressed contractility. The dominant abnormality is elevated afterload related to inadequate hypertrophy in the absence of significant dilation.[50] [51] Total cumulative dose, age at the time of doxorubicin therapy, and duration since completion of therapy each relate to the incidence of cardiac abnormalities. Excess afterload is a particular risk for young children; it appears gradually and is manifested as inadequate myocardial growth when compared with the rate of somatic growth. This form of doxorubicin-mediated cardiac injury appears to represent impaired growth capacity of the myocardium, a problem of particular importance to a small child. Numerous clinical studies have identified certain factors that place patients at increased risk for the adverse cardiac effects of doxorubicin. Patients younger than 4 years have an increased risk.[50] Females are at higher risk on a dose-matched basis.[52] [53] Mediastinal irradiation increases toxicity,[54] although the effect is not marked. However, the factor that has been consistently found to bear the strongest relationship to the incidence of cardiotoxicity is the total cumulative dose. The relationship between the total cumulative dose of doxorubicin and symptomatic cardiotoxicity is nonlinear, with an inflection point somewhere between 400 and 600 mg/m[2] . For example, in one study the incidence of cardiomyopathy was 7 percent in subjects who received less than 550 mg/m[2] , but it increased to 18 percent in the group that received 700 mg/m[2] .[55] Although some variation is seen in the dose at which the incidence of congestive heart failure has been observed to rise, this general pattern has been observed in the numerous studies that have examined it. PREVENTION.

Recognition of the dose-related nature of early-onset congestive heart failure has resulted in nearly universal limitation of the cumulative dose to less than 350 to 450 mg/m[2] , which successfully reduces this complication to 1 percent or less. Although late toxicity also appears to be dose related, doses as low as 90 to 220 mg/m[2] still represent a measurable risk,[50] [51] with no "safe" dose having been demonstrated. In addition to uniform dose reduction for all patients, alternative means of toxicity reduction that have been reported include dosing regimens designed to reduce peak serum levels (such as continuous infusion), coadministration of agents aimed at providing cardioprotection, and programmed dose reduction as dictated by one of several monitoring programs. Numerous agents with the potential to reduce doxorubicin cardiotoxicity have been tried in animal and human trials, but at present the most promising is dexrazoxane (ICRF-187). Dexrazoxane has a plausible mechanism of action (iron chelation),[56] evidence of reduced early and late toxicity in animals, and promising early results in clinical trials in children.[57] Cardiac monitoring programs that attempt to detect cardiotoxicity on an individual basis,

thereby permitting individual dosing regimens and dose reduction in patients with evidence of cardiac injury, are both widely used and highly contentious.[58] [59] Although the means used to detect myocardial injury has varied from study to study, in other regards the monitoring programs that have been recommended are quite similar. The basic approach is to evaluate patients periodically during doxorubicin therapy and to delay or discontinue treatment with the drug in patients with abnormal test results. It is generally agreed that the onset of congestive heart failure justifies cessation of doxorubicin therapy. However, the more typical scenario is a patient who has received some fraction of the intended cumulative dose of doxorubicin, at which time an asymptomatic drop in left ventricular function is detected. For patients treated by set protocols, if the fall in function exceeds some predefined criteria, cessation of anthracycline therapy is advised. This approach is advocated to minimize adverse cardiac outcomes.[58] However, opponents of published criteria voice concern that the impact of these programs on overall outcome has not been addressed. [59] Fundamentally, it is important to recognize that administration of anthracyclines is intrinsically a compromise between cancer cure and cardiac injury such that any reduction in the total cumulative dose decreases the antitumor effect. Even a reduction in cumulative dose from 270 to 180 mg/m[2] has been shown to have a detectable impact on the cancer cure rate. [51] Similarly, cardiotoxicity is a progressive phenomenon, with mild but detectable injury even at very low doses.[50] [51] Evaluation of the success of any cardiac monitoring program must include a decision regarding what severity of cardiac injury is unacceptable to achieve the desired antitumor effect. At

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perhaps the most simplistic level, dose reduction in response to a monitoring program should result in verifiable net improvement in survival. However, at present the benefits of serial cardiac assessment for doxorubicin-induced cardiomyopathy as a means of dose adjustment remain enticing but unproven. Hypertrophic Cardiomyopathy (see Chap. 48)

HCM is defined as the presence of ventricular hypertrophy without an identifiable hemodynamic cause such as hypertension, valvular heart disease, catecholamine-secreting tumors, hyperthyroidism, or any other condition that could secondarily stimulate cardiac hypertrophy. It is clear that HCM represents a heterogeneous group of disorders, and this diversity is more apparent in childhood than at any other age. These disorders can be subdivided into primary and secondary forms, where the primary form is a familial disorder ("familial HCM") typically devoid of findings outside of the heart. Secondary forms include diseases such as Friedreich ataxia, where ventricular hypertrophy is common but not the dominant clinical manifestation (see Chap. 71) , and others such as glycogenosis type IX, in which a systemic disorder has primarily or exclusively cardiac manifestations. Familial Hypertrophic Cardiomyopathy

CLINICAL DESCRIPTION.

In about half of affected patients, it is possible to elicit a history of another family member with familial HCM or a family history of sudden death at a young age. Although many young patients are asymptomatic, the full spectrum of symptoms associated with this disease can be present from early childhood. Limitation of exercise capacity because of either dyspnea or chest pain is often the primary and most disabling symptom in familial HCM. As a group, exercise performance is impaired, even when asymptomatic patients are included.[60] Chest pain, which is an extremely unusual finding in most forms of heart disease in children, is common in children with familial HCM and can have characteristics of angina; however, the chest pain is often atypical in that it occurs at rest, has a variable threshold of onset, and is at times prolonged. Infants with familial HCM often have clinical features more typical of congestive heart failure, with a history of tachypnea, hepatomegaly, and poor feeding and growth. Palpitations are common in adults but rarely noted by children. Syncope occurs in 15 to 25 percent of adult subjects. Although syncope is less common in childhood, it is strongly associated with the risk of sudden death. PHYSICAL FINDINGS.

Most children and young adults are remarkably healthy, with a frequent predilection for athletics. Although many physical findings have been described in this disease, most relate to dynamic ventricular outflow obstruction and are absent in subjects without obstruction. Therefore, a completely normal physical examination in a healthy patient who may be quite athletic does not exclude the presence of this potentially fatal disorder, an observation that has led some observers to suggest echocardiographic screening as part of an evaluation prior to sports participation. The apical and parasternal cardiac impulses are often augmented but rarely displaced. Hepatomegaly is common in infants but is generally not seen beyond this age. In the presence of outflow obstruction, a bisferious carotid pulse can be encountered that corresponds to the "spike-and-dome" aortic pulse contour of patients with dynamic outflow obstruction. Parasternal and carotid systolic thrills are frequent in patients with left or right ventricular outflow obstruction. The murmur of dynamic left ventricular outflow obstruction can be noted, and it rises in intensity with physiological maneuvers that lower preload or afterload or increase contractility. Very loud systolic murmurs are usually found in subjects with subpulmonary stenosis, which is more common in infants and children. The murmur of mitral regurgitation is frequent in patients with subaortic stenosis, although difficult to separate from the outflow murmur. Aortic regurgitation can be heard but is less commonly encountered than in discrete subaortic stenosis. ELECTROCARDIOGRAM AND HOLTER RECORDING.

Although the vast majority of patients with familial HCM and obstruction to left ventricular outflow have an abnormal ECG, about 25 percent of patients without obstruction have a normal ECG. The most common abnormalities are left ventricular hypertrophy, ST segment and T wave abnormalities, and abnormal Q waves. Atrial fibrillation develops in approximately 15 percent of adults with familial HCM but is

unusual in children. Symptomatic ventricular tachycardia on Holter recording or induced at electrophysiology study appears to identify a high-risk subgroup.[61] Although syncope is a risk factor for sudden death,[62] the presence of asymptomatic ventricular tachycardia on Holter recording is not a risk factor. [63] In children, ventricular arrhythmias on Holter recording are less frequent than in adults. ECHOCARDIOGRAM.

The echocardiogram permits noninvasive assessment of ventricular size, wall thickness, systolic and diastolic function, outflow obstruction, and valvar insufficiency. Localized hypertrophy of the anterior septum is seen in 10 to 15 percent of patients, and 20 to 35 percent of patients have involvement of both anterior and posterior portions of the septum. At least 50 percent of patients have involvement of the anterolateral free wall in addition to the septum. The incidence of isolated involvement of the posterior and apical portions of the septum or anterolateral free wall without hypertrophy of the anterior septum is as much as 20 percent. The reported incidence of concentric hypertrophy is quite variable but can be as much as 20 percent. The anatomical pattern has not proved to be predictive of outcome but is a primary determinant of outflow obstruction and is an important factor in surgical planning.[64] EXERCISE TESTING.

Quantitative assessment of functional capacity is useful for documenting clinical status, as well as for objectively assessing the response to therapeutic interventions. High-grade arrhythmias are elicited in some patients and have a negative prognostic implication. A hypotensive response to exercise appears to represent a risk for sudden death,[65] but more definitively, a normal exercise blood pressure response identifies a low-risk cohort.[66] Children and young adults with thallium scintigraphic evidence of ischemia have been reported to be at increased risk of sudden death.[67] Unfortunately, ECG changes with exercise are an unreliable marker of ischemia because they occur with equal frequency in patients with and without inducible ischemia. CATHETERIZATION.

The hemodynamic findings in familial HCM depend on the presence or absence of obstruction. The right ventricle can be involved, particularly in infants and children, and can demonstrate outflow gradients and elevated diastolic pressure. In infants, the septum often impinges on right ventricular outflow, and right ventricular cavity obliteration in systole can be noted. Myocardial bridges, i.e., muscle bands overlying epicardial coronary arteries, are congenital and sufficiently common (having been observed in 20 to 66 percent of hearts) that they are considered an anatomical variant rather than a congenital anomaly.[68] Despite angiographic evidence of systolic compression of the underlying coronary artery, little evidence supports the hypothesis that myocardial bridges can be associated with ischemia. Compression of the coronary artery by myocardial bridges has been detected angiographically in 30 percent of adults with familial HCM,[69] with no evidence of adverse impact on outcome. In a recent provocative report of a relationship between sudden death and the presence of myocardial bridging in children with familial HCM, Yetman and associates suggested

that surgical unroofing of the coronary artery can prevent sudden death.[70] These authors describe delayed diastolic filling of the affected coronary artery as a mechanism for ischemia. It is unclear why myocardial bridges would have a greater impact on children than has been described in adults, so further confirmation is required before myocardial bridging can be accepted as an adverse risk factor worthy of surgical intervention. DIFFERENTIAL DIAGNOSIS.

Ultimately, the diagnosis of familial HCM depends on molecular identification of the offending gene or the abnormal gene product. Until this test is available on a commercial basis, reliance on current, less than perfect diagnostic tools is necessary. Although echocardiographic identification of hypertrophy is the primary diagnostic modality in current clinical use, familial HCM with an associated risk of sudden death can be present even in the absence of hypertrophy. Surprisingly, when a genotyped population is investigated, the usual ECG and echocardiographic criteria accurately detect disease in only 83 percent of adults and only 50 percent of children.[71] Under these circumstances, the need for alternative diagnostic modalities is apparent. Endomyocardial biopsy is useful for excluding other causes of HCM, including mitochondrial disorders and storage diseases, and is therefore recommended in infants and young children. However, the

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primary histological abnormality of focal myocardial disarray is not unique to familial HCM and cannot be reliably detected on biopsy specimens. Although isolated case reports have described HCM in association with many disorders, in a number of disorders HCM is seen with sufficient frequency to indicate that it is an intrinsic element of the disease (Table 45-1) . Patients with Friedreich ataxia have a 25 to 50 percent incidence of HCM, with clinical characteristics quite different from those of familial HCM (see also Chap. 71) . HCM is seen in up to 20 to 30 percent of patients with Noonan syndrome,[72] with findings similar to those in familial HCM. Although the risk of congestive heart failure is more common than in familial HCM, there is also at least some risk of sudden death.[73] Infants of diabetic mothers and neonates exposed to corticosteroids often have transient biventricular hypertrophy, sometimes with outflow tract obstruction and occasionally causing symptoms. Finally, many genetic disorders are often accompanied by cardiac hypertrophy. Generally, HCM in infants is associated with unique problems in the differential diagnosis. In various series, diseases other than familial HCM have accounted for 30 to 70 percent of HCM cases in patients younger than 2 years.[73] Hypertrophy with depressed function is rare in familial HCM and highly suggestive of a metabolic or mitochondrial disorder.[74] Myocardial biopsy is often necessary to distinguish among these disorders, is recommended in all patients younger than 2 years, and can be particularly helpful in children with symmetrical hypertrophy or depressed function who have no family history of familial HCM.[74] Mitochondrial disorders present a particular problem in diagnosis because of variable

and often tissue-specific involvement. Differentiation between physiological hypertrophy secondary to athletic participation and pathological hypertrophy in familial HCM is a frequent and important problem in children and young adults. The cardiac response to chronic, intense exercise has been well characterized and includes dilation and hypertrophy with preservation of myocardial contractility. The hypertrophic response is most intense in sports that elicit a marked rise in blood pressure during exercise, such as rowing, wrestling, and power lifting. Wall thickness greater than 13 mm, as occasionally found in athletes, and the not infrequent TABLE 45-1 -- CONDITIONS OTHER THAN FAMILIAL HYPERTROPHIC CARDIOMYOPATHY ASSOCIATED WITH HYPERTROPHIC CARDIOMYOPATHY Syndromes Beckwith-Wiedemann syndrome Cardiac-facial-cutaneous syndrome Costello syndrome Friedreich ataxia Lentiginosis (LEOPARD syndrome) Noonan syndrome Secondary forms Anabolic steroid therapy and abuse Infant of diabetic mother Prenatal and postnatal corticosteroid therapy Metabolic disorders Carnitine deficiency (carnitine palmitoyltransferase II deficiency, carnitine-acylcarnitine translocase deficiency) Fucosidosis type 1 Glycogenoses types II, III, and IX (Pompe disease, Forbes disease, phosphorylase kinase deficiency) Glycolipid lipidosis (Fabry disease) I cell disease Lipodystrophy, total Mannosidosis Mitochondrial disorders (multiple forms) Mucopolysaccharidoses types I, II, and V (Hurler syndrome, Hunter syndrome, Scheie syndrome) Selenium deficiency LEOPARD=lentigenes (multiple), electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness. occurrence of mild left ventricular hypertrophy in patients with familial HCM result in a significant incidence of diagnostic ambiguity. ECG has not been particularly helpful in differentiation because of the frequent presence of ECG abnormalities in athletes.[75] Echocardiographic and clinical features that increase the probability of familial HCM include (1) a family history of HCM or early sudden death, (2) significant regional differences in hypertrophy, (3) diastolic dysfunction, (4) abnormal ultrasonic myocardial reflectivity, (5) absence of deconditioning-induced regression of hypertrophy, and (6)

abnormalities in coronary flow reserve.[76] Ultimately, differentiation by available techniques is simply not possible in some subjects. MANAGEMENT

The therapeutic options available in children are not fundamentally different from those in adults (see Chap. 48) . Although safety data from small series are available for most of these alternatives, no sufficiently large studies have independently addressed efficacy in infants or children. Chest pain and dyspnea are often relieved by propranolol, but improved exercise capacity is seen less often, and side effects such as fatigue and depression are often encountered. Calcium channel blockers can also reduce dyspnea and chest pain, and an increase in exercise capacity usually occurs. Although older patients with congestive heart failure can be intolerant of these drugs, pediatric tolerance has been excellent, even in neonates.[73] While several retrospective studies report a reduced risk of sudden death,[73] [77] [78] definitive controlled trials to support this finding are not available. Each of the several interventions used to reduce outflow obstruction in adults with familial HCM and subaortic stenosis (surgery, asynchronous pacing, and septal ablation) are also available to children, but additional technical considerations affect the risk-benefit ratio. Often, clinicians attach too much significance to the presence or absence of outflow obstruction, as discussed by Criley.[79] Outflow obstruction is present in less than half of patients with familial HCM and is not predictive of outcome, with symptomatic patients without obstruction faring more poorly than those who have gradients. The magnitude of outflow obstruction is unrelated to the occurrence of ventricular tachycardia or risk of sudden death. Surgical or pharmacological reduction in the outflow gradient in symptomatic patients is usually associated with a reduction in symptoms, although the incidence of sudden death is not improved. In general, dynamic outflow obstruction is not a negative prognostic factor, and interventions aimed at reducing the gradient are justified only inasmuch as symptomatic benefit can be anticipated. SEPTAL MYOTOMY-MYECTOMY.

In symptomatic HCM with subaortic stenosis, this procedure results in symptomatic improvement in nearly all patients despite the fact that symptoms are generally not correlated with the presence and degree of obstruction. Results in children have been similar to those reported in adults.[80] Although occasional studies have reported improved survival, most have documented no change. Consequently, surgery should be considered for relief of symptoms in patients with intractable and debilitating symptoms in spite of maximum medical therapy. Intervention based on gradient alone cannot be recommended. ASYNCHRONOUS VENTRICULAR PACING.

This technique has emerged as an effective method of symptomatic treatment in some patients with left ventricular outflow tract obstruction.[81] Studies in small cohorts of

children with outflow obstruction who were symptomatic despite medical therapy have reported symptomatic improvement, reduced outflow obstruction, and improved exercise tolerance.[82] [83] Controlled studies in adults found that only about 60 percent of patients improved, in two-thirds of these the benefit appeared to reflect a placebo effect, and an adverse effect on symptoms was seen in 5 percent. [84] Pacemaker implantation is associated with a significant incidence of complications,[85] particularly in growing children. Based on current information, dual-chamber pacing can be considered as an alternative to surgical or transcatheter septal reduction in patients with obstructive HCM who are symptomatic despite maximum medical therapy. EXERCISE RESTRICTION.

Avoidance of strenuous exercise is generally recommended for patients with familial HCM. The rationale for this restriction is based on the observations that sudden death is the usual cause of death in familial HCM and has a higher than expected association with exercise,[86] and that familial HCM is believed to be the most common cause of sudden death in young, competitive athletes.[87] Nevertheless, the basis for this recommendation has several serious weaknesses.[88] The true incidence of familial HCM in athletes who experience sudden death is uncertain since genetic confirmation was not available and diagnosis was based on morphological criteria that cannot unequivocally differentiate familial HCM from physiological hypertrophy. It is clear that some patients with familial HCM tolerate intense, competitive athletic participation without symptoms or sudden death.[89] Population studies have documented the

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Figure 45-3 Survival in infants with hypertrophic cardiomyopathy. Maron (1982): Maron BJ, Tajik AJ, Ruttenberg HD, et al: Hypertrophic cardiomyopathy in infants: Clinical features and natural history. Circulation 65:7, 1982; Moran (1998): Moran AM, Colan SD: Verapamil therapy in infants with hypertrophic cardiomyopathy. Cardiol Young 8:310, 1998.

apparent paradox that although patients with coronary artery disease who regularly participate in low- and high-level exertion have a transient increase in the risk for sudden death during intense exercise, these individuals experience an overall reduction in the risk for sudden death (see Chap. 26) .[90] In addition, patients who do not exercise regularly have an exaggerated risk of sudden death during exercise. Studies have not been conducted to determine whether athletic participation increases the overall risk for sudden death; it has not been shown that survival is improved in those who do not exercise, nor is the level of exercise that represents a safe limit known. Detraining and social stigmatization are particularly difficult problems for an adolescent who is excluded from the usual school activities and peer interactions. Competitive team sports elicit an emotional overlay that appears to increase the risk associated with the sport itself, in addition to demanding more intense exercise. Certain activities such as weightlifting are associated with high levels of circulating catecholamines that can predispose to arrhythmias and elicit a marked stimulus to eccentric cardiac hypertrophy. However,

little evidence indicates that moderate aerobic-type exercise is a significant risk in these patients, and it does provide measurable hemodynamic and psychological benefits. RISK STRATIFICATION.

Many prognostic factors for sudden death have been reported, but few have been confirmed. It is likely that the availability of genotyping will permit genetic risk stratification (see Fig. 48-11) (Figure Not Available) , but at present, four major risk factors have been identified: a family history of sudden death, exercise-induced hypotension, syncope, and symptomatic nonsustained ventricular tachycardia on Holter recording. Patients free of all risk factors are considered to be at low risk, and interventions (other than for symptoms such as chest pain or exercise intolerance) are not indicated. With two or more risk factors or with syncope alone in children, risk is considered high and aggressive management such as with an implantable cardioverter-fibrillator is recommended (see Chaps. 23 , 24 , and 25 ). No consensus has been reached on management of intermediate-risk patients. Additional negative prognostic factors such as evidence of ischemia on exercise thallium testing, marked QT dispersion, and myocardial bridging can also be useful in management decisions for these patients.[91] CLINICAL COURSE.

The clinical course of familial HCM is highly age dependent. HCM in infancy appears to carry a worse prognosis than in older age groups. Symptomatic infants generally manifest congestive heart failure and cyanosis and have been reported to have a particularly poor

Figure 45-4 Survival in children with hypertrophic cardiomyopathy. Maron (1976): Maron BJ, Henry WL, Clark CE, et al: Asymmetric septal hypertrophy in childhood. Circulation 53:9, 1976; McKenna (1984): McKenna WJ, Deanfield JE: Hypertrophic cardiomyopathy: An important cause of sudden death. Arch Dis Child 59:971, 1984; Yetman (1998): Yetman AT, Hamilton RM, Benson LN, et al: Long-term outcome and prognostic determinants in children with hypertrophic cardiomyopathy. J Am Coll Cardiol 32:1943, 1998.

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outlook, with 9 of 11 dying within the first 5 years in one series [92] and 10 of 19 dying in the first year of life in another.[93] However, some series have noted survival not dissimilar to that in older children, with reported survival rates of 100 percent at 6 years[94] and 85 percent at 12 years, [73] probably representing differences related to small series and the numerous etiologies of HCM in this age group. The reported survival in several series of HCM in infants (Fig. 45-3) and older children (Fig. 45-4) illustrate the diversity of results in these several series. Ventricular hypertrophy can develop during childhood or adolescence, and ECG abnormalities can precede its appearance, but new appearance in a previously normal adult has not been described. The severity of hypertrophy can progress during periods of accelerated somatic growth,

particularly during adolescence,[95] whereas in adults, progression does not appear to be a feature of the disease. Importantly, the increase in magnitude of hypertrophy that is sometimes seen does not have prognostic importance and does not justify an alteration in management.[96] Regression of hypertrophy is not generally considered a characteristic of the disease, although it has occasionally been reported in children.[97] Systolic function is nearly always normal or hyperdynamic and generally does not change over time unless transition to a thin-walled congestive cardiomyopathy occurs, a transformation rarely observed during childhood[97] and invariably associated with a grim prognosis. In patients with obstruction, the pressure gradient is also generally stable in adult subjects, although progression does occur in children and adolescents.[98] Sudden death in patients referred to tertiary care centers is seen annually in 3 to 5 percent of adults and 6 to 8 percent of children.[99] Recent population studies indicate a much lower annual mortality (0.1 to 1 percent), which indicates a major referral bias in these statistics.[100] Asymptomatic adults appear to be at even lower risk,[101] although a similar relationship to symptoms has not been demonstrated in children. While improved survival has been reported with medical and surgical interventions, the studies are invariably retrospective and usually rely on historical controls. Definitive evidence of improved survival with any available therapy has not yet appeared. Restrictive Cardiomyopathy (see also Chap. 48)

Restrictive cardiomyopathy is the least common form of cardiomyopathy and is quite rare among children. With the exception of occasional case reports, only four series in children with a total of 36 patients (8 patients in each of three studies[102] [103] [104] and 12 in the other[105] ) have appeared. Clinical characteristics have been similar to those in adults, with a pattern of normal ventricular size and function, severe elevation in diastolic filling pressure, and marked atrial dilation. Numerous secondary causes of restrictive cardiomyopathy have been described in adults, but the pediatric cases have been uniformly idiopathic despite tissue analysis in nearly all, although several cases were familial. Differentiation from many of the secondary causes, such as myocardial noncompaction (persistence of embryonic or "spongy" myocardium[106] ), can be made on morphological criteria. Tissue analysis is generally undertaken given the dismal prognosis of the disease and the desire to exclude any potentially treatable disorder. Methods of differentiation between restrictive cardiomyopathy and constrictive pericarditis have not been specifically investigated in children, primarily because constrictive pericarditis is virtually never encountered in children. The most striking characteristic of the reports in children has been the uniformly poor prognosis, with a 1-year survival rate of approximately 50 percent in all four series. Survival therefore appears to be even more limited than has been described in adults. Anticoagulation is recommended because a 25 percent incidence of thromboembolism has been seen in children. Therapy is otherwise nonspecific and usually of very limited benefit. The onset of irreversible elevation in pulmonary vascular resistance can occur within 1 to 4 years in these patients, and early cardiac transplantation is therefore recommended to avoid the need for heart and lung transplantation. [105] KAWASAKI DISEASE

Kawasaki disease is an acute vasculitis of unknown etiology that occurs predominantly in infants and young children. Kawasaki first described the illness in Japanese in l967,[107] but the entity is now recognized in both endemic and community-wide epidemic forms in children of all races throughout the world. Features of Kawasaki disease include fever, bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, changes in the extremities, rash, and cervical lymphadenopathy. Coronary artery aneurysms or ectasia develop in approximately 15 to 25 percent of untreated children with the disease and may lead to myocardial infarction, sudden death, or chronic coronary artery insufficiency.[108] In the United States, acquired heart disease in children is now caused more commonly by Kawasaki disease than by acute rheumatic fever (see Chap. 66) .[109] The cause of Kawasaki disease remains unknown. Clinical Features

The clinical criteria put forth in Kawasaki's first English language description of the disease are still in use today.[107] A child with Kawasaki disease must have fever lasting 5 or more days without another reasonable explanation and satisfy at least four of the following criteria: (1) bilateral, nonexudative conjunctival injection; (2) at least one of the following: mucous membrane changes, injected or fissured lips, injected pharynx, or "strawberry tongue"; (3) at least one of the following extremity changes: erythema of the palms or soles, edema of the hands or feet, or periungual desquamation; (4) polymorphous exanthem; and (5) acute nonsuppurative cervical lymphadenopathy (at least one node 1.5 cm or larger in diameter). An additional category of "atypical Kawasaki disease" includes patients with only four criteria and coronary artery abnormalities by echocardiography.[110] None of the clinical features of Kawasaki disease is pathognomonic. For this reason, the diagnosis of Kawasaki disease requires exclusion of other illnesses that might mimic its clinical features, including streptococcal and staphylococcal toxin-mediated illness; infection with adenovirus, enterovirus, and measles; and systemic allergic reactions to various medications. Many symptoms and signs apart from the diagnostic criteria are frequently present in children with Kawasaki disease and include arthralgias, arthritis, urethritis, aseptic meningitis, diarrhea, vomiting, and abdominal pain. The conventional diagnostic criteria should be viewed as guidelines; they are especially useful in preventing overdiagnosis but may result in failure to recognize incomplete forms of illness. Signs and symptoms of Kawasaki disease may be particularly subtle or absent in infants younger than 6 months, a subgroup at high risk for coronary lesions. The frequent occurrence of coronary artery involvement among children with incomplete criteria suggests that echocardiography should be performed in all children with prolonged, unexplained fever and some signs of Kawasaki disease. Cardiac Findings

CORONARY ARTERY ABNORMALITIES.

Coronary artery ectasia or aneurysms occur in 15 to 25 percent of children

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with Kawasaki disease who do not receive treatment with intravenous gamma globulin (IVIG) in the acute phase.[111] [112] Dilatation of coronary arteries (Japanese Ministry of Health criteria)[113] may be detected by echocardiography beginning 7 days after the first appearance of fever, with the coronary diameter usually peaking around 4 weeks after illness onset. In general, clinical and laboratory indices of greater inflammation are associated with a higher likelihood of aneurysm development. MYOCARDITIS.

Myocarditis has been demonstrated in autopsy and myocardial biopsy studies to be a universal feature of early Kawasaki disease. With high-dose IVIG treatment, myocardial function improves rapidly, i.e., within days, in patients with acute Kawasaki disease.[114] When myocardial dysfunction occurs after the acute phase of the disease, it is usually secondary to ischemia or infarction, with or without mitral regurgitation. With the use of endomyocardial biopsy, myocardial abnormalities have been detected in all time periods after disease onset; their severity was unrelated to the presence of coronary artery abnormalities. In addition, electron microscopic examination of endomyocardial biopsy specimens has demonstrated histological abnormalities late after Kawasaki disease.[115] Assessment of the full impact of Kawasaki disease on heart function and structure must await the follow-up of these children into later adult life. VALVAR REGURGITATION.

Mitral regurgitation may result from transient papillary muscle dysfunction, myocardial infarction, or valvulitis. Kato and colleagues reported mitral regurgitation in 1.0 percent of patients in their series.[116] The appearance of mitral regurgitation after the acute stage is usually secondary to myocardial ischemia, although late-onset valvulitis unrelated to ischemia has been documented. Aortic regurgitation has been documented angiographically by Nakano and colleagues in approximately 5 percent of children with Kawasaki disease and was attributed to valvulitis.[117] Others have observed a much lower incidence of aortic regurgitation in the acute phase.[116] Late-onset aortic regurgitation has been reported as a rare finding after Kawasaki disease and may be associated with the need for aortic valve replacement. Laboratory Data

GENERAL TESTS.

Laboratory findings in acute Kawasaki disease reflect the marked degree of systemic inflammation. Common initial findings include anemia, leukocytosis with a left shift, elevation of acute phase reactants, and mild elevation of liver transaminase levels. Thrombocytosis usually peaks in the third to fourth week after the onset of fever. Urinalysis may reveal the presence of white cells on microscopic examination. Since the white cells are mononuclear rather than polymorphonuclear, the dipstick test for nonspecific esterase activity (i.e., neutrophil enzyme) is usually negative. Examination of cerebrospinal fluid reveals a mild mononuclear cell pleocytosis with normal glucose and normal to mildly elevated protein.[118] ELECTROCARDIOGRAPHY.

The ECG in acute Kawasaki disease may show mild abnormalities consistent with myocarditis, most commonly a prolonged PR interval and nonspecific ST and T wave changes. TWO-DIMENSIONAL ECHOCARDIOGRAPHY.

Two-dimensional echocardiography has high sensitivity and specificity for proximal vessels of the right and left coronary arterial trees (see Chap. 7) . The initial echocardiogram should be obtained as soon as the diagnosis of Kawasaki disease is suspected.[110] Longitudinal echocardiographic follow-up should begin 10 to 14 days after the onset of illness, when early coronary dilation will first be noticed in the majority of children in whom aneurysms are destined to develop. In the absence of significant coronary dilation, cardiac ultrasound may be repeated approximately 6 to 8 weeks after illness onset. Follow-up of patients with coronary dilation should be adapted to their clinical course and the severity of their lesions. Echocardiographers often find it difficult to reach an agreement on the exact configuration and extent of any given coronary artery lesion as seen by two-dimensional echocardiography. In 1984, the Japanese Ministry of Health established criteria for coronary artery abnormalities in Kawasaki disease.[113] These criteria classify coronary arteries as abnormal if the internal lumen diameter is greater than 3 mm in children younger than 5 years or greater than 4 mm in children at least 5 years of age, if the internal diameter of a segment measures at least 1.5 times that of an adjacent segment, or if the coronary artery lumen is clearly irregular. Current statistics on the prevalence of coronary dilation secondary to Kawasaki disease are based on these criteria. Recently, de Zorzi and colleagues showed, in patients with Kawasaki disease whose coronary arteries are classified as "normal" by Japanese Ministry of Health criteria, that body surface area-adjusted coronary dimensions are larger than expected in the acute, convalescent, and late phases.[119] Thus, the Japanese Ministry of Health criteria may underestimate the true prevalence of coronary dilation following Kawasaki disease. Figure 45-5 A to C depicts normal left main, left anterior descending, and right coronary artery size, respectively, according to body surface area.

CORONARY ARTERIOGRAPHY.

Selective coronary arteriography can provide definitive delineation of coronary artery anatomy. This technique is especially useful for visualization of coronary artery stenoses or distal coronary artery lesions that are difficult to define by two-dimensional echocardiography. Based on the coronary artery classification system used in the Coronary Artery Surgery Study,[120] Takahashi and colleagues defined coronary artery aneurysms imaged at angiography as either localized or extensive.[121] Localized aneurysms, i.e., confined to one arterial segment, are further classified as either fusiform (spindle shaped) or saccular (showing abrupt transition from the normal to the dilated state, e.g., spherical, dumbbell shaped, triangular, or sack-like). Extensive aneurysms involve more than one segment and may be either ectatic (uniformly dilated) or segmented (having multiple dilated segments joined by normal or stenotic segments). Coronary aneurysms in early Kawasaki disease usually occur in the proximal segments of the major coronary vessels; aneurysms that occur distally are almost always associated with proximal coronary abnormalities. Aneurysms can also occur in arteries outside the coronary system, most commonly the subclavian, brachial, axillary, iliac, or femoral vessels and occasionally the abdominal aortic and renal arteries.[112] For this reason, abdominal aortography and subclavian arteriography are often performed in patients undergoing coronary arteriography for Kawasaki disease. Treatment

ASPIRIN.

Aspirin has been a standard therapy for Kawasaki disease because of its antiinflammatory and antithrombotic effects, but it does not reduce the prevalence of coronary artery aneurysms.[122] Therapy with aspirin is usually initiated at the time of initial assessment in a dose of 80 to 100 mg/kg/day divided into four doses. Once fever has resolved, the dose is lowered to an antiplatelet regimen of 3 to 5 mg/kg/day orally for up to 6 to 8 weeks. For children in whom coronary aneurysms develop, aspirin (with or without anticoagulation or other antiplatelet agents) may be continued indefinitely. INTRAVENOUS GAMMA GLOBULIN THERAPY.

Although its exact mechanism of action remains unknown, IVIG administered in the acute phase of Kawasaki disease reduces the prevalence of coronary artery abnormalities.[122] [123] Patients should be treated with IVIG 2 gm/kg in a single

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Figure 45-5 Mean and 95% prediction limits for size of the left main coronary artery (A), left anterior descending coronary artery (B), and proximal right coronary artery (C) according to body surface area for children younger than 18 years, as derived from 152 normal children at Children's Hospital, Boston.

infusion, together with aspirin.[110] Ideally, this therapy should be instituted within the first 10 days of illness (optimally by day 7 of illness), but it should be administered after the 10th day of illness to any child with persistent fever[124] or with aneurysms and ongoing signs of inflammation. Even when treated with high-dose IVIG regimens within the first 10 days of illness, however, approximately 5 percent of children with Kawasaki disease experience at least transient coronary artery dilation, and giant aneurysms develop in 1 percent.[125] Most experts recommend retreatment with IVIG 2 gm/kg in patients with persistent or recrudescent fever 48 to 72 hours after initial therapy. CORTICOSTEROIDS.

The subgroup of patients with Kawasaki disease resistant to IVIG therapy is at greatest risk for the development of coronary artery aneurysms and long-term sequelae of the disease.[126] [127] Although one early study showed a detrimental effect of steroid use in Kawasaki disease,[128] others have suggested that steroids may be beneficial in the prevention of coronary artery aneurysms.[129] [130] Further studies are needed to assess the risks and benefits of steroid administration in Kawasaki disease. OTHER THERAPIES DURING THE ACUTE PHASE.

High-dose pentoxifylline, a vasodilator and inhibitor of platelet aggregation and neutrophil activation, has been shown in one study to reduce the incidence of coronary artery aneurysms.[131] Case reports suggest that plasmapheresis may produce dramatic improvement in severe Kawasaki disease[132] ; however, it is a technically complex intervention in young children and should be reserved for those who remain desperately ill despite multiple doses of IVIG and intravenous methylprednisolone. ANTITHROMBOTIC THERAPY.

Paradoxically, the risk of coronary artery thrombosis is greatest after the acute phase subsides, when well-established coronary vasculitis occurs concomitantly with marked elevation of the platelet count and a hypercoagulable state. As above, low-dose aspirin (3 to 5 mg/kg/day given as a single dose) is the mainstay of antithrombotic therapy in Kawasaki disease. Other antiplatelet agents, such as clopidogrel or dipyridamole, may be substituted for aspirin when salicylates are contraindicated. For children without evidence of coronary artery ectasia or aneurysms, antiplatelet therapy is usually discontinued approximately 2 months after illness onset.

Children with coronary artery abnormalities require long-term antithrombotic therapy, usually with low-dose aspirin. The risk of coronary thrombosis and myocardial infarction is especially great in children with rapidly increasing coronary dimensions or with giant aneurysms during the subacute phase.[133] [134] During this period, some investigators advocate treatment with systemic heparin, together with an antiplatelet agent. For chronic antithrombotic therapy, therapeutic options include antiplatelet therapy with aspirin, with or without dipyridamole or another inhibitor of antiplatelet aggregation; anticoagulant therapy with warfarin; or a combination of anticoagulant and antiplatelet therapy, usually warfarin plus aspirin. No prospective data

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exist to guide the clinician in choosing the optimal regimen. The most common regimen for patients with giant aneurysms is low-dose aspirin together with warfarin, with the international normalized ratio maintained at 2.0:2.5. Some physicians substitute low-molecular-weight heparin for warfarin, although this therapy requires subcutaneous injections twice daily. THROMBOLYTIC THERAPY.

Despite the use of antithrombotic agents, myocardial infarction secondary to thrombotic occlusion of coronary aneurysms can develop in some children, especially those with giant aneurysms. Sometimes, coronary artery thrombus can be detected in asymptomatic patients by two-dimensional echocardiography. Because no large trials of thrombolytic therapy have been performed in children, the choice of thrombolytic agent for the treatment of infants and children with coronary thrombosis is derived from studies in adults with coronary thrombosis. Although effective in adults, the use of immediate coronary angioplasty has not been reported in children with Kawasaki disease and coronary artery thrombosis. SURGICAL MANAGEMENT.

Surgical management in Kawasaki disease consists primarily of coronary artery bypass grafts for obstructive lesions.[134A] However, indications for coronary bypass graft procedures in children have not been established. Such surgery should be considered when reversible ischemia is present on stress-imaging tests, the myocardium to be perfused through the graft is still viable, and no appreciable lesions are present in the artery peripheral to the planned graft site. The earliest coronary artery bypass operations in children with Kawasaki disease were performed with autologous saphenous veins or veins obtained from parents. However, the late results with this technique have been relatively unsatisfactory, especially in very young children. Kitamura and coworkers reported improved results with the use of internal mammary artery grafts in pediatric patients. [135] The diameter and length of internal mammary grafts increase with the general somatic growth of the child, as

opposed to the tendency of saphenous vein grafts to shorten somewhat over time. In children younger than 7 years, the arterial graft patency rate 90 months after surgery was 70 percent. Children who were older than 8 years at the time of coronary arterial grafting appeared to have even better long-term patency than seen in younger children; by 90 months after surgery, the arterial graft patency rate was 84 percent. Of note, 8 years after internal mammary artery grafting to the left anterior descending coronary artery, 98.7 percent of patients in the series of Kitamura and colleagues were still alive. INTERVENTIONAL CARDIAC CATHETERIZATION TECHNIQUES.

Although results over the first decade after surgery are encouraging, graft patency in later adult life after coronary artery bypass grafting in childhood is still unknown. When it is preferable to delay the time until surgery, percutaneous transluminal coronary angioplasty (PTCA) may be performed in the stenotic coronary arteries of children with Kawasaki disease[136] [137] (Fig. 45-6) . PTCA is not as effective in patients with Kawasaki disease as in adults with atherosclerotic coronary artery disease because the stenotic lesions in long-term Kawasaki disease are very stiff and often associated with marked calcifications, especially many years after illness onset. The relatively high balloon pressures necessary under these circumstances can lead to late aneurysm formation.[137] Intravascular ultrasound imaging has been found to be a useful tool for evaluating internal morphology before and after PTCA.[136] Once calcification and stenosis have become severe, rotational ablation techniques may be necessary for the success of coronary angioplasty. CARDIAC TRANSPLANTATION.

Cardiac transplantation has been performed in a small number of patients with severe ischemic heart disease resulting from Kawasaki disease.[138]

Figure 45-6 Left coronary arteriograms. A, Localized stenosis can be seen at a site just proximal to the aneurysm of the left anterior descending artery. B, The stenosis was dilated by conventional percutaneous transluminal coronary angioplasty (PTCA). C, Follow-up angiography performed 13 months after the initial PTCA revealed no significant restenoses. Pre=pre-PTCA; POST=post-PTCA. (From Ino T, Akimoto K, Ohkubo M, et al: Application of percutaneous transluminal angioplasty to coronary arterial stenosis in Kawasaki disease. Circulation 93:1711, 1996. By permission of the American Heart Association, Inc.)

This procedure should be considered only for individuals with severe, irreversible myocardial dysfunction and coronary lesions for which interventional catheterization procedures or coronary artery bypass is not feasible. Clinical Course

REGRESSION AND EVOLUTION OF CORONARY LESIONS.

Coronary artery lesions resulting from Kawasaki disease change dynamically with time.

Angiographic resolution 1 to 2 years after disease onset has been observed in approximately half to two-thirds of vessels with coronary aneurysms.[121] [139] The likelihood of resolution of the aneurysm appears to be determined in large measure by the initial

1634

size of the aneurysm, with smaller aneurysms having a greater likelihood of regression.[133] Takahashi and coauthors reported other factors positively associated with regression of aneurysms, including age younger than 1 year, saccular (rather than fusiform) aneurysm morphology, and aneurysm location in a distal coronary segment.[121] Vessels that do not undergo apparent resolution of abnormalities may show persistence of aneurysmal morphology, development of stenosis or occlusion, or abnormal tortuosity. PATIENTS WITH PERSISTENT CORONARY ARTERY ABNORMALITIES.

Whereas aneurysm size tends to diminish over time, stenotic lesions secondary to marked myointimal proliferation are frequently progressive.[112] In the series of Kato and coworkers, stenotic lesions were recognized within 2 years from disease onset in about half of the patients in whom coronary stenoses ultimately developed, but the prevalence of stenosis continued to rise almost linearly over time.[139] Kamiya and colleagues have also reported a steady increase in the presence of coronary artery stenoses with increasing duration since illness onset; the highest rate of progression to stenosis occurred among patients whose aneurysms were large.[140] The worst prognosis occurs in children with so-called giant aneurysms, i.e., those with a maximum diameter greater than 8 mm.[141] In these aneurysms, thrombosis is promoted by sluggish blood flow within the massively dilated vascular space, together with frequent development of stenotic lesions at the proximal or distal end of the aneurysms. Myocardial infarction caused by thrombotic occlusion in an aneurysmal and/or stenotic coronary artery is the principal cause of death in Kawasaki disease.[111] The highest risk of myocardial infarction occurs in the first year after disease onset, and most fatal attacks are associated with obstruction either in the left main coronary artery or in both the right main and left anterior descending coronary arteries.[111] Serial stress tests and myocardial imaging are mandatory in the management of patients with Kawasaki disease and significant coronary artery disease to determine the need for coronary angiography and for surgical or transcatheter intervention. Late cardiac sequelae of Kawasaki disease may first become apparent in adulthood. Burns and associates identified 74 patients in the English and Japanese literature with Kawasaki disease in childhood whose first symptoms of coronary artery disease occurred in young adulthood.[142] A history of a Kawasaki-like illness in childhood should be sought in patients with coronary aneurysms in the absence of generalized atherosclerotic disease. However, adult patients may be unable to recall an illness that

occurred so early in life. PATIENTS WITH SPONTANEOUS REGRESSION OF ANEURYSMS.

Approximately half of vascular segments with coronary artery aneurysms show angiographic regression of the aneurysms. This regression usually occurs by myointimal proliferation, although more rarely the mechanism of regression can be organization and recanalization of a thrombus. Pathological examination reveals fibrous intimal thickening despite normal coronary artery diameter. Similarly, transluminal (intravascular) ultrasound of regressed coronary aneurysms shows marked symmetrical or asymmetrical myointimal thickening.[143] Regressed coronary artery aneurysms not only are histopathologically abnormal but also show reduced vascular reactivity.[144] [144A] KAWASAKI DISEASE WITHOUT DETECTABLE CORONARY LESIONS.

Although coronary artery aneurysms produce the most serious sequelae of Kawasaki disease, vascular inflammation during the acute stage of the illness is diffuse. Generalized endothelial dysfunction has been suggested by the observation that plasma 6-ketoprostaglandin F1 remains generally undetectable over an observation period of 8 weeks after the onset of Kawasaki disease.[145] In addition, Kawasaki disease produces altered lipid metabolism that persists beyond clinical resolution of the disease.[146] Histological data concerning the long-term status of coronary arteries in children who never had demonstrable abnormalities are few and difficult to interpret.[147] Some investigators in Japan have studied coronary physiology in the population without aneurysms. Among children with a history of Kawasaki disease but with normal epicardial coronary arteries, Muzik and colleagues found lower myocardial flow reserve and higher total coronary resistance than in normal controls.[148] Children without a history of coronary aneurysms have also been reported to have abnormal endothelium-dependent brachial artery reactivity.[149] Data are conflicting regarding impairment in long-term endothelium-dependent relaxation of the epicardial coronary arteries among children with Kawasaki disease in whom coronary artery dilation was never detected.[150] [151] From a purely clinical perspective, children without known cardiac sequelae during the first month after diagnosis of Kawasaki disease appear to return to their previous, usually excellent state of health, without signs or symptoms of cardiac impairment.[139] Meaningful knowledge about long-term myocardial function, late-onset valvar regurgitation, and coronary artery status in this population must await their careful surveillance over the coming decades. SYSTEMIC HYPERTENSION Hypertension is well recognized as a major risk factor for cardiovascular disease, including stroke, myocardial infarction, congestive heart failure, and renal failure. Because the precursors of these processes are likely to arise early in life, evaluation and treatment of pediatric hypertension are important. Estimates of significant

hypertension in childhood have ranged from 0.26 to 2.0 percent.[152] The most common causes of hypertension change during childhood, with secondary causes of hypertension predominating in the youngest patients and those in whom systemic hypertension is the most severe. For many years, pediatricians focused solely on identification and treatment of secondary forms of hypertension, such as renal parenchymal disease and renal artery stenosis.[152] With recommendations for routine measurement of blood pressure during well-child visits to the pediatrician, as well as the publication of national norms for blood pressure in children, essential hypertension has been increasingly recognized, especially in adolescents with mild to moderate elevation of blood pressure. Children with higher blood pressure are more likely to have first-degree relatives with histories of hypertension, and the tracking correlation of blood pressure from childhood into young adult life is relatively high. Nonetheless, the sensitivities and predictive values for childhood blood pressure are only modest as a screening test for adult blood pressure.[153] DEFINITION.

The distribution of blood pressure in the normal pediatric population is shown in Tables 45-2 and 45-3 . The National High Blood Pressure Education Program has recommended that blood pressure between the 90th and 95th percentiles be considered high-normal or borderline hypertension. Hypertension is defined as average systolic or diastolic blood pressure greater than or equal to the 95th percentile for sex, age, and height on at least three separate occasions. Thus, elevation of blood pressure must be sustained to establish a diagnosis of hypertension. Ideally, blood pressure should be measured with a standard sphygmomanometer, blood pressure cuff, and stethoscope. Many centers currently use automated oscillometric blood pressure monitoring devices for ease of use and elimination of interobserver variability. In addition, 24-hour ambulatory

1635

TABLE 45-2 -- BLOOD PRESSURE LEVELS FOR THE 90TH AND 95TH PERCENTILES OF BLOOD PRESSURE FOR BOYS AGED 1 TO 17 YEARS BY PERCENTILES OF HEIGHT AGE BLOOD SYSTOLIC BLOOD PRESSURE BY DIASTOLIC BLOOD PRESSURE BY (yr) PRESSURE PERCENTILE OF HEIGHT (mm Hg) PERCENTILE OF HEIGHT (mm Hg) * PERCENTILE 5% 10% 25% 50% 75% 90% 95% 5% 10% 25% 50% 75% 1 2 3

90th

94

95

97

98

100 102 102 50 51

52

53

54

95th

98

99

101 102 104 106 106 55 55

56

57

58

90th

98

99

100 102 104 105 106 55 55

56

57

58

95th

101 102 104 106 108 109 110 59 59

60

61

62

90th

100 101 103 105 107 108 109 59 59

60

61

62

4 5 6 7 8 9 10 11 12 13 14 15 16 17

95th

104 105 107 109 111 112 113 63 63

64

65

66

90th

102 103 105 107 109 110 111 62 62

63

64

65

95th

106 107 109 111 113 114 115 66 67

67

68

69

90th

104 105 106 108 110 112 112 65 65

66

67

68

95th

108 109 110 112 114 115 116 69 70

70

71

72

90th

105 106 108 110 111 113 114 67 68

69

70

70

95th

109 110 112 114 115 117 117 72 72

73

74

75

90th

106 107 109 111 113 114 115 69 70

71

72

72

95th

110 111 113 115 116 118 119 74 74

75

76

77

90th

107 108 110 112 114 115 116 71 71

72

73

74

95th

111 112 114 116 118 119 120 75 76

76

77

78

90th

109 110 112 113 115 117 117 72 73

73

74

75

95th

113 114 116 117 119 121 121 76 77

78

79

80

90th

110 112 113 115 117 118 119 73 74

74

75

76

95th

114 115 117 119 121 122 123 77 78

79

80

80

90th

112 113 115 117 119 120 121 74 74

75

76

77

95th

116 117 119 121 123 124 125 78 79

79

80

81

90th

115 116 117 119 121 123 123 75 75

76

77

78

95th

119 120 121 123 125 126 127 79 79

80

81

82

90th

117 118 120 122 124 125 126 75 76

76

77

78

95th

121 122 124 126 128 129 130 79 80

81

82

83

90th

120 121 123 125 126 128 128 76 76

77

78

79

95th

124 125 127 128 130 132 132 80 81

81

82

83

90th

123 124 125 127 129 131 131 77 77

78

79

80

95th

127 128 129 131 133 134 135 81 82

83

83

84

90th

125 126 128 130 132 133 134 79 79

80

81

82

95th

129 130 132 134 136 137 138 83 83

84

85

86

90th

128 129 131 133 134 136 136 81 81

82

83

84

95th

132 133 135 136 138 140 140 85 85

86

87

88

From National Heart, Lung and Blood Institute: Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents: A working group report from the National High Blood Pressure Education Program. Pediatrics 98:649, 1996. Copyright American Academy of Pediatrics 1996. *Blood pressure percentile was determined by a single measurement. Height percentile was determined by standard growth curves.

blood pressure monitoring has been used when "white coat" hypertension is suspected and for management of known hypertension.[154] [155] [155A] EVALUATION.

Evaluation of an asymptomatic child or adolescent with hypertension should focus on potential etiologies. The family history should be carefully probed for hypertension, premature cardiovascular disease, and renal disease, medical conditions, or drugs. In adolescents, the possibility of substance abuse should always be considered. The physical examination should be directed toward signs of definable causes of hypertension, as well as toward its sequelae. Many adolescents whose blood pressure is at or just greater than the 95th percentile have family histories of hypertension and are overweight, but they have an otherwise negative history and physical examination.[152] For such patients, a work-up that includes urinalysis, urine culture, and electrolyte, serum creatinine (noting that normal values vary according to age), and blood urea nitrogen levels may be sufficient.[156] Such patients would also usually benefit from a lipid profile to exclude other risk factors for premature cardiovascular disease.[152] When children or adolescents with borderline high blood pressure are not obese and have no family history of hypertension, renal Doppler ultrasound provides a first-line screen for renovascular hypertension, parenchymal integrity, and hydronephrosis. For patients in whom blood pressure is well above the 95th percentile, secondary causes of hypertension should be pursued aggressively, with targeting of conditions believed to be most likely on the basis of age (Table 45-4) or targeting of findings on initial assessment. Most children with secondary hypertension (60 to 80 percent) have renal parenchymal disease,[156] commonly reflux nephropathy, pyelonephritis, and obstructive uropathy. Less common renal etiologies include glomerulonephritis, nephrotic syndrome, congenital renal dysplasia, renal damage following hemolytic-uremic syndrome, and polycystic disease.[156] Renal parenchymal disease can be assessed with imaging studies, including renal ultrasonography, voiding cystourethrography, or renal scintiscanning. Renovascular hypertension has been reported in 8 to 10 percent of children with secondary hypertension.[156] [157] In such patients, hypertension may be caused by stenosis of a main renal artery or by segmental renal artery stenoses in one or both kidneys.[156] Methods of evaluation of renovascular hypertension vary in different centers and include renal scanning before and after captopril challenge, intravenous digital subtraction angiography, captopril radionuclide renography, Doppler sonography, computed tomographic angiography, and magnetic resonance angiography. Conventional angiography and intraarterial digital subtraction angiography remain the gold standard for the diagnosis of renovascular hypertension and should be considered for children with severe, persistent hypertension without other findings, greatly elevated

plasma renin activity, a bruit, or a solitary kidney and severe hypertension. [156]

1636

TABLE 45-3 -- BLOOD PRESSURE LEVELS FOR THE 90TH AND 95TH PERCENTILES OF BLOOD PRESSURE FOR BOYS AGED 1 TO 17 YEARS BY PERCENTILES OF HEIGHT AGE BLOOD SYSTOLIC BLOOD PRESSURE BY DIASTOLIC BLOOD PRESSURE BY (yr) PRESSURE PERCENTILE OF HEIGHT (mm Hg) PERCENTILE OF HEIGHT (mm Hg) * PERCENTILE 5% 10% 25% 50% 75% 90% 95% 5% 10% 25% 50% 75% 1 2 3 4 5 6 7 8 9 10 11 12

90th

97

98

100 102 103 104 53 53

53

54

55

95th

101 102 103 104 105 107 107 57 57

57

58

59

90th

99

100 102 103 104 105 57 57

58

58

59

95th

102 103 104 105 107 108 109 61 61

62

62

63

90th

100 100 102 103 104 105 106 61 61

61

62

63

95th

104 104 105 107 108 109 110 65 65

65

66

67

90th

101 102 103 104 106 107 108 63 63

64

65

65

95th

105 106 107 108 109 111 111 67 67

68

69

69

90th

103 103 104 106 107 108 109 65 66

66

67

68

95th

107 107 108 110 111 112 113 69 70

70

71

72

90th

104 105 106 107 109 110 111 67 67

68

69

69

95th

108 109 110 111 112 114 114 71 71

72

73

73

90th

106 107 108 109 110 112 112 69 69

69

70

71

95th

110 110 112 113 114 115 116 73 73

73

74

75

90th

108 109 110 111 112 113 114 70 70

71

71

72

95th

112 112 113 115 116 117 118 74 74

75

75

76

90th

110 110 112 113 114 115 116 71 72

72

73

74

95th

114 114 115 117 118 119 120 75 76

76

77

78

90th

112 112 114 115 116 117 118 73 73

73

74

75

95th

116 116 117 119 120 121 122 77 77

77

78

79

90th

114 114 116 117 118 119 120 74 74

75

75

76

95th

118 118 119 121 122 123 124 78 78

79

79

80

90th

116 116 118 119 120 121 122 75 75

76

76

77

95th

120 120 121 123 124 125 126 79 79

80

80

81

99

99

13 14 15 16 17

90th

118 118 119 121 122 123 124 76 76

77

78

78

95th

121 122 123 125 126 127 128 80 80

81

82

82

90th

119 120 121 122 124 125 126 77 77

78

79

79

95th

123 124 125 126 128 129 130 81 81

82

83

83

90th

121 121 122 124 125 126 127 78 78

79

79

80

95th

124 125 126 128 129 130 131 82 82

83

83

84

90th

122 122 123 125 126 127 128 79 79

79

80

81

95th

125 126 127 128 130 131 132 83 83

83

84

85

90th

122 123 124 125 126 128 128 79 79

79

80

81

95th

126 126 127 129 130 131 132 83 83

83

84

85

From National Heart, Lung and Blood Institute: Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents: A working group report from the National High Blood Pressure Education Program. Pediatrics 98:649, 1996. Copyright American Academy of Pediatrics 1996. *Blood pressure percentile was determined by a single reading. Height percentile was determined by standard growth curves.

Coarctation of the aorta (see Chap. 43) , a common cause of hypertension in the first year of life, is present in one-third of infants with hypertension but accounts for only 2 percent of cases of secondary hypertension in childhood and adolescence.[156] This cause of hypertension is easily detected on physical examination by careful measurement of upper and lower extremity blood pressures, together with palpation of radial and femoral pulses. Since 80 percent of patients with coarctation have an associated bicuspid aortic valve, physical examination often includes a constant early systolic ejection click at the apex and base. A soft early to midsystolic ejection murmur is frequently heard over the left lateral aspect of the chest, and older children with collateral circulation may have continuous murmurs over the back. The diagnosis of coarctation of the aorta may be confirmed by two-dimensional echocardiography or, in an older child or adolescent, by magnetic resonance imaging (MRI). After the coarctation is repaired, a residual gradient may either remain or recur, sometimes necessitating late procedures such as balloon dilation or stenting of the aorta. Some patients require chronic antihypertensive medication after adequate repair of coarctation. More rarely, hypertension can be caused by endocrine disorders.[158] Pheochromocytoma alone causes approximately 0.5 to 2.0 percent of cases of secondary hypertension in children.[159] Most children with pheochromocytoma (88 percent) have sustained rather than episodic hypertension, and many have extraadrenal or multiple tumors (31 and 32 percent, respectively).[156] Elevation of urinary catecholamine levels in a 24-hour urine collection or elevation of plasma

catecholamines points to a diagnosis of pheochromocytoma (or other types of neural crest tumor). Definitive diagnosis is made with MRI (T2 weighted or gadolinium-labeled diethylenetriaminepentaacetic acid [DTPA] enhanced) or with meta-iodobenzylguaninine (MIBG) scanning.[156] [160] [161] Pheochromocytomas are removed surgically, after the hypertension is controlled.[159] [162] [163] Other endocrine causes of secondary hypertension (e.g., excess glucocorticoids or mineralocorticoids, hyperthyroidism) may be pursued if the history, physical examination, or screening tests are suggestive. Hypertension may rarely be associated with abnormalities of the central nervous system (CNS). These abnormalities may be primary (e.g., brain tumors, familial dysautonomia) or secondary (e.g., hypercalcemia or lead poisoning). Because hypertension of CNS origin may have a fulminant manifestation, CNS-mediated causes of hypertension should always be considered by the clinician.[156] [164] MANAGEMENT.

All children with blood pressure consistently above the 90th percentile should be introduced to nonpharmacological therapies, including a diet rich in fruits, vegetables, and low-fat dairy products, reduced intake

1637

TABLE 45-4 -- MOST COMMON CAUSES OF SECONDARY HYPERTENSION, BY AGE AGE GROUP CAUSE Newborn

Renal artery or venous thrombosis Renal artery stenosis Congenital renal abnormalities Coarctation of the aorta Bronchopulmonary dysplasia

First year

Coarctation of the aorta Renovascular disease Renal parenchymal disease Iatrogenic (medication, volume) Tumor

Infancy to 6 yr

Renal parenchymal disease Renovascular disease Coarctation of the aorta Endocrine causes* Iatrogenic* Essential hypertension*

Age 6-10 yr

Renal parenchymal disease Renovascular disease Essential hypertension Coarctation of the aorta Endocrine causes* Iatrogenic*

Age 12-18 yr

Essential hypertension Iatrogenic Renal parenchymal disease* Endocrine causes* Coarctation of the aorta*

From Swinford RD, Ingelfinger JR: Evaluation of hypertension in childhood diseases. In Barratt TM, Avner ED, Harmon WD (eds): Pediatric Nephrology. 4th ed. Baltimore, Lippincott Williams & Wilkins, 1999, p 1007. *Uncommon for category.

of saturated fat, [165] and for obese children, weight modification. Children and their families should also be counseled regarding the benefits of aerobic physical activity and the hazards of smoking.[152] Treatment with medications should be instituted for patients with severe hypertension or evidence of end-organ damage (e.g., increased left ventricular mass by two-dimensional echocardiography). In addition, pharmacological treatment of hypertension should be guided by the presence of other cardiovascular risk factors (e.g., childhood diabetes, chronic renal disease). When drugs are prescribed for children and adolescents with hypertension, the goal is to reduce blood pressure to below the 95th percentile for age, gender, and height. [152] Drug therapy should aim at prescribing the simplest regimen with the fewest adverse side effects. All antihypertensive medications should be individualized to the patient's medical history (including the etiology of the hypertension), severity of hypertension, response to therapy, and occurrence of side effects.[152] Thiazide diuretics and beta blockers have been used for years in children and adolescents and continue to have a role in the treatment of hypertension. Since publication of the Report of the Second Task Force on Blood Pressure Control in Children in 1987,[166] newer antihypertensive agents have come into common use in pediatric patients. These medications include ACE inhibitors and calcium channel blockers.[167] Use of the other classes of antihypertensive agents (e.g., central alpha-adrenergic agonists, alpha-adrenergic blocking drugs, direct vasodilators) is only rarely indicated in pediatric cardiology practice. Long-term clinical trials have not examined the benefits and risks of antihypertensive therapy in children and adolescents. Until such data are available, when choosing the optimal antihypertensive medication, physicians should draw on the adult experience. HYPERLIPIDEMIAS (see also Chaps. 30 , 31 , 32 , and 33 )

Abnormalities in plasma lipoproteins are an important cause of premature coronary artery disease. Because epidemiological and pathological observations have introduced the concept that the process of atherosclerosis begins early in life and progresses to cardiovascular morbidity and mortality in later life, efforts to prevent clinical disease have centered around the modification of plasma lipid concentrations in childhood and adolescence.[168] RATIONALE FOR LIPID MODIFICATION IN CHILDHOOD.

The rationale for modification of cholesterol in childhood is based on postmortem and epidemiological data. In 1953, Enos and colleagues first reported that postmortem examination showed advanced lesions in the coronary arteries of young American soldiers killed in the Korean war.[169] The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Study, a multiinstitutional study of atherosclerosis in 15- to 34-year-old males and females, demonstrated that the conditions predicting risk of coronary heart disease in adults are also associated with the extent and severity of atherosclerosis in youth.[170] Recently, this group reported on the ubiquity of fatty streaks in the abdominal aortas and the frequency of fibrous plaques in the aortas and coronary arteries in the 15- to 19-year-old age group. [171] Other autopsy studies have shown that antemortem low-density lipoprotein (LDL) and total cholesterol are highly associated with aortic fatty streaks in subjects aged 7 to 24 years.[172] Recently, Berenson and associates reported that serum concentrations of total cholesterol, triglycerides, LDL cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were strongly associated with the extent of lesions in the aorta and coronary arteries at autopsy in young persons who died of various causes, principally trauma.[173] Among these subjects, greater numbers of cardiovascular risk factors were directly associated with increased severity of asymptomatic coronary and aortic atherosclerosis.[173] Epidemiological investigations in children across and within different populations have provided further evidence of the importance of cholesterol in pediatrics. In cross-population studies, children from countries with a high incidence of coronary artery disease in adults have higher cholesterol levels than do children from countries where adults have a low incidence of coronary artery disease. Within populations, elevated levels of total cholesterol and LDL-C in children have been associated with coronary artery disease in their adult relatives. In a study of the progeny of individuals with premature coronary artery disease, half had abnormal lipid profiles.[174] The importance of monitoring lipid levels in childhood is further supported by evidence that children and adolescents with severe dyslipidemia are more likely than the general population to have abnormal lipid profiles as they grow older. Furthermore, long-term prospective studies have shown a strong association between cholesterol levels in young adult life and later risk of cardiovascular disease.[175] SCREENING FOR DYSLIPIDEMIAS.

The distribution of fasting lipid and lipoprotein levels in children and adolescents is

displayed in Table 45-5 . The value of selective versus universal screening strategies for hyperlipidemia in childhood has been controversial. The National Cholesterol Education Program (NCEP) has advocated a selective screening strategy in which high-risk children older than 2 years are targeted for cholesterol screening.[176] High-risk children are defined as those whose parents or grandparents, at 55 years of age or younger, underwent diagnostic coronary arteriography and were found to have coronary atherosclerosis or suffered a documented myocardial infarction, angina pectoris, peripheral vascular disease, cerebrovascular

1638

TABLE 45-5 -- FASTING LIPID AND LIPOPROTEIN LEVELS (mg/dl) IN CHILDREN BY AGE MALES FEMALES 5% 50% 95% 5% 50% 95% Cholesterol 0-4 yr

114 155 203 112 156 200

5-9 yr

121 160 203 126 164 205

10-14 yr

119 158 202 124 160 201

15-19 yr

113 150 197 120 158 203

Triglycerides 0-4 yr

29

56

98

34

64

112

5-9 yr

30

56

101 32

60

105

10-14 yr

32

66

125 37

75

131

15-19 yr

37

78

148 39

75

132

5-9 yr

38

56

74

36

53

73

10-14 yr

37

55

74

37

52

70

15-19 yr

30

46

63

35

52

74

5-9 yr

63

93

129 68

10-14 yr

64

100 140 68

97

132

15-19 yr

62

94

96

137

HDL cholesterol

LDL cholesterol

HDL=high-density lipoprotein; LDL=low-density lipoprotein.

130 59

100 140

Data from Lipid Research Clinics: Population Studies Data Book, Vol 1, The Prevalence Study. Bethesda, MD, Department of Health and Human Services, Publication (NIH) 80-1527. disease, or sudden cardiac death; those whose parent(s) have a total cholesterol level of 240 mg/dl or higher; those for whom the health history of a parent or grandparent is unknown; or those whose personal health includes risk factors (e.g., diabetes). In such a selective screening strategy, adult cardiologists should refer the children of their patients with premature atherosclerotic cardiovascular disease for cholesterol testing and follow-up. Some experts continue to recommend universal screening based on the observation that almost half of children with elevated cholesterol levels would be missed if screening were performed only on children with a positive family history.[177] [178] Moreover, a family history does not selectively identify the most severely affected children.[178] The relationship of parental history to children's lipid profiles appears to be associated with race.[177] Specifically, the Bogalusa Heart Study found that white children with a parental history of heart attack or diabetes were significantly more likely than black children to have elevated levels of total cholesterol and LDL-C, whereas in black children, a parental history of cardiovascular disease was more likely to be associated with low levels of HDL-C than in white children. Only 40 percent of white children and 21 percent of black children with elevated levels of LDL-C had a parent with a history of vascular diseases.[173] The NCEP formulated recommendations for the management of hypercholesterolemia in children.[176] When children or adolescents have a documented history of premature cardiovascular disease in a parent or grandparent, the initial test should be a fasting lipoprotein analysis. Random screening in the nonfasting state should always include both a total cholesterol and HDL-C level because total cholesterol alone is a poor screening test in childhood.[179] SECONDARY CAUSES.

Dyslipidemia most commonly results from a combination of genetic and dietary factors, but it can also be secondary to other systemic disorders. Indeed, the lipid profile can be affected by the use of medications and by endocrine and metabolic disorders, obstructive liver disease, or renal disease. Viral and bacterial infections, so common in childhood, can have profound effects on the lipid profile in the month after the onset of infection. In the first year of life, the most common causes of secondary hyperlipidemia are congenital biliary atresia and glycogen storage disease. Endocrine disorders (e.g., hypothyroidism and diabetes mellitus) and renal disease are the most common secondary causes later in childhood. Especially in adolescents, exogenous causes, such as medications, smoking, or alcohol, can affect the lipid profile. Secondary causes are usually evident from a careful review of the medical history and use of medications, together with a physical examination. When a secondary cause is not apparent, it may be appropriate to measure blood levels of thyroid-stimulating hormone, perform liver function tests, and obtain a urinalysis.

MANAGEMENT.

Because atherosclerosis is a continuous process throughout life, expert panels have suggested guidelines to reduce the risk of cardiovascular disease beginning in childhood. With the rationale that symptomatic adult coronary heart disease might be prevented or retarded by lowering of the LDL-C level in childhood and adolescence, the NCEP published guidelines for detection and management of childhood hyperlipidemia in a 1991 Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents.[176] The NCEP expert panel recommended initial nonpharmacological intervention in hyperlipidemic children, including diet modification. To lower the average population cholesterol levels, a so-called prudent diet was recommended for all children older than 2 years. In addition to providing adequate nutrients and calories to maintain ideal body weight, this diet restricts total fat calories to 30 percent or less, saturated fat calories to 40 percent or less, and cholesterol intake to 300 mg/day or less. Indeed, the long-term safety, efficacy, and acceptability of lower fat diets in high-risk pubertal children have been demonstrated in the Dietary Intervention Study in Children (DISC).[180] In children with severe familial hyperlipidemia, LDL-C rarely decreases by more than 15 percent with diet management alone. The NCEP guidelines recommended pharmacological therapy with bile acid sequestrants (cholestyramine or colestipol) for children older than 10 years who despite diet modification had an LDL-C level of 190 mg/dl or higher or a level of 160 mg/dl or higher with a family history of premature cardiovascular disease or with two other cardiovascular disease risk factors. Tonstad and coworkers studied 72 children in a randomized, placebo-controlled trial of cholestyramine and found only modest reductions (27 kg) were randomized to four doses of lovastatin ranging from 10 to 40 mg/day after a 4-week placebo period; LDL-C was reduced 21 to 36 percent in a dose-response relationship.[186] Increases in HDL-C and apolipoprotein A1 were also observed. Neither serious clinical adverse events nor important elevations in

serum

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transaminases or creatine kinase values were found. Most recently, in a randomized, placebo-controlled trial in 132 adolescent boys aged 10 to 17 years with familial hyperlipidemia, Stein and coauthors reported that lovastatin was effective in lowering LDL-C.[187] Comprehensive clinical and biochemical data on growth, hormonal, and nutritional status indicated no significant differences between the groups treated with lovastatin and placebo. Although HMG-CoA reductase inhibitor treatment of hyperlipidemic children and adolescents has been demonstrated to have short-term safety and efficacy in lowering the serum lipid profile, it is unknown whether such treatment affects preclinical disease in this age group. Antioxidant vitamins may also have a role in the treatment of dyslipidemic children and adolescents. In a recent study in children with familial hyperlipidemia, impaired brachial vasoreactivity was improved after therapy with vitamin E and vitamin C.[188] ASSESSMENT OF PRECLINICAL ATHEROSCLEROSIS.

Assessment of the effect of treatment of hyperlipidemia in childhood on vascular health is hampered by the long latency until occurrence of clinical disease. Therefore, the effects of therapies on preclinical markers of atherosclerosis are important. Methods of assessment of preclinical atherosclerosis that have been demonstrated to relate to risk factors in children include brachial artery flow-mediated dilation,[189] [189A] carotid intimal-medial thickness,[190] [191] and coronary artery calcification on electron beam computed tomography.[192]

REFERENCES CARDIOMYOPATHIES Report of the WHO/ISFC Task Force on the definition and classification of cardiomyopathies. Br Heart J 44:672, 1980. 1.

Crispell KA, Wray A, Ni H, et al: Clinical profiles of four large pedigrees with familial dilated cardiomyopathy: Preliminary recommendations for clinical practice. J Am Coll Cardiol 34:837, 1999. 2.

Katsuragi M, Yutani C, Mukai T, et al: Detection of enteroviral genome and its significance in cardiomyopathy. Cardiology 83:4, 1993. 3.

Bristow MR, Minobe W, Rasmussen R, et al: Beta-adrenergic neuroeffector abnormalities in the failing human heart are produced by local rather than systemic mechanisms. J Clin Invest 89:803, 1992. 4.

5.

Bohm M, La Rosee K, Schmidt U, et al: Force-frequency relationship and inotropic stimulation in the

nonfailing and failing human myocardium: Implications for the medical treatment of heart failure. Klin Wochenschr 70:421, 1992. Del Monte F, O'Gara P, Poole-Wilson PA, et al: Cell geometry and contractile abnormalities of myocytes from failing human left ventricle. Cardiovasc Res 30:281, 1995. 6.

Borst MM, Beuthien W, Schwencke C, et al: Desensitization of the pulmonary adenylyl cyclase system: A cause of airway hyperresponsiveness in congestive heart failure? J Am Coll Cardiol 34:848, 1999. 7.

Friedman RA, Moak JP, Garson A Jr: Clinical course of idiopathic dilated cardiomyopathy in children. J Am Coll Cardiol 18:152, 1991. 8.

Fishberger SB, Colan SD, Saul JP, et al: Myocardial mechanics before and after ablation of chronic tachycardia. Pacing Clin Electrophysiol 19:42, 1996. 9.

Matitiau A, Perez-Atayde A, Sanders SP, et al: Infantile dilated cardiomyopathy: Relation of outcome to left ventricular mechanics, hemodynamics, and histology at the time of presentation. Circulation 90:1310, 1994. 10.

Karr SS, Parness IA, Spevak PJ, et al: Diagnosis of anomalous left coronary artery by Doppler color flow mapping: Distinction from other causes of dilated cardiomyopathy. J Am Coll Cardiol 19:1271, 1992. 11.

Li DX, Tapscoft T, Gonzalez O, et al: Desmin mutation responsible for idiopathic dilated cardiomyopathy. Circulation 100:461, 1999. 12.

Webber SA, Boyle GJ, Jaffe R, et al: Role of right ventricular endomyocardial biopsy in infants and children with suspected or possible myocarditis. Br Heart J 72:360, 1994. 13.

Schwartz ML, Cox GF, Lin AE, et al: Clinical approach to genetic cardiomyopathy in children. Circulation 94:2021, 1996. 14.

14A. Bennett

MJ, Rinaldo P, Straiss AW: Inborn errors of mitochondrial fatty acid oxidation. Crit Rev Clin Lab Sci 37:1, 2000. 14B. Infante

JP, Huszagh VA: Secondary carnitine deficiency and impaired docosahexaenoic (22:6 n-3) acid synthesis: a common denominator in the pathophysiology of diseases of oxidative phosphorylation and beta-oxidation. FEBS Lett 468:1, 2000. Pierpont MEM, Breningstall GN, Stanley CA, Singh A: Familial carnitine transporter defect: A treatable cause of cardiomyopathy in children. Am Heart J 139:S96, 2000. 14C.

Strauss AW: Defects of mitochondrial proteins and pediatric heart disease. Prog Pediatr Cardiol 6:83, 1996. 15.

15A. Jarreta

D, Orus J, Barrientos A, et al: Mitochondrial function in heart muscle from patients with idiopathic dilated cardiomyopathy. Cardiovasc Res 45:860, 2000. 15B. Wallace

DC: Mitochondrial defects in cardiomyopathy and neuromuscular disease. Am Heart J 139:S70, 2000. Winter SC, Buist NRM: Cardiomyopathy in childhood, mitochondrial dysfunction, and the role of L -carnitine. Am Heart J 139:S63, 2000. 15C.

Remes AM, Hassinen IE, Ikaheimo MJ, et al: Mitochondrial DNA deletions in dilated cardiomyopathy: A clinical study employing endomyocardial sampling. J Am Coll Cardiol 23:935, 1994. 16.

Reddy M, Hanley FL: Mechanical support of the myocardium. In Chang AC, Hanley FL, Wernovsky G, et al (eds): Pediatric Cardiac Intensive Care. Baltimore, Williams & Wilkins, 1998, p 345. 17.

Pitt B, Zannad F, Remme WJ, et al: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone evaluation study investigators. N Engl J Med 341:709, 1999. 18.

Alexander ME, Walsh EP, Saul JP, et al: Value of programmed ventricular stimulation in patients with congenital heart disease. J Cardiovasc Electrophysiol 10:1033, 1999. 19.

Oliva F, Latini R, Politi A, et al: Intermittent 6-month low-dose dobutamine infusion in severe heart failure: DICE Multicenter Trial. Am Heart J 138:247, 1999. 20.

Ostman-Smith I, Brown G, Johnson A, et al: Dilated cardiomyopathy due to type II X-linked 3-methylglutaconic aciduria: Successful treatment with pantothenic acid. Br Heart J 72:349, 1994. 21.

Akagi T, Benson LN, Lightfoot NE, et al: Natural history of dilated cardiomyopathy in children. Am Heart J 121:1502, 1991. 22.

Arola A, Tuominen J, Ruuskanen O, et al: Idiopathic dilated cardiomyopathy in children: Prognostic indicators and outcome. Pediatrics 101:369, 1998. 23.

24.

Cooper HA, Gersh BJ: Treatment of chronic mitral regurgitation. Am Heart J 135:925, 1998.

Chen FY, Adams DH, Aranki SF, et al: Mitral valve repair in cardiomyopathy. Circulation 98(Suppl 2):124-127, 1998. 25.

Kim MH, Devlin WH, Das SK, et al: Effects of beta-adrenergic blocking therapy on left ventricular diastolic relaxation properties in patients with dilated cardiomyopathy. Circulation 100:729, 1999. 26.

26A. Cirillo

W, Decanini R, Coelho OR, et al: Effects of metoprolol CR in patients with ischemic and dilated cardiomyopathy--the randomized evaluation of strategies for left ventricular dysfunction pilot study. Circulation 101:378, 2000. Shaddy RE: beta-Blocker therapy in young children with congestive heart failure under consideration for heart transplantation. Am Heart J 136:19, 1998. 27.

Exner DV, Dries DL, Waclawiw MA, et al: Beta-adrenergic blocking agent use and mortality in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: A post hoc analysis of the studies of left ventricular dysfunction. J Am Coll Cardiol 33:916, 1999. 28.

Sander GE, McKinnie JJ, Greenberg SS, et al: Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in the treatment of heart failure caused by left ventricular systolic dysfunction. Prog Cardiovasc Dis 41:265, 1999. 29.

Johnson MR, Gheorghiade M: Growth hormone therapy in patients with congestive heart failure: Need for further research. Am Heart J 137:989, 1999. 30.

30A. Curry

CW, Nelson GS, Wyman BT, et al: Mechanical dyssynchrony in dilated cardiomyopathy with intraventricular conduction delay as depicted by 3D tagged magnetic resonance imaging. Circulation 101:E2, 2000. Kass DA, Chen CH, Curry C, et al: Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation 99:1567, 1999. 31.

31A. Kerwin

WF, Botvinick EH, O'Connell JW, et al: Ventricular contraction abnormalities in dilated cardiomyopathy: Effect of biventricular pacing to correct interventricular dyssynchrony. J Am Coll Cardiol 35:1221, 2000. Del Nido PJ: Editorial: Partial left ventriculectomy for dilated cardiomyopathy in children. J Thorac Cardiovasc Surg 117:918, 1999. 32.

Ratcliffe MB, Hong J, Salahieh A, et al: The effect of ventricular volume reduction surgery in the dilated, poorly contractile left ventricle: A simple finite element analysis. J Thorac Cardiovasc Surg 116:566, 1998. 33.

33A. Popovic

Z, Miric M, Gradinac S, et al: Partial left ventriculectomy improves left ventricular end systolic elastance in patients with idiopathic dilated cardiomyopathy. Heart 83:316, 2000. Burch M, Siddiqi SA, Celermajer DS, et al: Dilated cardiomyopathy in children: Determinants of outcome. Br Heart J 72:246, 1994. 34.

Pongpanich B, Isaraprasart S: Congestive cardiomyopathy in infants and children. Clinical features and natural history. Jpn Heart J 27:11, 1986. 35.

Lewis AB, Chabot M: Outcome of infants and children with dilated cardiomyopathy. Am J Cardiol 68:365, 1991. 36.

Ciszewski A, Bilinska ZT, Lubiszewska B, et al: Dilated cardiomyopathy in children: Clinical course and prognosis. Pediatr Cardiol 15:121, 1994. 37.

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Lewis AB: Late recovery of ventricular function in children with idiopathic dilated cardiomyopathy. Am Heart J 138:334, 1999. 38.

Infective Cardiomyopathy Nakagawa M, Sato A, Okagawa H, et al: Detection and evaluation of asymptomatic myocarditis in schoolchildren--report of four cases. Chest 116:340, 1999. 39.

Psani B, Taylor DO, Mason JW: Inflammatory myocardial diseases and cardiomyopathies. Am J Med 102:459, 1997. 40.

Luppi P, Rudert WA, Zanone MM, et al: Idiopathic dilated cardiomyopathy--a superantigen-driven autoimmune disease. Circulation 98:777, 1998. 41.

Chan KY, Iwahara M, Benson LN, et al: Immunosuppressive therapy in the management of acute myocarditis in children: A clinical trial. J Am Coll Cardiol 17:458, 1991. 42.

Balaji S, Wiles HB, Sens MA, et al: Immunosuppressive treatment for myocarditis and borderline myocarditis in children with ventricular ectopic rhythm. Br Heart J 72:354, 1994. 43.

Drucker NA, Colan SD, Lewis AB, et al: Gamma-globulin treatment of acute myocarditis in the pediatric population. Circulation 89:252, 1994. 44.

Endocardial Fibroelastosis 45.

Lurie PR: Endocardial fibroelastosis is not a disease. Am J Cardiol 62:468, 1988.

Ni JY, Bowles NE, Kim YH, et al: Viral infection of the myocardium in endocardial fibroelastosis--molecular evidence for the role of mumps virus as an etiologic agent. Circulation 95:133, 1997. 46.

Kuboki K, Ohkawa S, Chida K, et al: Torsades de pointes in a case of hypertrophic cardiomyopathy with special reference to the pathologic findings of the heart including the conduction system. Jpn Heart J 40:233, 1999. 47.

Mahle WT, Weinberg PM, Rychik J: Can echocardiography predict the presence or absence of endocardial fibroelastosis in infants 70 years of age); and in those with previous systemic emboli. Treatment with warfarin, to maintain the international normalized ratio (INR) between 2.0 and 3.0, is indicated.[54] However, no firm evidence exists that anticoagulant therapy reduces the incidence of pulmonary or systemic embolism in patients in sinus rhythm in whom such episodes have not previously occurred. TREATMENT OF ARRHYTHMIAS.

Frequent premature atrial contractions often presage atrial fibrillation. The administration of antiarrhythmic agents (see Chap. 23) may be effective in preventing this complication. However, once atrial fibrillation has developed, these agents may be ineffective in restoring sinus rhythm because of the pathological changes that occur in the atrium secondary to the arrhythmia itself. After electrical cardioversion, sinus rhythm can often be maintained with antiarrhythmic agents, especially in young patients with mild MS but without marked left atrial enlargement who have been in atrial fibrillation less than 6 months and who are maintained on adequate doses of quinidine. Immediate treatment of atrial fibrillation should include intravenous heparin followed by oral warfarin. The ventricular rate should be slowed with intravenous digoxin and a beta-blocking agent or rate-slowing calcium antagonist. An effort should be made to reestablish sinus rhythm by a combination of pharmacological treatment and cardioversion. If cardioversion is planned in a patient who has had atrial fibrillation for more than 24 hours before the procedure, anticoagulation with warfarin for more than three weeks is indicated. Alternatively, if a transesophageal echocardiogram shows no atrial thrombus, immediate cardioversion can be carried out using intravenous heparin.[55] Paroxysmal atrial fibrillation and repeated conversions, spontaneous or induced, carry the risk of embolization. In patients who cannot be converted or maintained in sinus rhythm, digitalis should be used to maintain the ventricular rate at rest at approximately 60 beats/min. If this is not possible, small doses of a beta-blocking

agent, such as atenolol (25 mg daily), may be added. Multiple repeat cardioversions are not indicated if the patient fails to sustain sinus rhythm while on adequate doses of an antiarrhythmic. Patients with chronic atrial fibrillation who undergo open mitral valve repair or replacement may undergo the Cox maze procedure (atrial compartment operation). More than 80 percent of patients undergoing this procedure can be maintained in sinus rhythm postoperatively[56] and can regain normal atrial function.[57] NEED FOR CATHETERIZATION.

There has been considerable debate concerning the need for routine cardiac catheterization in determining whether valvotomy is indicated.[51] A careful clinical evaluation and noninvasive assessment, particularly using two-dimensional and Doppler echocardiography, can provide sufficient information to permit an informed decision in the majority of patients. Preoperative catheterization is recommended for the following patients with MS: (1) patients who have a discrepancy between clinical and echocardiographic findings; hemodynamic measurements during exercise are often useful in these patients; (2) patients who have associated chronic obstructive pulmonary disease in whom it is important to determine the contribution of MS to the symptoms; (3) patients in whom left atrial myxoma should be excluded; (4) patients who have angina pectoris or angina-like chest pain in whom associated coronary artery disease must be excluded; and (5) men over 40 years of age and women over 50 years of age who have risk factors for coronary artery disease or a positive stress test and in whom surgery is planned; it is important to ascertain whether or not bypass grafting is indicated for those patients at risk of having coexisting coronary artery disease. Critical narrowing of one or more coronary vessels occurs in approximately 25 percent of all adults with severe MS. This finding is more common in men over 45 years of age who have angina and risk factors for coronary artery disease. [28] Natural History

The development of effective surgical treatment has obscured our understanding of the natural history of MS (Fig. 46-5) and, for that matter, of all valvular lesions. Although few meaningful data are available, it appears that in temperate zones, such as the United States and Western Europe, patients who develop acute rheumatic fever have an asymptomatic period of approximately 15 to 20 years before symptoms of MS develop. It then takes approximately 5 to 10 years for most patients to progress from mild disability (i.e., early NYHA Class II) to severe disability (i.e., NYHA Class III or IV). The progression is much more rapid in patients in tropical and subtropical areas,[58] in Polynesians, and in Alaskan Inuit. Both economic and genetic conditions may play a role. In India, critical MS may be present in children as young as 6 to 12 years old. In North America and Western Europe, however, symptoms develop

Figure 46-5 Schematic representation of the subsequent life history after the initial development of symptoms in a large group of patients with mitral stenosis. The colored solid circles and colored lines indicate a surgical procedure. The dashed lines represent estimated survival of patients who are not receiving the surgical procedure. MC = mitral commissurotomy; MVR = mitral valve replacement; TA = tricuspid annuloplasty; AVR = aortic valve replacement. (From Kirklin JW, Barratt-Boyes BG [eds]:

Cardiac Surgery. New York, John Wiley and Sons, 1986, p 328.)

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more slowly and occur most commonly between the ages of 45 and 65.[51] Two echocardiographic studies have reported hemodynamic progression in patients with MS who had not undergone surgery[59] [60] ; there was considerable interpatient variability, but on average the mitral valve area decreased by 0.09 cm2 /yr. In the presurgical era, Olesen found 62 percent 5-year survival rates and 38 percent 10-year survival rates among medically treated patients with MS in NYHA Class III but only 15 percent 5-year survival rates among patients in Class IV.[61] Among asymptomatic patients with MS treated medically, 40 percent deteriorated or died within 10 years. Among mildly symptomatic patients (NYHA Class II), the comparable number was 80 percent.[62] In medically treated patients with MS or with combined MS and MR, Munoz and associates found a 45 percent 5-year survival rate. [63] In a comparable group of patients who underwent mitral valvotomy, the 5-year survival rate was substantially better. Horstkotte et al. reported a 5-year survival rate of 44 percent in patients with symptomatic MS who refused valvotomy (Fig. 46-6) . [64] Valvotomy Indications

Patients with MS who are asymptomatic or minimally symptomatic frequently remain so for years. However, once moderate symptoms develop (NYHA Class II), if the stenosis is not relieved mechanically, the disease may progress relatively rapidly, as already discussed (Table 46-1) . Valvotomy (percutaneous balloon mitral valvuloplasty [BMV] or surgical valvotomy) should therefore be carried out in symptomatic patients with moderate to severe MS (i.e., a mitral valve orifice area < approximately 1.0 cm2 /m2 body surface area [BSA] or 5 mm diameter) mitral valve leaflets.[243] [254] [255] [256] Patients with the MVP syndrome are also at risk of developing infective endocarditis.[257] [257A] Although the incidence of infective endocarditis appears to be extremely low in patients with only a midsystolic click, it increases in patients with a systolic murmur. The incidence is higher in men than in women and in those more than 50 years of age. Infective endocarditis often aggravates the severity of MR and

therefore the need for surgical treatment. Acute hemiplegia, transient ischemic attacks, cerebellar infarcts, amaurosis fugax, and retinal arteriolar occlusions have been reported to occur more frequently in patients with the MVP syndrome, suggesting that cerebral emboli are unusually common in this condition.[258] [259] [259A] It has been proposed that these neurological complications are associated with loss of endothelial continuity and tearing of the endocardium overlying the myxomatous valve, which initiates platelet aggregation and the formation of mural platelet-fibrin complexes.[258] Although it has been proposed that embolization secondary to MVP may be a significant cause for unexplained strokes in young people without cerebrovascular disease, a large case-controlled study showed no association between MVP and ischemic neurological events in persons under 45 years of age.[260] MANAGEMENT (Table 46-6) Patients with the physical findings of MVP (and those without such findings who have been given the diagnosis) should have two-dimensional and color flow Doppler echocardiography. This procedure should also be performed in first-degree relatives of patients with MVP.[51] The diagnosis of MVP requires definitive echocardiographic findings, and overdiagnosis and incorrect "labeling" have been a major problem with this condition. Asymptomatic patients (or those whose principal complaint is anxiety), with no arrhythmias evident on a routine extended ECG tracing and without evidence of MR, have an excellent prognosis. They should be reassured about the favorable prognosis and be encouraged to engage in normal life styles, but should have follow-up examinations every every 3 to 5 years. This should include a two-dimensional echocardiogram and a color flow Doppler study. Patients with a long systolic murmur may show progression of MR and should be evaluated more frequently, at intervals of approximately 12 months. Endocarditis prophylaxis is advisable for patients with a typical click and systolic murmur and in those with only a click and characteristic echocardiographic features of MVP. Prophylaxis does not appear to be necessary for patients with a midsystolic TABLE 46-6 -- MATCHING RISK AND MANAGEMENT IN PATIENTS WITH MITRAL VALVE PROLAPSE RISK PATIENTS MANAGEMENT LEVEL Lowest

Patients without mitral regurgitant murmurs or regurgitation revealed by Doppler echocardiography, especially women younger than age 45

Reassurance; prophylactic antibiotics not clearly necessary and if used should not include medication with risk of allergic reactions; reevaluation and echocardiography at moderate intervals (5 years)

Moderate Patients with intermittent or persistent mitral murmurs and mild regurgitation revealed by Doppler echocardiography

Antibiotic prophylaxis with erythromycin or amoxicillin; treatment of even mild established hypertension; reevaluation and echocardiography more frequently (2 to 3 years)

High

Antibiotic prophylaxis with amoxicillin (unless allergic); optimization of afterload (arterial pressure); reevaluation with Doppler echocardiography and other tests if needed annually; consider valve repair or replacement for exertional dyspnea or decline of left ventricular function into low-normal range

Patients with moderate or severe mitral regurgitation

From Devereux RB: Recent developments in the diagnosis and management of mitral valve prolapse. Curr Opin Cardio 10:107, 1995. Modified from Devereux RB, Kligfield P: Mitral valve prolapse. In Rakel R: Current Therapy. Philadelphia, WB Saunders, 1992, pp 237, 241.

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click without a systolic murmur or without typical echocardiographic findings (see also Chap. 47) .[261] Patients with a history of palpitations, lightheadedness, dizziness, or syncope or those who have ventricular arrhythmias or QT prolongation on a routine ECG should undergo ambulatory (24-hour) ECG monitoring and/or exercise ECG to detect arrhythmias. Because of the risk, albeit very low, of sudden death,[238] electrophysiologic studies may be carried out to characterize arrhythmias if they exist. Beta-adrenergic blockers are useful in the treatment of palpitations secondary to frequent premature ventricular contractions and for self-terminating episodes of supraventricular tachycardia. These drugs may also be useful in the treatment of chest discomfort, both in patients with associated coronary artery disease and in those with normal coronary vessels in whom the symptoms may be due to regional ischemia secondary to MVP. Radiofrequency ablation of atrioventricular bypass tracts is useful for frequent or prolonged episodes of supraventricular tachycardia. Aspirin should be given to patients with MVP who have had a documented focal neurological event and in whom no other cause, such as a left atrial thrombus or atrial fibrillation, is apparent. Treatment with an angiotensin-converting enzyme inhibitor has been reported to reduce the severity of MR in patients with MVP. [171] Patients with MVP and severe MR should be treated similarly to other patients with severe MR (see p. 1661 ) and may require mitral valve surgery. Reconstructive surgery without valve replacement is usually possible (see Fig. 46-15) .[179A] [211] [261A] Therefore, the threshold for surgical treatment in these patients is lower than in patients with MR in

whom MVR may be necessary. Approximately 50 percent of all mitral valve reconstructions for MR are now carried out in patients with MVP. Among 252 such patients operated upon at the Brigham and Women's Hospital, resection of the most deformed leaflet segment and insertion of an annuloplasty ring to reduce the dilated annulus was the most commonly employed procedure. Rupture of the chordae tendineae to the anterior leaflet could sometimes be treated by chordal transfer from the posterior leaflet. In other patients, shortening of the chordae tendineae and/or papillary muscle was necessary. The operative mortality was 2 percent; structural valve degeneration occurred in 15 percent of patients at 5 years. Chordal replacement with polytetrafluoroethylene sutures has been reported to enhance mitral valve repair in patients with MVP.[210] Coronary arteriography should be performed in patients with angina pectoris on effort and/or ischemic ECG changes or those with abnormalities on a stress myocardial perfusion scan. Treatment should take into account both the responsiveness of symptoms to medical management and the coronary anatomy. Although this discussion has focused attention on complications of the MVP syndrome, it should not be forgotten that, on the whole, this is a benign condition and that the vast majority of patients with this syndrome remain asymptomatic for their entire lives and require, at most, observation every few years and reassurance.




Aortic Stenosis ETIOLOGY AND PATHOLOGY Obstruction to left ventricular outflow is localized most commonly at the aortic valve and is discussed in this section. However, obstruction may also occur above the valve (supravalvular stenosis) or below the valve (discrete subvalvular aortic stenosis [see Chap. 43 ]), or it may be caused by hypertrophic obstructive cardiomyopathy (see Chap. 48) . Valvular aortic stenosis (AS) without accompanying mitral valve disease is more common in men than in women and very rarely occurs on a rheumatic basis. Instead, isolated AS is usually either congenital or degenerative in origin[262] [263] (Figs. 46-26 and 46-27) . CONGENITAL AORTIC STENOSIS (See also Chaps. 43 and 44) .

Congenital malformations of the aortic valve may be unicuspid, bicuspid, or tricuspid, or there may be a dome-shaped diaphragm. Unicuspid valves produce severe obstruction in infancy and are the most frequent malformations found in fatal valvular AS in children under the age of 1 year. Congenitally bicuspid valves may be stenotic with commissural fusion at birth, but more often they are not responsible for serious narrowing of the aortic orifice during childhood. Their abnormal architecture induces turbulent flow, which traumatizes the leaflets and leads to fibrosis, increased rigidity, calcification of the leaflets, and narrowing of the aortic orifice in adulthood[264] (Fig. 46-28) . Infective endocarditis may develop on a congenitally bicuspid valve, which then becomes regurgitant. Rarely, a congenitally bicuspid valve is purely regurgitant in the absence of antecedent infection. A third form of a congenitally malformed valve is tricuspid, with the cusps of unequal

size and some commissural fusion. Although many of these valves retain normal function throughout life, it has been postulated that the turbulent flow produced by the mild congenital architectural

Figure 46-26 Types of aortic valve stenosis. A, Normal aortic valve. B, Congenital aortic stenosis. C, Rheumatic aortic stenosis. D, Calcific aortic stenosis. E, Calcific senile aortic stenosis. (From Brandenburg RO, et al: Valvular heart disease--When should the patient be referred? Pract Cardiol 5:50, 1979.)

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Figure 46-27 Causes of aortic stenosis, shown for two age groups. Among patients younger than 70 years (top), calcification of congenitally bicuspid valves accounted for half of the surgical cases. In contrast, in those 70 years of age or older (bottom), degenerative calcification accounted for almost half of the cases. (From Passik CS, et al: Temporal changes in the causes of aortic stenosis: A surgical pathologic study of 646 cases. Mayo Clin Proc 62:119, 1987.)

abnormality may lead to fibrosis and ultimately to calcification and stenosis. Tricuspid stenotic aortic valves in adults may be congenital, rheumatic, or degenerative in origin. ACQUIRED AORTIC STENOSIS.

Rheumatic AS results from adhesions and fusions of the commissures and cusps and vascularization of the leaflets of the valve ring, leading to retraction and stiffening of the free borders of the cusps. Calcific nodules develop on both surfaces, and the orifice is reduced to a small round or triangular opening. As a consequence, the rheumatic valve is often regurgitant as well as stenotic.[262] The heart frequently exhibits other stigmata of rheumatic disease, especially mitral valve involvement. With the decline in rheumatic fever in industrialized nations, rheumatic AS is decreasing in frequency. Age-related degenerative calcific (formerly termed senile) AS is now the most common cause of AS in adults and the most frequent reason for aortic valve replacement in patients with AS.[265] It appears to result from years of normal mechanical stress on a valve that sometimes exhibits inflammatory changes with infiltration of macrophages and T lymphocytes. The cusps are immobilized, and the stenosis is caused by deposits of calcium along the flexion lines at their bases. Immunohistochemical evidence of Chlamydia pneumoniae has been found in early lesions of age-related degenerative AS.[266] In a population-based echocardiographic study, 2 percent of persons 65 years of age or older had frank calcific AS, whereas 29 percent exhibited age-related aortic valve sclerosis without stenosis, defined by Otto and colleagues as irregular thickening of the aortic valve leaflets detected by echocardiography without significant obstruction and believed to represent a milder and/or earlier disease process.[265] This form of AS may be accompanied by calcifications of the mitral annulus and coronary arteries but rarely

by aortic regurgitation. Both diabetes mellitus and hypercholesterolemia are risk factors for the development of age-related AS or degenerative calcific AS.[267] [268] It has been suggested that the hypercholesterolemia accelerates age-related degenerative changes in the aortic root and valve.[269] In turn, it has been noted that age-related aortic valve sclerosis and calcific AS are associated with traditional risk factors for atherosclerosis such as cigarette smoking, a history of hypertension, and low high-density-lipoprotein cholesterol values.[270] Not surprisingly, age-related aortic valve sclerosis is associated with an increased risk of cardiovascular death and mycoardial infarction.[265] In atherosclerotic aortic valve stenosis, severe atherosclerosis involves the aorta and other major arteries; this form of AS occurs most frequently in patients with severe hypercholesterolemia and is observed in children with homozygous type II hyperlipoproteinemia.[271] Calcific AS is observed in a number of other conditions, including Paget disease of bone[272] and end-stage renal disease.[273] Rheumatoid involvement of the valve is a rare cause of AS and results in nodular thickening of the valve leaflets and involvement of the proximal portion of the aorta. Ochronosis with alkaptonuria is another rare cause of AS.[274] Roberts studied hearts with AS obtained at autopsy from patients between 15 and 65 years of age and found that almost 40 percent had tricuspid aortic valves. [275] Because thickening of the mitral valve and a history of acute rheumatic fever were present in 50 percent of these patients, it is likely that the AS was rheumatic in etiology; in the remainder, it was either congenital or degenerative in origin. In 90 percent of hearts examined at autopsy in patients with AS who were older than 65 years of age, the valves were tricuspid, with nodular calcific deposits on the aortic aspects of the cusps, but without commissural fusion,[275] indicative of age-related degenerative calcific AS. Hemodynamically significant AS leads to severe concentric left ventricular hypertrophy,[276] with heart weights as great as 1000 gm. The interventricular septum often bulges into and encroaches on the right ventricular cavity. When left ventricular failure supervenes, the ventricle dilates, the left atrium enlarges, and changes secondary to backward failure occur in the pulmonary vascular bed, the right side of the heart, and the systemic venous bed. PATHOPHYSIOLOGY (Fig. 46-29) The left ventricle responds to sudden severe obstruction to outflow by dilatation and reduction of stroke volume.[277] However, in adults with AS, the obstruction usually develops and increases gradually over a prolonged period. In infants and children with congenital AS, the valve orifice shows little change as the child grows, thereby intensifying the relative obstruction quite gradually. Left ventricular function can be well maintained in experimentally produced, gradually developing subcoronary AS in animals. In the experimental model, as well as in children and adults

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Figure 46-28 Calcific aortic stenosis. A, Congenitally bicuspid aortic valve, characterized by two equal cusps with basal mineralization. B, Congenitally bicuspid aortic valve having two unequal cusps, the larger with a central raphe (arrow). C, Otherwise anatomically normal tricuspid aortic valve in an elderly patient, characterized by isolated cusps with calcification localized to basilar aspect; cuspal free edges are not involved. D and E, Photomicrographs of calcific deposits in calcific aortic stenosis; deposits are rimmed by arrows (hematoxylin and eosin, original magnification ×15). D, Deposits with underlying cusp largely intact; transmural calcific deposits are shown in E. (A and C from Schoen FJ, St. John Sutton M: Contemporary issues in the pathology of valvular heart disease. Hum Pathol 18:568, 1987.)

with chronic, severe AS, left ventricular output is maintained by the presence of left ventricular hypertrophy, which may sustain a large pressure gradient across the aortic valve for many years without a reduction in cardiac output, left ventricular dilatation, or the development of symptoms. Critical obstruction to left ventricular outflow is usually characterized by (1) a peak systolic pressure gradient exceeding 50 mm Hg in the presence of a normal cardiac output or (2) an effective aortic orifice (calculated by the Gorlin formula [see Chap. 11 ]) less than about 0.8 cm2 in an average-sized adult, i.e., 0.5 cm2 /m2 of body surface area (less than approximately one-fourth of the normal aortic orifice of 3.0 to 4.0 cm2 ). An aortic valve orifice of 1.0 to 1.5 cm2 is considered moderate stenosis, and an orifice of 1.5 to 2.0 cm2 is referred to as mild stenosis (see Fig. 11-13) . As contraction of the left ventricle becomes progressively more isometric, the left ventricular pressure pulse exhibits a rounded, rather than flattened, summit. The elevated left ventricular end-diastolic pressure, which is characteristic of severe AS, often reflects diminished compliance of the hypertrophied left ventricular wall.[278] [279] In patients with severe AS, large a waves usually appear in the left atrial pressure pulse because of the combination of enhanced contraction of a hypertrophied left atrium and diminished left ventricular compliance. Atrial contraction plays a particularly important role in filling of the left ventricle in AS. It raises left ventricular end-diastolic pressure

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Figure 46-29 Pathophysiology of aortic stenosis. Left ventricular (LV) outflow obstruction results in an increased LV systolic pressure, increased left ventricular ejection time (LVET), increased left ventricular diastolic pressure, and decreased aortic (Ao) pressure. Increased LV systolic pressure with LV volume overload increases LV mass, which may lead to LV dysfunction and failure. Increased LV systolic pressure, LV mass, and LVET increase myocardial oxygen (O 2 ) consumption. Increased LVET results in a decrease of diastolic time (myocardial perfusion time). Increased LV diastolic pressure and decreased Ao diastolic pressure decrease coronary perfusion pressure. Decreased diastolic time and coronary

perfusion pressure decrease myocardial O 2 supply. Increased myocardial O2 consumption and decreased myocardial O 2 supply produce myocardial ischemia, which further deteriorates LV function ( = increased, = decreased). (From Boudoulas H, Gravanis MB: Valvular heart disease. In Gravanis MB: Cardiovascular Disorders: Pathogenesis and Pathophysiology. St. Louis, CV Mosby Co, 1993, p 64.)

without causing a concomitant elevation of mean left atrial pressure.[280] This "booster pump" function of the left atrium prevents the pulmonary venous and capillary pressures from rising to levels that would produce pulmonary congestion, while at the same time maintaining left ventricular end-diastolic pressure at the elevated level necessary for effective contraction of the hypertrophied left ventricle. Loss of appropriately timed, vigorous atrial contraction, as occurs in atrial fibrillation or atrioventricular dissociation, may result in rapid clinical deterioration in patients with severe AS. Although the cardiac output at rest is within normal limits in the majority of patients with severe AS, it often fails to rise normally during exertion. Late in the course of the disease, the cardiac output, stroke volume, and therefore the left ventricular-aortic pressure gradient all decline, whereas the mean left atrial, pulmonary capillary, pulmonary arterial, right ventricular systolic and diastolic, and right atrial pressures rise, often sequentially. As a consequence of pulmonary hypertension and/or bulging of the hypertrophied septum into the right ventricular cavity, the a wave in the right atrial pressure pulse becomes prominent. Left ventricular end-diastolic volume usually remains normal until late in the course of severe AS, but left ventricular mass increases in response to the chronic pressure overload, resulting in an increase in the mass/volume ratio. However, the increase in mass may not be as great as that seen with aortic regurgitation (AR) or combined AS and AR. Gender differences in the response of the left ventricle to AS have been reported. [281] [282] [283] Women more frequently exhibit normal or even supernormal ventricular performance and a smaller, thicker-walled, concentrically hypertrophied left ventricle with diastolic dysfunction (to be discussed) and normal or even subnormal systolic wall stress. Men more frequently have eccentric left ventricular hypertrophy, excessive systolic wall stress, systolic dysfunction, and ventricular dilatation[284] [285] [286] (Fig. 46-30) . MYOCARDIAL FUNCTION IN AORTIC STENOSIS

When the aorta is suddenly constricted in experimental animals, left ventricular pressure rises, wall stress increases significantly, and both the extent and the velocity of shortening decline. As pointed out in Chapter 16 , the development of ventricular hypertrophy is one of the principal mechanisms by which the heart adapts to such an increased hemodynamic burden. The increased systolic wall stress induced by AS leads to parallel replication of sarcomeres and concentric hypertrophy (see Fig. 16-4) . The increase in left ventricular wall thickness is often sufficient to counterbalance the increased pressure, so that peak systolic wall tension returns to normal or remains normal if the obstruction develops slowly.[287] An inverse correlation between wall stress

and ejection fraction has been described in patients with AS.[288] This suggests that the depressed ejection fraction and velocity of fiber shortening that occur in some patients are a consequence of inadequate wall thickening,[289] resulting in "afterload mismatch."[290] In others, the lower ejection fraction is secondary to a true depression of contractility; in this group, surgical treatment is less effective.[291] Thus, both increased afterload and altered contractility are operative to varying extents in depressing left ventricular performance.[281] [282] In order to evaluate myocardial function in patients with AS, the ejection

Figure 46-30 The difference in pressure-generating capabilities of the left ventricle in an 83-year-old woman and a 60-year-old man with a similar degree of aortic stenosis is shown. dP/dt = rate of pressure increase. (Reproduced with permission from Carroll JD, Carroll EP, Felman T, et al: Sex-associated differences in left ventricular function in aortic stenosis of the elderly. Circulation 86:1099, 1992. Copyright 1992 American Heart Association.)

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phase indices, such as ejection fraction and myocardial fiber shortening, should be related to the existing wall tension. DIASTOLIC PROPERTIES (see also Chap. 15) .

Although ventricular hypertrophy is a key adaptive mechanism to the pressure load imposed by AS, it has an adverse pathophysiological consequence; i.e., it increases diastolic stiffness. As a result, greater intracavitary pressure is required for ventricular filling.[278] [279] [292] Some patients with AS manifest an increase in stiffness of the left ventricle (increased chamber stiffness) due simply to increased muscle mass with no alteration in the diastolic properties of each unit of myocardium (normal muscle stiffness); others exhibit increases in both chamber and muscle stiffness. This increased stiffness, however produced, contributes to the elevation of ventricular diastolic filling pressure at any level of ventricular diastolic volume[293] [294] and may be responsible for flash pulmonary edema in patients with AS. Diastolic dysfunction may revert toward normal as hypertrophy regresses following relief of AS.[279] CARDIAC STRUCTURE.

An increase in the total collagen volume of the myocardium and in the orthogonal collagen fiber network in AS has been reported.[295] [296] This likely contributes to the altered diastolic properties just discussed. An inverse correlation between the left ventricular ejection fraction and myocardial fiber diameter has been reported.[297] Changes in the myocardial ultrastructure in patients with severe AS include unusually large nuclei, loss of myofibrils, accumulation of mitochondria, large cytoplasmic areas devoid of contractile material, and proliferation of fibroblasts and collagen fibers in the interstitial space. The depression of myocardial function that occurs late in the course of the disease may well be related to these morphological alterations. In adults with AS,

both myocardial cellular hypertrophy and relative and absolute increases in connective tissue occur. ISCHEMIA.

In patients with AS, coronary blood flow at rest is elevated in absolute terms but is normal when corrections are made for myocardial mass.[298] There may be inadequate myocardial oxygenation in patients with severe AS, even in the absence of coronary artery disease. The hypertrophied left ventricular muscle mass, the increased systolic pressure, and the prolongation of ejection all elevate myocardial oxygen consumption. The abnormally heightened pressure compressing the coronary arteries may exceed the coronary perfusion pressure, and the shortening of diastole interferes with coronary blood flow,[299] [300] thus leading to an imbalance between myocardial oxygen supply and demand. Myocardial perfusion is also impaired by the relative decrease in myocardial capillary density as myocardial mass increases and by the elevation of left ventricular end-diastolic pressure, which lowers the aortic-left ventricular pressure gradient in diastole (i.e., the coronary perfusion pressure gradient). This underperfusion may be responsible for the development of subendocardial ischemia, especially during tachycardia. Marcus and associates have demonstrated a reduction in the velocity of coronary blood flow during reactive hyperemia in patients with severe AS,[301] and this may correlate with the angina pectoris commonly observed in these patients. Myocardial ischemia in patients with severe AS and normal coronary arteries may be secondary to high systolic and diastolic stresses caused by inadequate ventricular hypertrophy and the reduced coronary flow reserve just described.[302] [303] Metabolic evidence of myocardial ischemia, i.e., lactate production, can be demonstrated when myocardial oxygen needs are stimulated by exercise or by isoproterenol in patients with AS, even in the absence of coronary artery narrowing. CLINICAL MANIFESTATIONS History

In the natural history of adults with AS, a long latent period exists during which there is gradually increasing obstruction and an increase in the pressure load on the myocardium while the patient remains asymptomatic.[304] The cardinal manifestations of acquired AS, which commence most commonly in the fifth or sixth decades of life, are angina pectoris, syncope, exertional dyspnea, and ultimately heart failure.[305] Angina occurs in approximately two-thirds of patients with critical AS (about half of whom have associated significant coronary artery obstruction).[306] It usually resembles the angina observed in patients with coronary artery disease, in that it is commonly precipitated by exertion and relieved by rest. In patients without coronary artery disease, angina results from the combination of the increased oxygen needs of the hypertrophied myocardium and the reduction of oxygen delivery secondary to the excessive compression of coronary vessels[298] [301] [302] [303] (see Ischemia, just discussed). In patients with coronary artery disease, angina is caused by a combination of the

epicardial coronary artery obstruction and the earlier-described oxygen imbalance characteristic of AS. Rarely, angina results from calcium emboli to the coronary vascular bed.[307] Syncope is most commonly due to the reduced cerebral perfusion that occurs during exertion when arterial pressure declines consequent to systemic vasodilation in the presence of a fixed cardiac output. Syncope has also been attributed to malfunction of the baroreceptor mechanism in severe AS[277] , as well as to a vasodepressor response to a greatly elevated left ventricular systolic pressure during exercise.[308] Premonitory symptoms of syncope are common. Exertional hypotension may also be manifested as "graying out" spells or dizziness on effort. Syncope at rest may be due to transient ventricular fibrillation,[309] from which the patient recovers spontaneously; to transient atrial fibrillation with loss of the atrial contribution to left ventricular filling, which causes a precipitous decline in cardiac output; or to transient atrioventricular block due to extension of the calcification of the valve into the conduction system. Exertional dyspnea with orthopnea, paroxysmal nocturnal dyspnea, and pulmonary edema reflect varying degrees of pulmonary venous hypertension. These are relatively late symptoms in patients with AS, and their presence for more than 5 years should suggest the possibility of associated mitral valvular disease. Gastrointestinal bleeding, either idiopathic or due to angiodysplasia (most commonly of the right colon) or other vascular malformations, occurs more often in patients with calcific AS than in persons without this condition; it may cease after aortic valve replacement.[310] Infective endocarditis is a greater risk in younger patients with milder valvular deformity than in older patients with rocklike calcific aortic deformities. Cerebral emboli resulting in stroke or transient ischemic attacks may be due to microthrombi on thickened bicuspid valves.[311] Calcific AS may cause embolization of calcium to various organs, including the heart, kidneys, and brain. Abrupt loss of vision has been reported when calcific emboli occlude the central retinal artery.[307] [312] Because cardiac output is usually well maintained for many years in patients with severe AS, marked fatigability, debilitation, peripheral cyanosis, and other clinical manifestations of a low cardiac output are usually not prominent until quite late in the course of the disease. Other late findings in patients with isolated AS include atrial fibrillation, pulmonary hypertension, and systemic venous hypertension. Although AS may be responsible for sudden death, this usually occurs in patients who had previously been symptomatic (see Chap. 26) . In patients in whom the obstruction remains unrelieved, the prognosis is poor once these symptoms are manifested. Survival curves show that the interval from the onset of symptoms to the time of death is approximately 2 years in patients with heart failure, 3 years in those with syncope, and 5 years in those with angina (Fig. 46-31) . Physical Examination (Table 46-7)

The arterial pulse characteristically rises slowly and is small and sustained (pulsus parvus et tardus) (see Fig. 4-8 B).[313] [314] In the late stage of AS, systolic and pulse pressures are both reduced. However, in patients with mild AS with associated AR and

in older patients with an inelastic arterial bed, both systolic and pulse pressures may be normal or even increased. A systolic pressure exceeding 200 mm Hg is rare in patients with critical AS. The anacrotic notch and coarse systolic vibrations are felt most readily in the carotid arterial pulse, producing the so-called carotid shudder. Simultaneous palpation of the apex and carotid arteries reveals a lag in the latter in patients with

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Figure 46-31 Natural history of aortic stenosis without operative treatment. (Reproduced with permission from Ross J Jr, Braunwald E: Aortic stenosis. Circulation 38[Suppl V]:61, 1968. Copyright 1968 American Heart Association.)

severe AS.[315] Although left ventricular alternans occurs commonly in patients who have AS with left ventricular dysfunction,[316] obstruction of the aortic valve may prevent its recognition in the peripheral arterial pulse. The jugular venous pulse usually shows prominent a waves, reflecting reduced right ventricular compliance consequent to hypertrophy of the ventricular septum. [317] With pulmonary hypertension and secondary right ventricular failure and tricuspid regurgitation, v or c-v waves may become prominent. The cardiac impulse is sustained and becomes displaced inferiorly and laterally with left ventricular failure. Presystolic distention of the left ventricle (i.e., a prominent precordial a wave) is often both visible and palpable. A hyperdynamic left ventricle suggests concomitant aortic and/or mitral regurgitation. A systolic thrill is usually best appreciated when the patient leans forward during full expiration. It is palpated most readily in the second left intercostal space on either side of the sternum or in the suprasternal notch and is frequently transmitted along the carotid arteries. A systolic thrill is quite specific for severe AS. Rarely, right ventricular failure with systemic venous congestion, hepatomegaly, and edema precedes left ventricular failure. This is probably caused by the so-called Bernheim effect, which results when the hypertrophied ventricular septum bulges into and encroaches on the right ventricular cavity and leads to impairment of right ventricular filling. In such cases, the jugular venous pressure is elevated, and the a wave is prominent. AUSCULTATION (See Table 46-7) .

S1 is normal or soft and S4 is prominent, presumably because atrial contraction is vigorous and the mitral valve is partially closed during presystole.[318] S2 may be single because calcification and immobility of the aortic valve make A2 inaudible, because P2 is buried in the prolonged aortic ejection murmur, or because prolongation of left ventricular systole makes A2 coincide with P2 . Paradoxical splitting of S2 , which

suggests associated left ventricular dysfunction, may also occur. In patients with left ventricular failure and secondary pulmonary hypertension, P2 may become accentuated. When the aortic valve is rigid, which is the usual finding in adults with severe AS, A2 may be inaudible, but when the valve is flexible, as may occur in patients with congenital AS, A2 may be snapping and accentuated. An aortic ejection sound occurs simultaneous with the halting upward movement of the aortic valve (see Fig. 4-15) . Like an audible A2 , this sound is dependent on mobility of the valve cusps and disappears when they become severely calcified. Thus, it is common in children with congenital AS but is rare in adults with acquired calcific AS and rigid valves. The ejection sound occurs approximately 0.06 second after the onset of S1 . The systolic murmur of AS is usually late peaking and heard best at the base of the heart but is often well transmitted both along the carotid vessels and to the apex. Cessation of the murmur before A2 is usually helpful in differentiating it from a pansystolic mitral murmur. However, the systolic murmur may be mistaken for a pansystolic murmur because it may end with S2 , which represents pulmonic valve closure, whereas the pansystolic murmur is soft or even inaudible. In patients with calcified aortic valves, the systolic murmur is loudest at the base of the heart, but high-frequency components selectively radiate to the apex (the so-called Gallavardin phenomenon [see Fig. 4-24 ]), where it may actually be more prominent and where it may be mistaken for the murmur of MR. Frequently, there is a TABLE 46-7 -- DIFFERENTIAL DIAGNOSIS OF AORTIC STENOSIS: PHYSICAL FINDINGS TYPE OF MAXIMUM AORTIC AORTIC REGURGITANT ARTERIAL STENOSIS MURMUR EJECTION COMPONENT DIASTOLIC PULSE AND SOUND OF SECOND MURMUR THRILL SOUND Acquired Second Uncommon nonrheumatic right sternal or rheumatic border to neck; may be at apex in the aged

Decreased or absent

Common

Delayed upstroke; anacrotic notch; ± small amplitude

Hypertrophic Fourth left subaortic sternal border to apex (± regurgitant systolic murmur at apex)

Normal or decreased

Very rare

Brisk upstroke, sometimes bisferiens

Rare

Congenital valvular

Second right sternal border to neck (along left sternal border in some infants)

Very common in children, disappearing with decrease in valve mobility with age

Normal or increased in children; decreased with decrease in valve mobility with age

Congenital subvalvular

Discrete: like valvular; tunnel: left sternal border

Rare

Not helpful Almost all (normal, increased, decreased, or absent)

Congenital First right Rare supravalvular sternal border to neck and sometimes to medial aspect of right arm; occasionally greater in neck than in chest

Normal or decreased

Uncommon in children; not uncommon in adults

Uncommon

Delayed upstroke; anacrotic notch; ± small amplitude

Rapid upstroke in right carotid, delayed in left carotid; right arm pulse pressure greater than left

From Levinson GE: Aortic stenosis. In Dalen JE, Alpert JS (eds): Valvular Heart Disease. 2nd ed. Boston, Little, Brown and Co, 1987, p 202.

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"quiet area" between the base and apex where the murmur is diminished in intensity, supporting the erroneous impression that the apical and basal murmurs have different origins. In general, the more severe the stenosis, the longer the duration of the murmur and the more likely that it peaks later in systole.[320] Patients with degenerative aortic sclerosis may have severe valvular calcification; however, obstruction may be mild or absent because the commissural fusion characteristic of congenital and rheumatic AS is not present. [92] The nonfused, calcified cusps vibrate freely, resulting in a softer and more musical murmur that is more prominent at the apex than the murmur of congenital or rheumatic AS. High-pitched decrescendo diastolic murmurs secondary to aortic regurgitation are common in many patients with dominant AS.

When the left ventricle fails and the stroke volume falls, the systolic murmur of AS becomes softer; rarely, it disappears altogether. The slow rise in the arterial pulse is more difficult to recognize. Stated simply, with left ventricular failure, the clinical picture changes from typical AS to that of severe left ventricular failure with a low cardiac output. Thus, occult AS may be a cause of intractable heart failure, and critical AS should be ruled out by echocardiography in patients with severe heart failure of unknown cause because operative treatment may be life-saving and may result in substantial clinical improvement.[321] DYNAMIC AUSCULTATION (see Table 46-4) .

The intensity of the systolic murmur varies from beat to beat when the duration of diastolic filling varies, as in atrial fibrillation or following a premature contraction. This characteristic is helpful in differentiating AS from MR, in which the murmur is usually unaffected. The murmur of valvular AS is augmented by squatting, which increases stroke volume. It is reduced in intensity during the strain of the Valsalva maneuver and when standing, which reduce transvalvular flow.[322] Findings on physical examination including a delay in the carotid upstroke, a loud, long systolic murmur, and a single S2 all correlate with severe stenosis.[323] LABORATORY EXAMINATION ELECTROCARDIOGRAPHY.

The principal ECG change is left ventricular hypertrophy (Fig. 5-19) , which is found in approximately 85 percent of patients with severe AS. The absence of left ventricular hypertrophy does not exclude the presence of critical AS, and the correlation between the absolute ECG voltages in precordial leads and the severity of obstruction is poor in adults but is quite good in children with congenital AS. T wave inversion and ST segment depression in leads with upright QRS complexes are common. ST segment depressions greater than 0.2 mV in patients with AS (left ventricular "strain") suggest that severe ventricular hypertrophy is present. Occasionally, a "pseudoinfarction" pattern is present, characterized by a loss of r waves in the right precordial leads. There is evidence of left atrial enlargement in more than 80 percent of patients with severe, isolated AS. The principal manifestation is prominent late negativity of the P wave in lead V1 rather than an increased duration in lead II, suggesting hypertrophy rather than dilatation. Atrial fibrillation is an uncommon and late sign of pure AS, and its presence in a patient who does not appear to have end-stage aortic disease should suggest coexisting mitral valvular disease. The extension of calcific infiltrates from the aortic valve into the conduction system may cause various forms and degrees of atrioventricular and intraventricular block in 5 percent of patients with calcific AS.[324] Such conduction defects are more common in patients who have associated mitral annular calcification.

RADIOLOGICAL FINDINGS.

(See Figs. 8-8 , 8-19 , and 8-20) . Routine radiological examination may be normal in patients with critical AS. The heart is usually of normal size or slightly enlarged, with a rounding of the left ventricular border and apex, unless regurgitation or left ventricular failure is present and causes substantial cardiomegaly. Poststenotic dilatation of the ascending aorta is a common finding. Calcification of the aortic valve is found in almost all adults with hemodynamically significant AS.[325] It is more readily detected on fluoroscopy or echocardiography than on roentgenography. The absence of calcium in the aortic valve region on careful fluoroscopic examination in a patient older than 35 years of age essentially rules out severe valvular AS. The converse is not true, however, and in patients over the age of 65 with degenerative AS, severe calcification of the aortic valve may occur with no or only mild obstruction. The left atrium may be slightly enlarged in patients with severe AS, and there may be radiological signs of pulmonary venous hypertension. However, when left atrial enlargement is marked, the presence of associated mitral valvular disease should be suspected. ANGIOGRAPHY.

There is some hazard associated with the rapid injection of a large volume of contrast material into a high-pressure left ventricle, and therefore this procedure is usually not advisable in patients with AS and critical obstruction. Angiographic studies of the left ventricle and aortic valve in these patients are best performed by injecting contrast material into the pulmonary artery and filming in the 30-degree right anterior oblique and 60-degree left anterior oblique projections. These examinations often make it possible to ascertain the number of cusps of the stenotic valve and to demonstrate doming of a thickened valve and a systolic jet. ECHOCARDIOGRAPHY (see also Chap. 7 and Figs. 7-60 to 7-63) .

The normal range of opening of the aortic valve is 1.6 to 2.6 cm. Two-dimensional transthoracic echocardiography is helpful in detecting valvular calcification, in outlining the valve leaflets, and sometimes in determining the severity of the stenosis by imaging the orifice.[326] The orifice may be more clearly defined by transesophageal echocardiography, which offers a precise short-axis view of the aortic valve.[327] Multiplanar transesophageal echocardiography is particularly useful.[328] Two-dimensional echocardiography is invaluable in detecting associated mitral valve disease and in assessing left ventricular systolic performance, diastolic function, dilatation, and hypertrophy. Doppler echocardiography allows calculation of the left ventricular-aortic pressure gradient[329] using a modified Bernoulli (continuity) equation (see Fig 7-25) . The gradients noninvasively determined by this method correlate well with those determined by left-heart catheterization.[329] [330] Color flow Doppler imaging is helpful in detecting and determining the severity of aortic regurgitation (which coexists in approximately 75 percent of patients with predominant AS) and in estimating pulmonary artery pressure.[331] Indeed, in a large majority of patients the echocardiographic examination provides the information obtained by cardiac catheterization (except for the status of the coronary arteries).[329] Echocardiography has become the most important

laboratory technique for evaluating and following patients with AS and selecting them for operation. NATURAL HISTORY In contrast to MS, which leads to symptoms almost immediately after its development, patients with severe AS may be asymptomatic for many years despite the presence of severe obstruction.[304] [306] The systolic pressure gradient may exceed 150 mm Hg, and the peak left ventricular systolic pressure may reach approximately 300 mm Hg with relatively little increase in overall heart size on radiological examination and with normal left ventricular end-diastolic and end-systolic volumes. Patients with severe, chronic AS tend to be free of cardiovascular symptoms until relatively late in the course of the disease. Thus, there is a long latent period during which mortality and morbidity are very low.[51] In Rapaport's report, 40 percent of patients treated medically survived for 5 years and 20 percent for 10 years after diagnosis.[147] In another series of patients with hemodynamically significant valvular AS treated medically, the 5-year survival rate was 64 percent. However, obstruction is progressive and often insidious, with the aortic valve area decreasing by an average of 0.12 cm2 /year in one study.[331] When symptoms develop, the valve area is, on average, 0.6 cm2 .[332] Once patients with AS develop angina pectoris or syncope, the average survival is 1 to 3 years[333] [334] [335] (see Fig. 46-31) . In an analysis of elderly patients with severe AS and symptoms of heart failure who declined surgery, 50 percent had died by 18 months of follow-up; the ejection fraction correlated

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inversely with survival.[336] Among symptomatic patients with severe AS, the outlook is poorest when the left ventricle has failed and the cardiac output and transvalvular gradient are both low. Asymptomatic patients have an excellent prognosis.[92] [337] [338] Sudden death, like syncope, in patients with severe AS may be due to cerebral hypoperfusion followed by arrhythmia. Although severe AS is a potentially lethal disease, death (even when sudden) usually occurs in symptomatic patients. A number of authors who have followed asymptomatic patients with critical AS have found that sudden death is extremely rare in this group. Of 229 asymptomatic patients with critical AS, only 5 (2 percent) died suddenly (certainly not higher than the mortality from operation). [51] [337] MANAGEMENT Medical Treatment

Patients with known severe AS who are asymptomatic should be advised to report promptly the development of any symptoms possibly related to AS. Patients with critical

obstruction should be cautioned to avoid vigorous athletic and physical activity. However, such restrictions do not apply to patients with mild obstruction. The need for infective endocarditis prophylaxis should be explained (see Chap 47) . Because of the gradual increase in the severity of obstruction, noninvasive assessment of this finding by Doppler echocardiography should be carried out at intervals. Doppler-derived gradients have been shown to increase by 4 to 8 mm Hg per year.[92] In patients with mild obstruction, this measurement should be repeated every 2 years. In asymptomatic patients with severe obstruction, repeat echocardiography should be carried out every 6 to 12 months, with particular attention to detecting changes in left ventricular function. Exercise stress testing should be avoided in symptomatic patients, but may be carried out in asymptomatic patients to detect limited exercise capacity. Symptomatic patients with severe AS are usually operative candidates, as medical therapy has little to offer. However, medical therapy may be necessary in patients who are considered to be inoperable (usually because of comorbid conditions that preclude surgery.) Digitalis glycosides are indicated if the ventricular volume is increased or the ejection fraction is reduced. Although diuretics are beneficial when there is abnormal accumulation of fluid, they must be used with caution because hypovolemia may reduce the elevated left ventricular end-diastolic pressure, lower cardiac output, and produce orthostatic hypotension. Betaadrenergic blockers can depress myocardial function and induce left ventricular failure and should be avoided in patients with AS. Atrial flutter or fibrillation occurs in fewer than 10 percent of patients with severe AS, perhaps because of the late occurrence of left atrial enlargement in this condition. When such an arrhythmia is observed in a patient with AS, the possibility of associated mitral valvular disease should be considered. When atrial fibrillation occurs, the rapid ventricular rate may cause angina pectoris. The loss of the atrial contribution to ventricular filling and a sudden fall in cardiac output may cause serious hypotension. Therefore, atrial fibrillation should be treated promptly, usually with cardioversion, and a search for previously unrecognized mitral valvular disease should be undertaken. Adults with severe AS who are being considered for surgical therapy should undergo coronary arteriography. Left-heart catheterization is also indicated if there is a discrepancy between the clinical picture and the echocardiographic findings.[50] Surgical Treatment INDICATIONS FOR OPERATION.

Children.

The indications for surgery, as well as the techniques and results of operation, depend on the patient's age, the type of valvular deformity, and the function of the left ventricle. In children and adolescents with noncalcific congenital AS, who most commonly have bicuspid aortic valves, simple commissural incision under direct vision usually leads to substantial hemodynamic improvement with low risk (i.e., a mortality rate of less than 1 percent) (see Chap. 43) .[339] Therefore, this procedure (or now, more commonly, balloon aortic valvuloplasty) is indicated not only in symptomatic patients but also in asymptomatic children and adolescents with severe AS, which is often defined as a

calculated effective orifice less than 0.8 cm2 or 0.5 cm2 /m2 body surface area (BSA). Despite the salutary hemodynamic results following this procedure, the valve is not rendered entirely normal anatomically. The turbulent blood flow through the valve may subsequently lead to further deformation, calcification, the development of regurgitation, and restenosis after 10 to 20 years, probably requiring reoperation and valve replacement later. Adults.

In most adults with calcific AS, satisfactory long-term valvular function cannot usually be restored even by careful sculpturing procedures under direct vision, and valve replacement is the surgical treatment of choice. Aortic valve replacement (AVR) (Fig. 46-32) should, in general, be performed in adults who have hemodynamic evidence of severe obstruction (aortic valve orifice 25 mm/m2 BSA.[417] Gradual deterioration of left ventricular function may occur even during the asymptomatic period; it is therefore important to intervene surgically before these changes have become irreversible.[418] A review of multiple studies on the natural history of chronic AR has been described by Bonow and associates[51] (Table 46-9) . ACUTE AORTIC REGURGITATION.

Since early death due to left ventricular failure is frequent in patients with acute, severe AR despite intensive medical management, prompt surgical intervention is indicated. Even a normal ventricle cannot sustain the burden of acute, severe volume overload; therefore, the risk of acute AR is much greater than that of chronic AR.[394] [404] While the patient is being prepared for surgery, treatment with an intravenous positive TABLE 46-9 -- NATURAL HISTORY OF AORTIC REGURGITATION Asymptomatic patients with normal LV systolic function: 65 years of age).[557] Good results have also been reported for this valve in the mitral position, in which the results are also exceptional in older patients. However, there is a greater risk for the development of stenosis in the mitral position.[558] HEMODYNAMICS OF VALVE REPLACEMENTS

The most commonly used prosthetic valves, i.e., mechanical prostheses and stented porcine xenografts, have an effective in vitro orifice size that is smaller than the normal valve at the same site. (Unstented, i.e., free, homografts and pulmonary autografts do not have this problem.) After implantation, tissue ingrowth and endothelialization reduce the size of the effective orifice even more. Therefore, the prosthetic valves that are currently available must be considered to be mildly stenotic. However, postoperative hemodynamic measurements of the mechanical prostheses show reasonably good function, with effective mitral valve orifice areas averaging 1.7 to 2.0 cm 2 and mitral valve gradients of 4 to 8 mm Hg at rest. The cloth-covered StarrEdwards valve appears to be intrinsically slightly more stenotic than the Medtronic-Hall or Omniscience tilting-disc valves. The bileaflet St. Jude and Carbomedics valves, in turn, may be slightly superior to the Medtronic-Hall or Omniscience valve. In hemodynamic studies, the stented porcine mitral valves behave in a manner similar to mechanical prosthetic valves of the same diameter. Serious hemodynamic obstruction of an artificial valve in the mitral position is quite uncommon, unless the valve (most commonly the Starr-Edwards valve) is placed into a small left ventricular cavity or into an unusually small mitral annulus or the prosthesis chosen is of inappropriate size. The problem of prosthetic valve stenosis may be more serious in patients who undergo aortic valve replacement for AS. The annulus into which the prosthesis is inserted in these patients is usually smaller than it is in patients with AR, and the surgeon may be forced to select an artificial valve of relatively small size. As a consequence, aortic valve replacement, may not abolish obstruction in patients with AS but may merely convert severe to mild or moderate obstruction. When the smaller models of the stented porcine xenograft or mechanical prosthesis are placed into the aortic position, effective orifice areas of about 1.1 to 1.3 cm 2 are common. In such patients, peak transvalvular gradients as high as 40 mm Hg during exercise have been recorded. The poor late results observed in a minority of patients undergoing replacement of stenotic aortic valves may possibly be related to the moderate stenosis of the prosthesis. In patients with AS who do not exhibit clinical improvement postoperatively, it is important to evaluate the function of both the prosthetic valve and the left ventricle. Rarely, reoperation to correct a malfunctioning prosthesis may be necessary.

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SELECTION OF AN ARTIFICIAL VALVE (Table 46-13) Most comparisons of mechanical and bioprosthetic valves indicate similar overall results in terms of early and late mortality, prosthetic valve endocarditis and other complications, and the need for reoperation, at least for the first 5 years postoperatively. As indicated, there appear to be no significant differences insofar as hemodynamics are concerned, except that patients with an unusually small left ventricular cavity or mitral or aortic annulus may have better results with the low-profile (tilting-disc) St. Jude or Carbomedics prosthesis or a tissue valve.[559] Patients with a small aortic annulus may

be better candidates for unstented homografts, heterografts, or pulmonary autografts. The major task in selecting an artificial valve is to weigh the advantage of durability and the disadvantages of the risks of thromboembolism and anticoagulant treatment inherent in mechanical prostheses on the one hand with the advantage of low thrombogenicity and the disadvantage of abbreviated durability of bioprostheses on the other. Hammermeister and associates[560] have compared the outcome in 575 men who were randomized to replacement of the mitral or the aortic valve with either mechanical or a bioprosthetic valve. There was no difference in survival or in the probability of developing a valve-related complication, including endocarditis, valve thrombosis, and systemic embolism, in patients receiving either a mechanical or a bioprosthetic valve. The rate of structurally related valve failure requiring reoperation (which is associated with about twice the mortality of the initial procedure) was much higher in patients receiving tissue as opposed to mechanical valves. As anticipated, anticoagulant-related bleeding was higher in patients receiving mechanical valves. Patients with mechanical valves also had a higher incidence of perivalvular regurgitation in the mitral position. In the Edinburgh randomized trial, which also compared a mechanical with a porcine xenograft valve,[561] actuarial survival rates tended to be better and the freedom from all valve-related adverse events was significantly better with mechanical valves. Retrospective cohort analyses are in agreement with the results of these trials.[562] [563] [564] Therefore, mechanical prostheses, usually of the bileaflet variety, are the valves of choice in the majority of patients under 65 years of age. However, the following groups of patients should receive bioprostheses: (1) patients with coexisting disease who are prone to hemorrhage and who therefore tolerate anticoagulants poorly, such as those with bleeding disorders, intestinal polyposis, and angiodysplasia; (2) patients who are TABLE 46-13 -- VALVE SELECTION FOR AN INDIVIDUAL PATIENT RELATIVE INDICATIONS FOR A MECHANICAL VALVE Long expected lifetime (age 0.12 mug/mL).[40] This finding raises the concern that strains causing IE may also be less susceptible to penicillin than in the past. Abiotrophia species, previously called S. adjacens and S. defectivus, appear more resistant to penicillin (MIC > 0.12 mug/ml in more than 30 percent of strains).[39] Although penicillin-aminoglycoside synergy was not demonstrated in vitro with S. adjacens and S. defectivus, in therapy of experimental endocarditis caused by these organisms, penicillin-aminoglycoside combinations were more effective than penicillin alone; also, therapy with vancomycin alone was comparable to that with the penicillin-aminoglycoside combination.[39] STREPTOCOCCUS BOVIS AND OTHER STREPTOCOCCI.

S. bovis, part of the gastrointestinal tract normal flora, causes 27 percent of the episodes of streptococcal NVE. Although superficially resembling the enterococci, this species can be easily distinguished by its biochemical characteristics. The distinction is important because S. bovis is highly penicillin susceptible, in contrast to the relative penicillin resistance of enterococci. S. bovis NVE is frequently associated with coexistent colonic polyps or malignancy.[41] Group A streptococci, which can infect normal valves, cause rare episodes of endocarditis. Among IV drug abusers, group A streptococci have caused tricuspid valve IE similar to that noted with S. aureus. Group B organisms, Streptococcus agalactiae, are part of the normal flora of the mouth, genital tract, and gastrointestinal tract. Group B streptococci infect normal and abnormal valves and cause a morbid NVE syndrome with a high incidence of systemic emboli and septic musculoskeletal complications (arthritis, diskitis, osteomyelitis).[42] The organisms' failure to produce fibrinolysin may result in large vegetations and a high rate of systemic emboli. Endocarditis caused by this organism may be associated with villous adenomas and colonic neoplasms. Group G streptococci also produce a destructive, highly morbid left-sided NVE. The S. milleri group, now divided into three species--Streptococcus intermedius, Streptococcus constellatus, and Streptococcus anginosus--are highly pyogenic organisms that cause destructive infections similar to those caused by S. aureus and accounted for 2 to 5

percent of streptococcal NVE cases.[38] STREPTOCOCCUS PNEUMONIAE.

Although pneumococcal bacteremia occurs frequently, S. pneumoniae accounts for only 1 to 3 percent of NVE cases. When causing IE, S. pneumoniae frequently involves a previously normal aortic valve and progresses rapidly with valve destruction, myocardial abscess formation, and acute congestive heart failure (CHF). [43] The mortality rate among medically treated patients exceeded 60 percent but was 32 percent among those undergoing medical-surgical therapy.[43] Alcoholism is a risk factor for pneumococcal IE, and concurrent pneumonia or meningitis is common. Pneumococci that are resistant to penicillin and ceftriaxone are increasingly common causes of infection, particularly in children. These strains remain susceptible to vancomycin. In the future, these penicillin-resistant strains are likely to cause sporadic cases of IE; therefore, vancomycin might be included in the therapy of suspected pneumococcal IE until definitive susceptibility results for the isolate become available.[44] ENTEROCOCCI.

E. faecalis and Enterococcus faecium cause 85 percent and 10 percent of cases of enterococcal IE, respectively. Enterococci are part of the normal gastrointestinal flora and cause genitourinary tract infection. Enterococci account for 5 to 15 percent of cases of NVE and a similar percentage of PVE cases (see Tables 47-2 and 47-3) .[9] [28] [45] Cases occur in young women as a consequence of genitourinary tract manipulation or infection and in older predominantly male patients, who have the urinary tract as a likely portal of entry. Enterococci infect either normal or previously abnormal valves and present as either acute or subacute IE.[45] Enterococci are overtly resistant to cephalosporins, semisynthetic penicillinase-resistant penicillins (oxacillin and nafcillin), and therapeutic concentrations of aminoglycosides. Most enterococci are inhibited by modest concentrations of the cell wall-active antibiotics--penicillin, ampicillin, vancomycin, and teicoplanin (not licensed in the United States). Bactericidal antienterococcal activity can be achieved by combining an inhibitory cell wall-active agent and an appropriate aminoglycoside. This bactericidal activity called synergy, is essential for optimal treatment of enterococcal IE.[45] Strains of enterococci that are highly resistant to penicillin and ampicillin, resistant to vancomycin, and highly resistant to all aminoglycosides have been identified as causes of nosocomial infections.[45] [46] STAPHYLOCOCCI.

The coagulase-positive staphylococci are a single species, S. aureus. Of the 13 species of coagulase-negative staphylococci that colonize humans, one, S. epidermidis, has emerged as an important pathogen in the setting of implanted devices and hospitalized patients. Coagulase-negative staphylococci on the surface of foreign devices have altered phenotypes, including increased resistance to the bactericidal effects of many

antibiotics.[47] [48] Antibiotic Resistance.

In excess of 90 percent of S. aureus cases, whether acquired in the hospital or community, produce beta-lactamase and thus are resistant to penicillin, ampicillin, and the ureidopenicillins. These organisms are, however, susceptible to the penicillinase-resistant beta-lactam antibiotics (oxacillin, nafcillin, cefazolin, and other first-generation cephalosporins). Methicillin-resistant strains of S. aureus are increasingly prevalent in nosocomial settings and among selected, nonhospitalized populations (IV drug abusers, nursing home residents) and must be considered when selecting initial empirical therapy for IE in patients from these groups.[17] [49] Coagulase-negative staphylococci frequently produce beta-lactamase; furthermore, strains causing community-acquired infections are frequently methicillin susceptible, whereas those causing nosocomial infections, including IE, are commonly methicillin resistant.[50] Coagulase-negative staphylococci may not always phenotypically express methicillin resistance (a property called heteroresistance). Consequently, special testing may be required to detect this resistance. [49] [50] Staphylococci, including most strains that are resistant to methicillin, remain susceptible to vancomycin and telcoplanin.[49] Clinical Features.

S. aureus is a major cause of IE in all population groups (see Tables 47-1 and 47-2) . S. aureus IE is characterized by a highly toxic febrile illness, frequent focal metastatic infection, and a 30 to 50 percent rate of central nervous system complications.[49] A cerebrospinal fluid polymorphonuclear pleocytosis, with or without S. aureus cultured from the cerebrospinal fluid, is common.[49] Heart murmurs are heard in 30 to 45 percent of patients on initial evaluation and are ultimately heard in 75 to 85 percent as a consequence of intracardiac damage. The mortality rate in nonaddicts with left-sided S. aureus endocarditis ranges from 16 to 46 percent overall and increases in those over 50 years of age, in those with significant underlying diseases, and when IE is complicated by a major neurologic event valve dysfunction or CHF.[49] [51] [52] Among addicts, left-sided S. aureus IE resembles that in nonaddicts. In contrast, in patients with IE limited to the tricuspid valve, complications are rare and mortality rates are only 2 to 4 percent.[18] Tricuspid staphylococcal IE occasionally results in overwhelming septic pulmonary emboli, pyopneumothorax, and severe respiratory insufficiency. Coagulase-Negative Staphylococci.

These are a major cause of PVE, particularly during the initial year after valve surgery, an important cause of nosocomial IE, and the cause of 3 to 8 percent of NVE cases, usually in the setting of prior valve abnormalities (see Tables 47-1 and 47-2 .[49] [50] The vast majority of coagulase-negative staphylococci causing PVE, when speciated, are S. epidermidis.[49] In contrast, when infection involves native valves, only 50 percent of isolates are S. epidermidis. [49] [50] Staphylococcus lugdunensis, a coagulase-negative species, has caused highly destructive, often fatal NVE and PVE.[53] S. lugdunensis IE is usually community acquired, and the organism is often susceptible to many

antistaphylococcal antibiotics, including penicillin.[53] GRAM-NEGATIVE BACTERIA.

Organisms of the so-called HACEK group, which are part of the upper respiratory tract and oropharyngeal flora, infect abnormal cardiac valves, causing subacute NVE, and cause PVE that occurs a year or more after valve surgery.[54] in NVE, the HACEK organisms have been associated with large vegetations and a high incidence of systemic emboli.[54] These organisms are fastidious and slow growing; when they are suspected, blood cultures should be incubated for 3 weeks. Haemophilus species, primarily H. aphrophilus followed by H. parainfluenzae and H. Influenzae, account for 0.5 to 1.0 percent of all IE. P. aeruginosa is the gram-negative bacillus that most commonly causes endocarditis. The proclivity of P. aeruginosa, as opposed to Enterobacteriaceae, to cause IE correlates with its resistance to the bactericidal activity of human sera and its adherence to cardiac valves and platelet-fibrin thrombi. Pseudomonal IE involves normal and abnormal valves on both sides of the heart and often causes valve destruction and heart failure.[54] The Enterobacteriaceae, despite causing frequent episodes of bacteremia, are implicated in only sporadic cases of IE. Neisseria gonorrhoeae, a common cause of IE during the preantibiotic era, rarely causes endocarditis today.[55] [56] Gonococci, similar to pneumococci, infect the aortic valve of young patients, resulting in valve destruction abscess formation, and a probable need for valve replacement.[53] [54] [55] [56] Penicillinase production and intrinsic resistance

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to penicillin are common among gonococci; however, all strains remain susceptible to ceftriaxone. OTHER ORGANISMS.

Corynebacterium species, often called diphtheroids, although often contaminants in blood cultures, cannot be ignored when isolated from multiple blood cultures. Prolonged incubation of blood cultures is often required to isolate these slow-growing, fastidious organisms from patients with IE. They are an important cause of PVE occurring during the initial year after valve surgery and a surprisingly common cause of endocarditis involving abnormal valves.[28] [56] [57] Listeria monocytogenes, a small gram-positive rod, causes occasional cases of IE involving abnormal left heart valves and prosthetic devices.[56] Bartonella quintana, Bartonella elizabethae, and Bartonella henselae have caused IE and can be isolated from blood cultures by prolonged incubation (2 weeks) followed by blind subculturing to fresh chocolate agar or sheep blood agar, which is in

turn incubated for 2 to 3 weeks in 5 to 8 percent carbon dioxide.[58] [59] In the absence of special efforts in culturing, or serologic testing, many cases would have been "culture negative."[15] [58] [59] Tropheryma whippelii, the cause of Whipple's disease, has caused a cryptic afebrile form of IE with associated arthralgias but without diarrhea. The diagnosis has been established by examination of valve tissue by polymerase chain reaction and by microscopic identification of the organism in periodic acid-Schiff (PAS) or silver-stained vegetations.[60] The rickettsia C. burnetii infects humans after inhalation of desiccated materials from infected animals or contact with infected parturient animals. At variable intervals after acute infection by C. burnetii (Q fever), persons with abnormal mitral or aortic valves who have not been able to eradicate the organism develop subacute IE with typical manifestations and often with valve dysfunction causing heart failure.[14] The diagnosis is typically based on high IgG and IgA antibody titers to phase I C. burnetii antigens. The organism can be demonstrated in excised cardiac valves by immunohistological or Gimenez staining.[14] Chlamydia psittaci, the agent of psittacosis, has caused occasional episodes of subacute IE and has resulted in hemodynamically significant valve damage. FUNGI.

Candida albicans, nonalbicans Candida species, Torulopsis glabrata, and Aspergillus species are the most common of the many fungal organisms identified as causing IE. Fungal endocarditis arises in specific settings. Valve replacement cardiac surgery and IV drug abuse are major predispositions. The most frequent fungi causing PVE are C. albicans, Aspergillus species, and nonalbicans Candida species, whereas addiction-associated fungal IE is most commonly caused by nonalbicans Candida species, particularly C. parapsilosis.[61] [62] [63] [64] Fungal IE resulting from prolonged IV antimicrobial therapy and parenteral alimentation is caused predominantly by C. albicans and T. glabrata. Patients who are severely immunodepressed occasionally experience IE caused by Candida species, Aspergillus species, or opportunistic mycelia fungi. Blood cultures frequently are positive when Candida species or T. glabrata causes IE but rarely yield organisms when IE is caused by mycelial organisms. Bulky vegetations, which embolize frequently, are common in fungal IE. Removal and careful microbiological evaluation of an embolic vegetation may provide an etiological diagnosis in fungal IE.[61] [62] PATHOGENESIS The interactions between the human host and selected microorganisms that culminate in IE involve the vascular endothelium, hemostatic mechanisms, the host immune system, gross anatomic abnormalities in the heart, surface properties of microorganisms, and peripheral events that initiate bacteremia. Each component of these interactions is in itself complex, influenced by many factors and not fully elucidated. The rarity of endocarditis and endarteritis in the presence of frequent transient asymptomatic and symptomatic bacteremia indicates that the intact endothelium is resistant to infection. Endothelial damage results in platelet-fibrin deposition, which in turn is more receptive to colonization by bacteria than is the intact endothelium. It is hypothesized that platelet-fibrin deposition occurs spontaneously in

persons vulnerable to endocarditis and that these deposits, called nonbacterial thrombotic endocarditis (NBTE), are the sites at which microorganisms adhere during bacteremia to initiate IE.[65] The relative uniformity of organisms causing IE, as contrasted with the variety of organisms causing overt and asymptomatic bacteremia, and the infectiousness of specific organisms in animal models of endocarditis indicate that certain microorganisms are advantaged in their ability to colonize and infect NBTE. The events after colonization that lead to IE entail survival and multiplication of microorganisms and the accrual of vegetation, as well as complex host-pathogen interactions.[66] DEVELOPMENT OF NONBACTERIAL THROMBOTIC ENDOCARDITIS.

Two major mechanisms appear pivotal in the formation of NBTE: endothelial injury and a hypercoagulable state. NBTE has been found in 1.3 percent of patients at autopsy and is more common with increasing age. These lesions have also been noted frequently in patients with malignancy, disseminated intravascular coagulation, uremia, burns, systemic lupus erythematosus, valvular heart disease, and intracardiac catheters.[66] The platelet-thrombin deposits are found at the valve closure-contact line on the atrial surfaces of the mitral and tricuspid valves and on the ventricular surfaces of the aortic and pulmonic valves, the sites of infected vegetations in patients with IE. Three hemodynamic circumstances may injure the endothelium, initiating NBTE: (1) a high-velocity jet impacting endothelium, (2) flow from a high- to a low-pressure chamber, and (3) flow across a narrow orifice at high velocity. Flow through a narrowed orifice, as a consequence of Venturi's effect, deposits bacteria maximally at the low-pressure sink immediately beyond an orifice or at the site where a jet stream impacts a surface. These are the same sites where NBTE forms as a result of hemodynamic circumstances. The superimposition of NBTE formation and preferential deposition of bacteria help to explain the distribution of infected vegetations. [67] CONVERSION OF NBTE TO IE.

Bacteremia is the initiating event that ultimately converts NBTE to IE. The frequency and magnitude of bacteremia associated with daily activities and health care procedures appear related to specific mucosal surfaces and skin, the density of colonizing bacteria, the disease state of the surface, and the extent of the local trauma. Bacteremia rates are highest for events that traumatize the oral mucosa, particularly the gingiva, and progressively decrease with procedures involving the genitourinary tract and the gastrointestinal tract.[68] A diseased mucosal surface--particularly one that is infected--is associated with an increased risk of bacteremia. Although IE develops when circulating microorganisms are deposited at a site of NBTE, the coincidence of bacteremia and NBTE does not uniformly result in IE. To cause IE, the organism must be able to persist and propagate on the endothelium. This requires resistance to host defenses. The complement-mediated bactericidal activity of serum limits the ability of susceptible aerobic gram-negative bacilli to cause IE. Only strains resistant to the bactericidal activity of serum, e.g., selected E. coli, P. aeruginosa, and Serratia marcescens, cause IE with significant frequency or are virulent in the rabbit

model of endocarditis.[66] The precise role of granulocytes in eradicating early colonizing organisms is not clear. Platelet-released microbicidal material has been shown to eliminate recently adherent, susceptible viridans streptococci from valves in experimental endocarditis, and the resistance of S. aureus to these peptides correlates with ability of strains to cause endocarditis in animal models as well as IE and intravascular infection in patients.[68] [69] [70] [71] The adherence of microorganisms to the NBTE is a pivotal early event in the development of IE. Those organisms that most frequently cause endocarditis adhere more vigorously in vitro to cardiac valves than do organisms that rarely cause IE. Many mechanisms promote this adherence, including the surface carbohydrates of bacteria. Bacteremic steptococci that produce extracellular dextran cause endocarditis more frequently than do strains that do not produce dextran. Dextran on the surface of streptococci can be shown to mediate adherence to platelet fibrin lattices and injured valves. Dextran production, however, is not universal among the major microbial causes of IE; thus, other mechanisms of adherence are likely. Fibronectin has been identified as an important factor in this process. Fibronectin has been identified in lesions on heart valves and is produced by endothelial cells, platelets, and fibroblasts in response to vascular injury; a soluble form binds to exposed subendothelial collagen. Receptors for fibronectin are present on the surface of S. aureus; viridans streptococci; groups A, C, and G streptococci; enterococci;

1729

S. pneumoniae; and C. albicans. Fibronectin has numerous binding domains and thus can bind simultaneously to fibrin, collagen, cells, and microorganisms and can serve to facilitate adherence of bacteria to the valve at the site of injury or NBTE. Clumping factor (or fibrinogen-binding surface protein) of S. aureus also mediates the binding of these organisms to platelet fibrin thrombin and to aortic valves in models of endocarditis.[72] The glycocalyx or slime on the surface of S. epidermidis does not appear to function as an adhesin but may render organisms more virulent by virtue of enhancing their ability to avoid eradication by host defenses.[73] The mechanism by which virulent organisms colonize and infect intact valvular endothelium is less clearly understood. Endothelial cells in monolayers in vitro can phagocytize S. aureus and Candida. Multiplication of the organism intracellularly results in cell death, which in turn disrupts the endothelial surface and initiates formation of platelet-fibrin deposits. Alternatively, fibronectin may facilitate the adherence of S. aureus to intact endothelium. After adherence to the NBTE or endothelium, persistence and multiplication result in a complex dynamic process during which the infected vegetation increases in size by platelet-fibrin aggregation, microorganisms are shed into the blood, and vegetation fragments embolize. Staphylococci and streptococci promote platelet aggregation and growth of the vegetation. Surface antigens that promote platelet adhesion (class I

antigen) and aggregation (class II antigen that functionally mimics a platelet interactive domain of collagen) are expressed by S. aureus. Strains of S. sanguis with the aggregation antigen cause more severe endocarditis in the rabbit model than do antigen-negative strains.[74] Fibrin deposition is enhanced by tissue factor (a tissue thromboplastin that binds to factor VII) elaborated by endothelial cells, fibroblasts, or monocytes interacting with bacteria.[75] The persistence of this cycle results in the clinical syndrome of IE. PATHOPHYSIOLOGY Aside from the constitutional symptoms of infection, which are likely mediated by cytokines, the clinical manifestations of IE result from (1) the local destructive effects of intracardiac infection; (2) the embolization of bland or septic fragments of vegetations to distant sites, resulting in infarction or infection; (3) the hematogenous seeding of remote sites during continuous bacteremia; and (4) an antibody response to the infecting organism with subsequent tissue injury due to deposition of preformed immune complexes or antibody-complement interaction with antigens deposited in tissues. The intracardiac consequences of IE range from trivial, characterized by an infected vegetation with no attendant tissue damage, to catastrophic, when infection is locally destructive or extends beyond the valve leaflet. Distortion or perforation of valve leaflets, rupture of chordae tendineae, and perforations or fistulas between major vessels and cardiac chambers or between chambers themselves as a consequence of burrowing infection may result in CHF that is progressive (Fig. 47-3) .[76] [77] Infection, particularly that involving the aortic valve or prosthetic valves, may extend into paravalvular tissue and result in abscesses and persistent fever due to antibiotic-unresponsive infection, disruption of the conduction system with electrocardiographic conduction abnormalities and clinically relevant arrhythmias, or purulent pericarditis.[78] Large vegetations, particularly at the mitral valve, can result in functional valvular stenosis and hemodynamic deterioration.[28] [79] In general, intracardiac complications involving the aortic valve evolve more rapidly than those associated with the mitral valve; nevertheless, the progression is highly variable and unpredictable in individual patients. Embolization of fragments from vegetations is clinically evident in 11 to 43 percent of patients.[9] [67] [80] [81] However, pathologic evidence of emboli at autopsy is found more frequently (45 to 65 percent). Emboli from left-sided IE produce symptoms by infection or infarction at the site of lodgment. Although not demonstrated in all studies, pooled data suggest that larger vegetations (>10 mm) are associated with a higher frequency of emboli, as are hypermobile vegetations and those attached to the mitral valve, particularly the anterior leaflet.[82] [83] Pulmonary emboli, which are often

Figure 47-3 A normal valve with a large, bulky vegetation caused by Staphylococcus aureus infection. Clot is present centrally in the vegetation, obscuring a valve fenestration.

septic, occur in 66 to 75 percent of IV drug abusers with tricuspid valve IE (Fig. 47-4) .[16] [18]

The persistent bacteremia of IE, with or without septic emboli, may result in metastatic infection. These infections may present as local signs and symptoms or as persistent fever during therapy.[78] [84] IE caused by virulent organisms, particularly S. aureus or beta-hemolytic streptococci, is complicated more frequently by metastatic infection than is that due to avirulent bacteria, e.g., viridans streptococci. Virtually any organ or tissue may be hematogenously infected. Metastatic abscesses are often small and miliary. Metastatic infection assumes particular importance when the required therapy is more than the antibiotics indicated for IE or when these infections constitute a focus that engenders relapse.[84] The humoral and cell-mediated arms of the immune system are stimulated in patients with IE. Antibodies to the infecting organism in the three major classes--IgM, IgG, and IgA--with functional capacity including opsonization, agglutination, and complement fixation have been noted. Additionally, hypergammaglobulinemia and cryoglobulinemia have been noted. Cellular responses are suggested by activated circulating macrophages and splenomegaly. Circulating immune complexes in high titer have been detected in most patients with bacteremic IE and PVE. The frequency and titer of the circulating immune complexes are highest in IE of long duration, in the presence of extravalvular manifestation, and in right-sided IE. Although circulating immune complex titers fall with effective antibiotic therapy, titers are not widely used to monitor therapy. Immune complexes are clinically relevant when, with complement, they deposit

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Figure 47-4 Infiltrates in the right and left midlung fields caused by septic pulmonary emboli arising from Staphylococcus aureus tricuspid valve infective endocarditis in an intravenous drug abuser.

subepithelially along the glomerular basement membrane to cause diffuse or focal glomerulonephritis.[67] Histological examination of affected glomeruli stained with fluorescent-labeled antibody to human globulin reveals a "lumpy-bumpy" pattern. The immunoglobulin eluted from the glomerular lesions reacts with bacterial antigens. Rheumatological manifestations of IE and some peripheral manifestations of IE, such as Osler's nodes, have been attributed to local deposition of immune complexes.[67] Osler's nodes, however, have also been associated with septic embolization in S. aureus IE. Rheumatoid factor (an IgM antibody directed against IgG) is present in half of the patients with IE of greater than 6 weeks' duration. [67] The titer of rheumatoid factor decreases slowly with effective antimicrobial therapy. CLINICAL FEATURES

The interval between the presumed initiating bacteremia and the onset of symptoms of IE is estimated to be less than 2 weeks in more than 80 percent of patients with NVE. Interestingly, in some patients with intraoperative or perioperative infection of prosthetic valves, the incubation period may be prolonged (2 to 5 or more months). [28] Fever is the most common symptom and sign in patients with IE (Table 47-4) . Fever may be absent or minimal in the elderly or in those with CHF, severe debility, or chronic renal failure and occasionally in patients with NVE caused by coagulase-negative staphylococci.[50] [85] Heart murmurs are noted in 80 to 85 percent of patients with NVE and are emblematic of the lesion predisposing to IE. Murmurs are commonly not audible in patients with tricuspid valve IE. Similarly, in acute NVE due to S. aureus, murmurs are heard in only 30 to 45 percent of patients on initial evaluation but are ultimately noted in 75 to 85 percent. The new or changing murmurs (alterations unrelated to heart rate or cardiac output but rather regurgitant murmurs indicative of valve dysfunction) are relatively infrequent TABLE 47-4 -- CLINICAL FEATURES OF INFECTIVE ENDOCARDITIS SYMPTOMS PERCENT SIGNS PERCENT Fever

80-85

Fever

80-90

Chills

42-75

Murmur

80-85

Changing/new murmur

10-40

Neurological abnormalities

30-40

Sweats

25

Anorexia

25-55

Weight loss

25-35

Malaise

25-40

Dyspnea

20-40

Embolic event

20-40

Cough

25

Splenomegaly

15-50

Stroke

13-20

Clubbing

10-20

Headache

15-40

Peripheral manifestation

Nausea/vomiting

15-20

Myalgia/arthralgia

15-30

Osler's nodes

7-10

Chest pain

8-35

Splinter hemorrhage

5-15

Abdominal pain

5-15

Back pain

7-10

Petechiae

10-40

Confusion

10-20

Janeway's lesion

6-10

*

Retinal lesion/Roth's spots

4-10

Central nervous system. *More common in intravenous drug abusers.

in subacute NVE and are more prevalent in acute IE and PVE.[28] [86] They frequently are important harbingers of CHF. Enlargement of the spleen is noted in 15 to 50 percent of patients and is more common in subacute IE of long duration. The classical peripheral manifestations of IE are encountered less frequently today and are absent in IE restricted to the tricuspid valve.[4] [16] Petechiae (Fig. 47-5) , the most common of these manifestations, are found on the palpebral conjunctiva, the buccal and palatal mucosa, and the extremities. They are not specific for endocarditis even on the conjunctiva. Splinter or subungual hemorrhages (Fig. 47-6) are dark red, linear, or occasionally flame-shaped streaks in the nail bed of the fingers or toes. Distal lesions are likely due to trauma, whereas the more proximal ones are more likely related to IE. Osler's nodes are small, tender subcutaneous nodules that develop in the pulp of the digits or occasionally more proximally in the fingers and persist for hours to several days. These too are not pathognomonic for

Figure 47-5 Conjunctival petechiae in a patient with infective endocarditis. (From Kaye D: Infective Endocarditis. Baltimore, University Park Press, 1976.)

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Figure 47-6 Subungual hemorrhages (splinter hemorrhages) and digital petechiae in a patient with infective endocarditis.(From Korzeniowski OM, Kaye D: Infective endocarditis. In Braunwald E [ed]: Heart Disease. 4th ed. Philadelphia, WB Saunders, 1992.)

IE. [86] Janeway's lesions are small erythematous or hemorrhagic macular nontender lesions on the palms and soles and are the consequence of septic embolic events. Roth's spots (Fig. 47-7) , oval retinal hemorrhages with pale centers, are infrequent findings in patients with IE. They have been noted in patients with collagen vascular disease and hematologic disorders, including severe anemia. Musculoskeletal symptoms, unrelated to focal infection, are relatively common in patients with IE. These include arthralgias and myalgias, occasional true arthritis with nondiagnostic but inflammatory synovial fluid findings, and prominent back pain without evidence of vertebral body, disc space, or sacroiliac joint infection.[86] In patients with arthritis or back pain, focal infection must be precluded because additional therapy may

be required. Systemic emboli are among the most common clinical sequelae of IE, occurring in up to 40 percent of patients, and are frequent subclinical events found only at autopsy.[9] [67] [80] [81] Emboli often antedate diagnosis. Although embolic events may occur during or after antimicrobial therapy, the incidence decreases promptly during administration of effective

Figure 47-7 Roth spot (retinal hemorrhage with a clear center) in a patient with infective endocarditis.(From Korzeniowski OM, Kaye D: Infective endocarditis. In Braunwald E [ed]: Heart Disease. 4th ed. Philadelphia, WB Saunders, 1992.)

antibiotic therapy.[85] [87] Embolic splenic infarction may cause left upper quadrant abdominal pain and left shoulder pain. Renal emboli may occur asymptomatically or with flank pain and may cause gross or microscopic hematuria. Embolic stroke syndromes, predominantly involving the middle cerebral artery territory, occur in 15 to 20 percent of patients with NVE and PVE.[28] [88] Coronary artery emboli are common findings at autopsy but rarely result in transmural infarction. Emboli to the extremities may produce pain and overt ischemia, and those to mesenteric arteries may cause abdominal pain, ileus, and guaiac-positive stools. Neurological symptoms and signs occur in 30 to 40 percent of patients with IE, are more frequent when IE is caused by S. aureus, and are associated with increased mortality rates.[80] [86] [89] [90] Embolic stroke is the most common and clinically important of the neurological manifestations. Intracranial hemorrhage occurs in 5 percent of patients with IE. Bleeding results from rupture of a mycotic aneurysm, rupture of an artery due to septic arteritis at the site of embolic occlusion, or hemorrhage into an infarct.[91] Mycotic aneurysms, with or without rupture, occur in 2 to 10 percent of patients with IE; approximately half of these involve intracranial arteries (Fig. 47-8) . Cerebritis with microabscesses complicates IE caused by invasive pathogens such as S. aureus, but large brain abscesses are rare.[88] Purulent meningitis complicates some episodes of IE caused by S. aureus or S. pneumoniae, but more typically the cerebrospinal fluid has an aseptic profile.[43] [89] Other neurological manifestations include severe headache (a potential clue to a mycotic aneurysm), seizure, and encephalopathy. CHF complicating IE is primarily the result of valve destruction or distortion or rupture of chordae tendineae. Intracardiac fistulas, myocarditis, or coronary artery embolization may occasionally contribute to the genesis of CHF, as obviously can underlying cardiac disease. In the absence of surgery to correct valvular dysfunction, CHF, particularly that due to aortic insufficiency, is associated with very high mortality rates. [76] Renal insufficiency as a result of immune complex-mediated glomerulonephritis occurs in less than 15 percent of patients with IE. Azotemia as a result of this process may develop or progress during initial therapy; it usually improves

Figure 47-8 An irregular mycotic aneurysm of the middle cerebral artery lies laterally on the cerebral cortex. A second aneurysm is projected just lateral to the anterior cerebral artery.

with continued administration of effective antibiotic therapy.[86] Focal glomerulonephritis and embolic renal infarcts cause hematuria but rarely result in azotemia. Renal dysfunction in patients with IE is most commonly a manifestation of impaired hemodynamics or toxicities associated with antimicrobial therapy (interstitial nephritis or aminoglycoside-induced injury). 1732

DIAGNOSIS The symptoms and signs of endocarditis are often constitutional and, when localized, often result from a complication of IE rather than reflect the intracardiac infection itself (see Table 47-4) . Consequently, if physicians are to avoid overlooking the diagnosis of IE, a high index of suspicion must be maintained. The diagnosis must be investigated when patients with fever present with one or more of the cardinal elements of IE: a predisposing cardiac lesion or behavior pattern, bacteremia, embolic phenomenon, and evidence of an active endocardial process. Because patients with prosthetic heart valves are always at risk for PVE, the presence of fever or new prosthesis dysfunction at any time warrants considering this diagnosis. In patients at risk for endocarditis, concurrent illnesses or iatrogenic events may create clusters of symptoms and signs that superficially mimic IE and require careful consideration to arrive at a correct diagnosis. Even when the illness seems typical of endocarditis, the definitive diagnosis requires positive blood cultures or positive cultures (or histology or polymerase chain reaction recovery of a microorganism's DNA) from the vegetation or embolus. There are many culture-negative mimics of IE: atrial myxoma, acute rheumatic fever, systemic lupus erythematosus or other collagen-vascular disease, marantic endocarditis, the antiphospholipid syndrome, carcinoid syndrome, renal cell carcinoma with increased cardiac output, and thrombotic thrombocytopenic purpura. When used judiciously over the entire evaluation sequence, i.e., not limited to initial findings, published criteria provide a sensitive and specific approach to the diagnosis of IE (Table 47-5) .[92] [94] Erroneous rejection of the diagnosis of endocarditis is unlikely. When using these diagnostic criteria to guide therapy, patients who are categorized with possible endocarditis should be treated as if they have IE. This management philosophy, however, may lead to the treatment of individuals as possible IE patients who are not likely to have the infection.[96] Requiring at least one major criterion or three minor criteria to designate possible endocarditis may reduce this potential for overdiagnosis.[94] To use bacteremia due to coagulase-negative staphylococci or diphtheroids (organisms that may cause IE but more often contaminate blood cultures) to support the diagnosis of endocarditis, blood cultures must be persistently positive or the organisms recovered

in several sporadically positive cultures must be proved to represent a single clone.[92] Inclusion of echocardiographic evidence of endocardial infection in these criteria recognizes the high sensitivity of two-dimensional echocardiography with color Doppler, especially if multiplanar TEE and TTE are combined, and the relative infrequency of false-positive studies when experienced operators use specific definitions for vegetations.[94] [97] [98] Although the sensitivity of TEE to detect vegetations in patients with suspected infective endocarditis is 82 to 94 percent (or higher if a follow-up study is performed), a negative study result does not preclude the diagnosis or the need for therapy if the clinical suspicion is high.[98] The likelihood of a false-negative result can be reduced to 5 to 10 percent if TEE is repeated, especially if the study is biplanar or multiplanar.[94] [98] Thus, these studies help to preclude the diagnosis when the clinical suspicion is TABLE 47-5 -- DIAGNOSIS OF INFECTIVE ENDOCARDITIS Definitive Infective Endocarditis Pathological criteria Microorganisms: demonstrated by culture or histology in a vegetation, or in a vegetation that has embolized, or in an intracardiac abscess, or Pathological lesions: vegetation or intracardiac abscess present, confirmed by histology showing active endocarditis Clinical criteria, using specific definitions listed below Two major criteria, or One major and three minor criteria, or Five minor criteria Possible Infective Endocarditis Findings consistent with infective endocarditis that fall short of definite endocarditis but are not rejected Rejected Firm alternative diagnosis for manifestations of endocarditis, or Sustained resolution of manifestations of endocarditis, with antibiotic therapy for 4 days or less, or No pathological evidence of infective endocarditis at surgery or autopsy, after antibiotic therapy for 4 days or less Criteria for Diagnosis of Infective Endocarditis Major Criteria Positive blood culture Typical microorganism for infective endocarditis from two separate blood cultures Viridans streptococci, Streptococcus bovis, HACEK group or

Community-acquired Staphylococcus aureus or enterococci in the absence of a primary focus, or Persistently positive blood culture, defined as recovery of a microorganism consistent with infective endocarditis from: Blood cultures drawn more than 12 hr apart, or All of three or a majority of four or more separate blood cultures, with first and last drawn at least 1 hr apart Evidence of endocardial involvement Positive echocardiogram Oscillating intracardiac mass, on valve or supporting structures, or in the path of regurgitant jets, or on implanted material, in the absence of an alternative anatomical explanation, or Abscess, or New partial dehiscence of prosthetic valve, or New valvular regurgitation (increase or change in preexisting murmur not sufficient) Minor Criteria Predisposition: predisposing heart condition or intravenous drug use Fever 38.0°C (100.4°F) Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, Janeway's lesions Immunological phenomena: glomerulonephritis, Osler's nodes, Roth's spots, rheumatoid factor Microbiological evidence: positive blood culture but not meeting major criterion as noted previously* or serologic evidence of active infection with organism consistent with infective endocarditis Echocardiogram: consistent with infective endocarditis but not meeting major criterion Adapted from Durack DT, Lukes AS, Bright DK: New criteria for diagnosis of infective endocarditis: Utilization of specific echocardiographic findings. Am J Med 96:200, 1994. *Excluding single positive cultures for coagulase-negative staphylococci and organisms that do not cause endocarditis.

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low. [94] [98] Nevertheless, when the clinical suspicion is high, even these highly sensitive tests cannot preclude the diagnosis. These guidelines are vulnerable to misidentifying

as culture-negative IE the vegetations that complicate marasmus, malignancy, cryptic collagen-vascular disease, or the antiphospholipid antibody syndrome. A microbial cause of IE is established by recovering the infecting agent from the blood or by identifying it in surgically removed vegetations or embolic material. In detecting the bacteremia of IE there is no advantage to obtaining blood cultures in relationship to fever nor from arterial blood (as opposed to venous blood). In patients who have not received prior antibiotics and who will ultimately have blood culture-positive IE, it is likely that 95 to 100 percent of all cultures obtained will be positive and that one of the first two cultures will be positive in at least 98 percent of patients. Prior antibiotic therapy is a major cause of blood culture-negative IE, particularly when the causative microorganism is highly antibiotic susceptible. At least 35 percent of cases of culture-negative IE can be attributed to prior antimicrobial therapy.[99] After subtherapeutic antibiotic exposure, the time required for reversion to positive cultures is directly related to the duration of antimicrobial therapy and the susceptibility of the causative agent; days to a week or more may be required. OBTAINING BLOOD CULTURES.

Three separate sets of blood cultures, each from a separate venipuncture, obtained over 24 hours, are recommended to evaluate patients with suspected endocarditis.[94] Each set should include two flasks, one containing an aerobic medium and the other containing thioglycollate broth (anaerobic medium) into which at least 10 ml of blood should be placed. For optimal processing, the laboratory should be advised that endocarditis is a possible diagnosis and which, if any, unusual bacteria are suspected (Legionella species, Bartonella species, HACEK organisms). If a clinically stable patient has received an antimicrobial agent during the past several weeks, it is prudent to delay therapy so that repeat cultures can be obtained on successive days. If fungal endocarditis is suspected, blood cultures should be obtained using the lysis-centrifugation method. The laboratory should be asked to save the organism causing endocarditis until successful therapy has been completed. Serologic tests are occasionally used to make the presumptive etiological diagnosis of endocarditis caused by Brucella species, Legionella species, Bartonella species, C. burnetii, or Chlamydia species. By special techniques, including polymerase chain reaction, these agents and others that are difficult to recover in blood culture can be identified in or recovered from blood or vegetations.[14] [58] [59] [60] [94] [100] [101] Laboratory Tests

Many other tests are inevitably performed in the evaluation of patients with suspected IE.[102] Hematological parameters are commonly abnormal. Anemia, with normochromic normocytic red blood cell indices, a low serum iron level, and low serum iron-binding capacity, is found in 70 to 90 percent of patients. Anemia worsens with increased duration of illness and thus in acute IE may be absent. In subacute IE, the white blood cell count is usually normal; in contrast, a leukocytosis with increased segmented granulocytes is common in acute IE. Thrombocytopenia occurs only rarely. The erythrocyte sedimentation rate (ESR) is elevated (average approximately 55 mm/hr)

in almost all patients with IE; the exceptions are those with CHF, renal failure, or disseminated intravascular coagulation. Other tests often indicate immune stimulation or inflammation (see Pathophysiology): circulating immune complexes, rheumatoid factor, quantitative immune globulin determinations, cryoglobulins, and C-reactive protein. Although the results of these tests parallel disease activity, the tests are costly and not efficient ways to diagnose IE or monitor response to therapy. Measurement of circulating immune complexes and complement may be useful in evaluating for azotemia due to diffuse immune complex glomerulonephritis.[102] The urinalysis result is often abnormal, even when renal function remains normal. Proteinuria and microscopic hematuria are noted in 50 percent of patients. Urinalysis has a standard role in the evaluation of azotemia. Serological tests are used to evaluate blood culture-negative IE (see Diagnosis). The presence or absence of antibodies to ribitol teichoic acids from staphylococci does not distinguish uncomplicated S. aureus bacteremia from that associated with IE or other deep-seated infection. Echocardiography (See also Chap. 7)

Evaluation of patients with clinically suspected IE by this technique frequently allows morphological confirmation of infection and increasingly aids in decisions about management.[97] [98] Echocardiography should not be used as a screening test for IE in unselected patients with positive blood cultures or in patients with fevers of unknown origin when the clinical probability is low.[94] [95] Nevertheless, echocardiographic evaluation should be performed in all patients with clinically suspected IE, including those with negative blood cultures.[94] Although many patients with NVE involving the aortic or mitral valve can be imaged adequately by TEE using biplane or multiplane technology with incorporated color flow and continuous as well as pulsed Doppler is the state of the art.[94] [99] [103] TEE allows visualization of smaller vegetations and provides improved resolution compared with TTE. Not only is TEE the preferred approach in patients with clinically suspected IE in whom TTE is suboptimal, it is also the procedure of choice for imaging the pulmonic valve, patients with PVE (especially at the mitral site), and patients who are at high risk for intracardiac complications or those with signs of persistent or invasive infection despite adequate antimicrobial therapy.[94] [97] [103] [104] [105]

A decision analysis evaluation of echocardiography for diagnosis of IE involving native valves suggests that, assuming the diagnostic enhancement of TEE over TTE is 15 percent, the most cost-effective strategy (yielding optional quality adjusted life years) is 1) if prior probability of IE is less than 2 percent, treat for bacteremia without echocardiography; 2) if prior probability is 2 to 4 percent, use TTE; 3) if prior probability is 5 to 45 percent, use TEE in lieu of TTE, which would be followed by TEE if negative. If the prior probability of IE is greater than 45 percent, therapy without echocardiography is cost effective, although studies may still be desirable to evaluate for complications and other risks.[105A] The sensitivity of TTE for the detection of vegetations in NVE is less than 65 percent,

although its specificity is excellent. In contrast, in proven NVE, the sensitivity for vegetation detection of TEE was 100 and 90 percent, and in clinically suspected NVE, it ranged from 82 to 94 percent (see Diagnosis).[98] In patients with PVE, TTE is limited by the shadowing effect of mitral valve prostheses. The sensitivity of TEE for detecting vegetations in PVE involving mechanical or bioprosthetic devices ranged from 82 to 96 percent, whereas that of TTE was from 36 to 16 percent.[104] [105] [106] Despite the sensitivity of TEE in detecting vegetations in patients with proven IE, echocardiography does not itself provide a definite diagnosis. Vegetations and valve dysfunction may be demonstrated, but determination of causality requires clinical or direct anatomical and microbiological confirmation. Infectious vegetations cannot be distinguished from marantic lesions, nor can vegetations be distinguished from thrombus or pannus on prostheses. Furthermore, it is usually not possible to distinguish active from healed vegetations in NVE.[97] [107] Thickened valves, ruptured chordae or valves, valve calcification, and nodules may be mistaken for vegetations, indicating the specificity limitations of echocardiography.[97]

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Valve dysfunction due to tissue disruption or large obstructing vegetations can be visualized and quantitated by echocardiogram with Doppler.[82] [97] Some degree of regurgitation by Doppler is almost universal early in the course of NVE and PVE and does not necessarily predict subsequent hemodynamic deterioration.[97] Extension of infection beyond the valve leaflet into surrounding tissue is an ominous step in the progression of IE. It can result in abscesses in various areas of the annulus or adjacent structures, mycotic aneurysms of the sinus of Valsalva or mitral valve, intracardiac fistulas, and purulent pericarditis. Myocardial abscesses are more readily detected by TEE than TTE in patients with NVE or PVE.[104] [105] [106] The sensitivity and specificity for abscess detection were 28 percent and 98 percent for TTE, compared with 87 percent and 95 percent for TEE. Other studies have reported similar findings, especially in recognizing subaortic invasive disease.[108] The natural history of vegetations during therapy is variable. On repeat echocardiogram 3 weeks to 3 months after initiation of ultimately effective antimicrobial therapy, 29 percent of 41 initial vegetations were no longer detectable. Of the 29 vegetations that remained detectable, 58 percent were unchanged, 24 percent were smaller, and 17 percent were larger. Mobility and extent (valves involved) of vegetations were unchanged in 86 and 65 percent, respectively. The evolution of these vegetations was not related to the duration of therapy or initial vegetation size, nor did it predict late complications of IE.[107] [108] In another study among patients, not all of whom were responding to therapy, persistence or increase in vegetation size during therapy was associated with an increased rate of complications. Accordingly, changes in vegetations must be interpreted in a clinical context and do not in themselves reflect the efficacy of therapy. Stratification of patients into groups that are at high and low risk for CHF, systemic embolization, need for surgical intervention, and death based on the presence or

absence of vegetations remains controversial.[82] [94] [97] The heterogeneous nature of the patients examined, the technologies used, and the lack of correlation with other features of IE, as well as the increasing ability to visualize vegetations in most patients with IE using TEE, undermine this debate. Although not demonstrated in all individual studies, pooled data from two-dimensional echocardiographic studies suggest that patients with larger vegetations (>10 mm in diameter) are at increased risk for embolic complications (20 percent versus 40 percent).[82] [97] This increased risk appears to be associated with large vegetations involving the mitral valve, particularly the anterior leaflet, and with the mobility of vegetations.[94] [97] The correlation of aortic or mitral valve vegetation size, extent, mobility, and site with CHF, need for surgical intervention, and mortality (other than that associated with embolic events) has not been fully established.[94] [97] Among patients with right-sided IE, visualization of vegetations by TTE has been correlated with prolonged fever during therapy and increased right ventricular end-diastolic dimensions. These findings were not related to vegetation size, nor did the presence of vegetations or their size predict the failure of medical therapy and a need for surgical intervention. MAGNETIC RESONANCE IMAGING.

This technique has identified paravalvular extension of infection, aortic root aneurysms, and fistulas; however, its utility relative to echocardiography has not been established. SCINTIGRAPHY.

Efforts to identify vegetations and intracardiac abscess in patients with IE and in animal models have used scintigraphy with gallium-67 citrate, indium-111-labeled granulocytes, and indium-111-labeled platelets. These efforts have not been sufficiently sensitive or anatomically localizing to be useful clinically.[109] TREATMENT Two major objectives must be achieved to treat IE effectively. The infecting microorganism in the vegetation must be eradicated. Failure to accomplish this results in relapse of infection. Also, invasive, destructive intracardiac and focal extracardiac complications of infection must be resolved if morbidity and mortality are to be minimized. The second objective often exceeds the capacity of effective antimicrobial therapy and requires cardiac or other surgical intervention. Bacteria in vegetations multiply to population densities approaching 10[9] to 10[10] organisms per gram of tissue, become metabolically dormant, and are difficult to eradicate. Clinical experience and animal model experiments suggest that optimal therapy should use bactericidal antibiotics or antibiotic combinations rather than bacteriostatic agents. Additionally, antibiotics reach the central areas of avascular vegetations by passive diffusion. To reach effective antibiotic concentrations in vegetations, high serum concentrations must be achieved, and penetration by some agents is limited even then. Parenteral antimicrobial therapy is used whenever feasible

in order to achieve suitable serum antibiotic concentrations and to avoid the potentially erratic absorption of orally administered therapy. Treatment is continued for prolonged periods to ensure eradication of dormant microorganisms. In selecting antimicrobial therapy for patients with IE, one must consider the ability of potential agents to kill the causative organism as well as the MIC and minimum bactericidal concentration (MBC) of these antibiotics for the organism. The MIC is the lowest concentration that inhibits growth, and the MBC is the lowest concentration that decreases a standard inoculum of organisms 99.9 percent during 24 hours. For the vast majority of streptococci and staphylococci, the MIC and MBC of penicillins, cephalosporins, or vancomycin are the same or differ by only a factor of two to four. Organisms for which the MBC for these antibiotics is 10-fold or greater than the MIC are occasionally encountered. This phenomenon has been termed tolerance.[110] Most of the tolerant strains are simply killed more slowly than nontolerant strains, and with prolonged incubation (48 hours) their MICs and MBCs are similar. Enterococci exhibit what superficially appears to be tolerance when tested against penicillins and vancomycin; however, these organisms are, in fact, not killed by these agents but are merely inhibited, even after longer incubation times. Enterococci can be killed by the combined activity of selected penicillins or vancomycin and an aminoglycoside. This enhanced antibiotic activity of the combination against enterococci, if of sufficient magnitude, is called synergy or a synergistic bactericidal effect.[45] [110] A similar effect can be seen with these combinations against streptococci and staphylococci; this effect overcomes tolerance.[110] A synergistic bactericidal effect is required for optimal therapy of enterococcal endocarditis and has been used to achieve more effective therapy or effective short-course therapy of IE caused by other organisms. Tolerance in streptococci or staphylococci has been associated with reduced eradication of organisms from vegetations in animal model experiments.[111] [112] However, this finding in organisms causing endocarditis has not been correlated with decreased cure rates or delayed responses to treatment with penicillins, cephalosporins, or vancomycin. Accordingly, the presence of tolerance in streptococci or staphylococci has not required combination therapy, and, in fact, regimens are designed using the MICs of these organisms. [113] The regimens recommended for the treatment of IE caused by specific organisms are designed to provide high concentrations of antibiotics in serum, also deep in vegetations. Concentrations that exceed the organism's MIC throughout most, if not all, of the interval between doses are recommended. Although antibiotic concentrations in vegetations of patients with IE have been measured infrequently, the success of the recommended regimens suggests that this goal has been achieved. Accordingly, for optimal therapy, it is important that the recommended regimens be followed carefully. Antimicrobial Therapy for Specific Organisms

The antimicrobial therapy for endocarditis should not only eradicate the causative agent but should do so while causing little or no toxicity. Therapy for a given patient requires

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modification to accommodate end-organ dysfunction, existing allergies, and other anticipated toxicities. With the exception of staphylococcal endocarditis, the antimicrobial regimens recommended for the treatment of NVE and PVE are similar, although more prolonged treatment is often advised for PVE.[28] [113] PENICILLIN-SUSCEPTIBLE VIRIDANS STREPTOCOCCI OR STREPTOCOCCUS BOVIS.

Four regimens provide highly effective, comparable therapy for patients with endocarditis caused by penicillin-susceptible TABLE 47-6 -- TREATMENT FOR NATIVE VALVE ENDOCARDITIS DUE TO PENICILLIN-SUSCEPTIBLE VIRIDANS STREPTOCOCCI AND STREPTOCOCCUS BOVIS (MINIMUM INHIBITORY CONCENTRATION 0.1 mug/ml)* ANTIBIOTIC DOSAGE AND ROUTE DURATION (WK) Aqueous penicillin G

12-18 million units/24 hr IV either continuously or every 4 hr in six equally divided doses

4

Ceftriaxone

2 gm once daily IV or IM

4

Aqueous penicillin G

12-18 million units/24 hr IV either continuously or every 4 hr in six equally divided doses

2

Gentamicin

1 mg/kg IM or IV every 8 hr

2

Vancomycin

30 mg/kg/24 hr IV in two equally divided doses, not to exceed 2 gm/24 hr unless serum levels are monitored

4

plus

Modified from Wilson WR, Karchmer AW, Dajani AS, et al: Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, staphylococci, and HACEK microorganisms. JAMA 274:1706, 1995. Copyright 1995 American Medical Association. *For nutritionally variant streptococci (Streptococcus adjacens, Streptococcus defectivus ), see Table 47-8 . Dosages given are for patients with normal renal function. Vancomycin and gentamicin doses must be reduced for treatment of patients with renal dysfunction. Vancomycin and gentamicin doses are calculated using ideal body weight (men=50 kg+2.3 kg per inch over 5 feet; women=45.5 kg+2.3 kg per inch over 5 feet).

TABLE 47-7 -- TREATMENT FOR NATIVE VALVE ENDOCARDITIS DUE TO STRAINS OF VIRIDANS STREPTOCOCCI AND STREPTOCOCCUS BOVIS RELATIVELY RESISTANT TO PENICILLIN G (MINIMUM INHIBITORY CONCENTRATION >0.1 mug/ml AND 2000 mug/ml) and are not killed synergistically by penicillin plus streptomycin. These highly streptomycin-resistant strains are, however, killed synergistically by penicillin plus gentamicin. Consequently, unless a causative streptococcus can be evaluated to preclude high-level resistance to streptomycin, gentamicin is recommended for use in the short-course combination regimen.[114] Ceftriaxone 2 gm once daily plus either gentamicin (3 mg/kg) or netilmicin (4 mg/kg) given as a single daily dose for 14 days has effectively treated endocarditis caused by penicillin-susceptible streptococci.[115] [116] Nevertheless, experience with single daily doses of aminoglycosides in the treatment of IE is limited, and these regimens are not currently recommended. The Abiotrophia species, previously called nutritionally variant streptococci, S. adjacens and S. defectivus, are generally more resistant to penicillin than are other viridans streptococci.[39] Patients with endocarditis caused by these organisms are treated with regimens recommended for enterococcal endocarditis (see Table 47-8) ; however, outcome remains unsatisfactory.

For the treatment of streptococcal endocarditis in patients with a history of immediate allergic reactions (urticarial or anaphylactic reactions) to a penicillin or cephalosporin antibiotic, vancomycin is recommended (see Table 47-6) . Patients with other forms of penicillin allergy (delayed maculopapular skin rash) may be treated cautiously with the ceftriaxone regimen (see Table 47-6) or with cefazolin, 2 gm IV every 8 hours for 4 weeks. For patients with PVE caused by penicillin-susceptible streptococci, treatment with 6 weeks of penicillin is recommended, with gentamicin given during the initial 2 weeks.[28] RELATIVELY PENICILLIN-RESISTANT STREPTOCOCCI.

Four weeks of high-dose parenteral penicillin plus an aminoglycoside (primarily gentamicin for the reasons noted previously) during the initial 2 weeks is recommended for treatment of patients with endocarditis caused by streptococci with MICs for penicillin between 0.2 and 0.5 mug/ml (Table 47-7) . Patients who cannot tolerate penicillin because of immediate hypersensitivity reactions can be treated with vancomycin alone. For those with nonimmediate penicillin hypersensitivity, effective treatment can be accomplished with either vancomycin alone or by adding gentamicin to the initial 2 weeks of the ceftriaxone regimen (see Table 47-6) . Patients with endocarditis caused by streptococci that are highly resistant to penicillin (MIC > 0.5 mug/ml) should be treated with one of the regimens recommended for enterococcal endocarditis (see Table 47-8) . STREPTOCOCCUS PYOGENES, STREPTOCOCCUS PNEUMONIAE, AND GROUPS B, C, AND G STREPTOCOCCI.

Endocarditis caused by these streptococci has been either refractory to antibiotic therapy or associated with extensive valvular damage. Penicillin G in a dose of 3 million units IV every 4 hours for 4 weeks is recommended for the treatment of group A streptococcal and pneumococcal endocarditis. Pneumococci that are relatively resistant (MIC>0.1

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mug/ml to 1.0 mug/ml) and highly resistant (MIC>1.0 mug/ml) to penicillin are widely distributed and likely to cause sporadic cases of endocarditis. Treatment with ceftriaxone plus vancomycin may be preferable until the penicillin susceptibility of the infecting strain is confirmed.[44] IE caused by group G, C, or B streptococci is more difficult to treat than that caused by penicillin-susceptible viridans streptococci. Consequently, the addition of gentamicin to the first 2 weeks of a 4-week regimen using high doses of penicillin is often advocated[42] (see Table 47-7) . Early cardiac surgery to correct intracardiac complications is needed in almost half of these cases; prompt intervention may improve outcome.[42]

BACTEREMIA.

Sustained bacteremia is typical of IE. In evaluating positive blood cultures, sustained bacteremia (persisting over >1 hour) should be distinguished from transient bacteremia. When several blood cultures obtained over 24 hours or more are positive, the diagnosis of IE must be considered. The identity of the organism is also helpful in determining the intensity with which the diagnosis is entertained. Organisms can be divided into those that commonly cause IE, those that rarely cause IE, and the intermediate-behaving organisms, e.g., enterococci and S. aureus, which, when in the blood, may or may not indicate IE. Finally, the presence or absence of alternative sources for the bacteremia aids in the assessment of bacteremia. These considerations are embodied in the diagnostic criteria for IE (see Table 47-5) .[90] [92] Among patients with S. aureus bacteremia, the risk of IE has been greatest in those with community-acquired infection, those who lack a peripheral site of infection, those who are IV drug abusers, those who have evidence of valvular disease, and those who are diabetic with chronic cutaneous infections. Screening of patients with community-acquired S. aureus bacteremia using TTE demonstrated 20 percent of the patients to have either occult IE or valve lesions predisposing to IE.[93] Early studies have suggested that S. aureus catheter-associated bacteremia leads to IE in only 6.1 percent of patients.[34] IE was noted in 23 percent of 69 patients with catheter-associated S. aureus bacteremia. [35] In an additional study, 50 percent of patients with S. aureus IE had an intravascular catheter or a hemodialysis graft as the presumed source of infection.[52] In both of these studies, TTE was not sufficiently sensitive, and TEE was frequently required to diagnose IE. Thus, it is prudent to use TTE to evaluate patients with catheter-associated S. aureus, who appear to be at moderate clinical risk of having IE and to use TEE if that is negative or not diagnostic. [51] [94] [95] Patients with S. aureus bacteremia who have known underlying valvular heart disease, have a new significant heart murmur, or have persistent fever or bacteremia for 3 days or more after removal of the presumed primary focus of infection (intravascular catheter or drainage of an abscess) and initiation of therapy are at high risk for IE and require full echocardiographic evaluation.[36] [93] ENTEROCOCCI.

Optimal therapy for enterococcal endocarditis requires synergistic bactericidal interaction of an antimicrobial targeted against the bacterial cell wall (penicillin, ampicillin, or vancomycin) and an aminoglycoside that is able to exert a lethal effect (primarily streptomycin or gentamicin). High-level resistance, defined as the inability of high concentrations of streptomycin (2000 mug/ml) or gentamicin (500 to 2000 mug/ml) to inhibit the growth of an enterococcus, is predictive of the agent's inability to exert this lethal effect and participate in the bactericidal synergistic interaction in vitro and in vivo.[45] [46] The standard regimens recommended for the treatment of enterococcal endocarditis (Table 47-8) are designed to achieve bactericidal synergy. Synergistic combination therapy has resulted in cure rates of approximately 85 percent, compared with 40 percent with single-agent, nonbactericidal treatment.[45]

TABLE 47-8 -- STANDARD THERAPY FOR ENDOCARDITIS DUE TO ENTEROCOCCI * ANTIBIOTIC DOSAGE AND ROUTE DURATION (WK) Aqueous penicillin G

18-30 million units/24 hr IV given continuously or every 4 hr in six equally divided doses

4-6

Gentamicin


4-6

Ampicillin

12 gm/24 hr IV given continuously or every 4 hr in six equally divided doses

4-6

Gentamicin


4-6

Vancomycin

30 mg/kg/24 hr IV in two equally divided doses not to exceed 2 gm/24 hr unless serum levels are monitored

4-6


4-6

plus

plus

plus Gentamicin

Modified from Wilson WR, Karchmer AW, Dajani AS, et al: Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, staphylococci, and HACEK microorganisms. JAMA 274:1706, 1995. Copyright 1995 American Medical Association. *All enterococci causing endocarditis must be tested for antimicrobial susceptibility in order to select optimal therapy. These regimens are for treatment of endocarditis caused by enterococci that are susceptible to vancomycin or ampicillin and not highly resistant to gentamicin. These may also be used for treatment of endocarditis caused by penicillin-resistant (MIC>0.5) viridans streptococci and nutritionally variant streptococci (S. defectivus, S. adjacens), or enterococcal PVE. Dosages are for patients with normal renal function. See Table 47-6 , footnote. Cephalosporins are not alternatives to penicillin/ampicillin in penicillin-allergic patients.

Some authorities prefer gentamicin doses of 1.5 mg/kg every 8 hours; however, because this dose may be associated with an increased frequency of nephrotoxicity, others advocate doses of 1 mg/kg every 8 hours. Peak serum gentamicin concentrations of approximately 5 mug/ml and 3.5 mug/ml are sought with these doses, respectively. In the absence of high-level resistance to streptomycin in a causative strain, streptomycin, 7.5 mg/kg intramuscularly (IM) or IV, every 12 hours, to achieve a peak serum concentration of approximately 20 mug/ml, can be substituted for gentamicin in the standard regimens. For patients allergic to penicillin, the vancomycin-aminoglycoside regimen (Table 47-8) is recommended; alternatively, patients can be desensitized to penicillin. Desensitization may be desirable when

preexisting renal dysfunction favors avoiding the potentially more nephrotoxic vancomycin-aminoglycoside combination. Cephalosporins are not effective in the treatment of enterococcal endocarditis. Therapy is administered for 4 to 6 weeks, with the longer course used to treat patients with IE that was symptomatic for more than 3 months, with complicated disease, and with enterococcal PVE. During treatment, careful clinical follow-up of patients and aminoglycoside levels is required to prevent nephrotoxicity and ototoxicity. Previously, 40 percent of enterococci demonstrated high-level resistance to streptomycin, and none was highly resistant to gentamicin. Furthermore, penicillin, ampicillin, and vancomycin inhibited all enterococci at concentrations achieved in the serum with standard IV doses. Accordingly, one of the standard regimens could be selected for treatment with confidence that bactericidal synergy would be achieved. Antimicrobial resistance among enterococci is now complex and cannot be predicted without in vitro testing. High-level resistance to gentamicin has been noted in 25 percent of E. faecalis and 50 percent of E. faecium infections, and resistance to penicillin, ampicillin, and vancomycin has become commonplace, especially in E. faecium infections. Resistance to these antibiotics is most common among enterococci isolated from hospitalized or previously hospitalized persons. Nevertheless, all enterococci causing endocarditis must be evaluated carefully in order to select effective therapy (Table 47-9) . The strain causing endocarditis must be tested for high-level resistance to both streptomycin and gentamicin, as well as to determine its susceptibility to penicillin, ampicillin, and vancomycin. If the strain is either resistant to achievable serum concentrations of the cell wall-active agent or highly resistant to the aminoglycosides, synergy and optimal therapy cannot be obtain with a standard regimen that includes the inactive antimicrobial. Furthermore, high-level resistance to gentamicin predicts resistance to all other aminoglycosides except

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TABLE 47-9 -- STRATEGY FOR SELECTING THERAPY FOR ENTEROCOCCAL ENDOCARDITIS CAUSED BY STRAINS RESISTANT TO COMPONENTS OF THE STANDARD REGIMEN 1 I. Ideal therapy includes a cell wall-active agent plus an effective aminoglycoside to achieve bactericidal synergy II. Cell wall-active antimicrobial A. Determine MIC for ampicillin and vancomycin; test for beta-lactamase production (nitrocefin test) B. If ampicillin and vancomycin susceptible, use ampicillin C. If ampicillin resistant (MIC 16 mug/ml) and vancomycin susceptible, use vancomycin D. If beta-lactamase produced, use vancomycin or consider ampicillin-sulbactam

E. If ampicillin resistant and vancomycin resistant (MIC 16 mug/ml), consider teicoplanin* F. If ampicillin resistant and highly resistant to vancomycin and teicoplanin (MIC 256 mug/ml), see IV C, D III. Aminoglycoside to be used with cell wall-active antimicrobial A. If no high level resistance to streptomycin (MIC10 mm diameter) hypermobile vegetation (with or without prior arterial embolus) Endocarditis due to highly antibiotic-resistant enterococci PVE=prosthetic valve endocarditis; NVE=native valve endocarditis. *Surgery commonly required for optimal outcome.

the majority of surgically treated patients but also require surgery on a more urgent basis when heart failure supervenes. Severe mitral valve insufficiency, nevertheless, results in inexorable heart failure and ultimately requires surgical intervention. Doppler echocardiography and color flow mapping indicating significant valvular regurgitation during the initial week of endocarditis treatment do not reliably predict those patients who will require valve replacement during active endocarditis. Alternatively, despite the absence of significant valvular regurgitation on early echocardiography, marked CHF may still develop. Decisions about surgical intervention should not be made solely on the basis of echocardiographic findings but rather by integrating clinical data during careful serial monitoring. On occasion, very large vegetations on the mitral valve, particularly a mitral valve prosthesis, result in significant obstruction and require surgery.[28] UNSTABLE PROSTHESES.

Dehiscence of an infected prosthetic valve is a manifestation of perivalvular infection and often results in hemodynamically significant valvular dysfunction. Surgical intervention is recommended for PVE patients with these complications.[28] [130] The risk of invasive infection is increased among patients with onset of PVE within the year after valve implantation and those with infection of an aortic valve prosthesis. Endocarditis in these patients is often caused by invasive antimicrobial-resistant organisms; consequently, the benefit of combined medical-surgical therapy is enhanced further. Patients who appear clinically stable but who have overtly unstable and hypermobile prostheses, a finding indicative of dehiscence in excess of 40 percent of the circumference, are likely to experience progressive valve instability and warrant surgical treatment. Occasional patients with PVE caused by noninvasive, highly antibiotic-susceptible organisms, e.g., streptococci, despite a favorable clinical course during antibiotic therapy, late in treatment experience minor valve dehiscence without prosthesis instability or hemodynamic deterioration. Surgical treatment of these patients can be deferred unless clear indications arise. UNCONTROLLED INFECTION OR UNAVAILABLE EFFECTIVE ANTIMICROBIAL THERAPY.

Surgical intervention has improved the outcome of several forms of endocarditis when maximal antibiotic therapy fails to eradicate infection or, in some instances, even to suppress bacteremia. Amphotericin B is inadequate therapy for fungal endocarditis, including that caused by Candida species, and surgical intervention is recommended shortly after initiation of full doses of antifungal therapy. Endocarditis caused by some gram-negative bacilli, e.g., P. aeruginosa, Achromobacter xylosoxidans, may not be eradicated by maximum tolerable antibiotic therapy and may require surgical excision of the infected tissue to achieve cure. Similarly, standard therapy of endocarditis caused by Brucella species includes surgery because medical therapy is rarely successful.[94] Surgical intervention is recommended when patients with enterococcal endocarditis caused by a strain resistant to synergistic bactericidal therapy do not respond to initial therapy or relapse. Perivalvular invasive infection is in some instances a form of

ineradicable infection. Relapse of PVE after optimal antimicrobial therapy reflects invasive disease or the difficulty in eradicating infection involving foreign devices. Patients with relapse of PVE are treated surgically.[28] In contrast, patients with NVE that relapses, unless it is associated with a highly resistant microorganism or demonstrable perivalvular infection, often are treated again with an intensified, prolonged course of antimicrobial therapy.[132] S. AUREUS PROSTHETIC VALVE ENDOCARDITIS.

Among 129 patients who had S. aureus PVE and who were culled from large retrospective general series of PVE, the crude mortality rate for those treated with antibiotics alone and with antibiotics plus surgery was 73 and 25 percent, respectively.[51] [122] [133] [134] The overall mortality rate in 33 cases of S. aureus PVE treated at a single institution was 42 percent.[122] In these latter cases, when a multivariate model was used for analysis to adjust for confounding variables, the presence of intracardiac complications was associated with a 13.7-fold increased risk of death, and surgical intervention during active disease was accompanied by a 20-fold reduction in mortality. These data suggest that surgical treatment can improve outcome. Although the occurrence of central nervous system emboli is often considered to limit the opportunity for surgical intervention, in fact, appropriately timed surgery remains the preferred treatment. Thus, surgical intervention is recommended for S. aureus PVE with intracardiac complication and may benefit even those patients with uncomplicated S. aureus PVE.[122] [133] PERIVALVULAR INVASIVE INFECTION.

NVE at the aortic site and PVE are most commonly associated with perivalvular invasion with abscess or intracardiac fistula formation.[28] Invasive infection occurs in 10 to 14 percent of patients with NVE and 45 to 60 percent of those with PVE.[28] Persistent, otherwise unexplained fever despite appropriate antimicrobial therapy or pericarditis in patients with aortic valve endocarditis suggests infection extending beyond the valve leaflet.[78] New-onset and persistent electrocardiographic conduction abnormalities, although not a sensitive indicator of perivalvular infection (28 percent), are relatively specific (85 to 90 percent).[135] TEE is superior to TTE for detecting invasive infection in patients with NVE and PVE. Doppler and color flow Doppler or contrast two-dimensional echocardiography optimally define fistulas. Patients who have IE and in whom an abscess is suspected but not detected by an initial and repeat TEE should undergo magnetic resonance imaging, including magnetic resonance angiography. Cardiac catheterization adds little to these imaging studies and is not recommended unless coronary angiography is needed. In patients with endocarditis complicated by perivalvular extension of infection, cardiac surgery should be considered to debride invasive infection, ablate abscesses, and reconstruct anatomical damage. Surgery is warranted in patients with invasive disease that significantly disrupts cardiac structures, that is associated with CHF, that results in instability of a prosthetic valve, or that renders infection uncontrolled (persistent fever). However, it is likely that increasingly sensitive imaging techniques will elucidate invasive

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infections that do not require immediate surgery. Sporadic case reports of medically treated invasive infection suggest that these infections will be small, structurally nonsignificant abscesses in which the cavity is open to the circulatory stream. LEFT-SIDED S. AUREUS ENDOCARDITIS.

Because this infection is difficult to control, highly destructive, and associated with high mortality, some investigators have suggested that these patients should be considered for surgical treatment when the response to antimicrobial therapy is not prompt and complete. Additionally, patients with S. aureus NVE (aortic or mitral valve) and vegetations that are visible by TTE are at increased risk for arterial emboli and death and should be considered for surgery.[52] In contrast, IV drug abusers with S. aureus endocarditis limited to the tricuspid or pulmonary valves often experience prolonged fever during antimicrobial therapy; nevertheless, the vast majority of these patients respond to antimicrobial therapy and do not require surgery.[136] UNRESPONSIVE CULTURE-NEGATIVE ENDOCARDITIS.

Patients who have culture-negative endocarditis and who experience unexplained persistent fever during empirical antimicrobial therapy, particularly those with PVE, should be considered for surgical intervention. If endocarditis is not marantic, persistent fever in these patients is likely to represent either unrecognized perivalvular infection or ineffective antimicrobial therapy. LARGE VEGETATIONS (>10 mm) AND THE PREVENTION OF SYSTEMIC EMBOLI.

Systemic embolization was increased in patients with vegetations greater than 10 mm versus those with smaller or no detectable vegetations, 33 percent versus 19 percent.[82] Larger mitral valve vegetations (>10 mm), particularly those on the anterior mitral valve leaflet, are uniquely associated with systemic emboli. Although a relationship may exist between vegetation characteristics--including size, mobility, and extent (number of leaflets involved)--and embolic complications, the implications for surgical intervention are not clear. Yet to be performed are multivariate analyses examining the relationship between outcome or the need for surgical intervention and variables including not only vegetation characteristics but also valve dysfunction, perivalvular invasion by infection, organism, and infection site. Nevertheless, some researchers have concluded that vegetation characteristics alone might warrant surgery to prevent arterial emboli. This recommendation can be questioned, as can the recommendation for valve surgery after two major arterial emboli.[94] In deciding to intervene in the therapy of IE with cardiac surgery to prevent arterial emboli, many factors must be considered carefully. The rate of systemic or cerebral emboli in patients with NVE and PVE decreases during the course of effective antibiotic

therapy.[87] [137] Additionally, it is not clear that surgical intervention reduces the frequency of systemic emboli.[76] [130] Finally, the risks of morbidity and mortality caused by cerebral and coronary emboli, the major events to be prevented, must be compared with the immediate and long-term risks of valve replacement surgery. The latter include perioperative mortality, recrudescent endocarditis on the prosthesis, thromboembolic complications, early and late valve dysfunction requiring repeat valve replacement, the hazards of warfarin anticoagulation (including its contraindication during pregnancy), and the risk and morbidity of late-onset PVE.[128] Vegetation size alone is rarely an indication for surgery. The clinical findings and echocardiographic evidence for other intracardiac complications must be weighed against the immediate and remote hazards of cardiac surgery, including the possibility of valve preservation by vegetectomy and valve repair, when recommending therapy.[82] [94] Thus, the risk for systemic embolization as related to vegetation size or prior systemic embolus is not an independent indication for surgical intervention but is only one of many factors to be considered when planning treatment.[87] [94] [137] TECHNIQUES FOR REPAIR OF INTRACARDIAC DEFECTS.

New surgical techniques to address severe tissue destruction in NVE and PVE have been developed. Although these are beyond the scope of this discussion, examples include valve composite graft replacement of the aortic root, use of sewing skirts attached to the prostheses, and homograft replacement of the aortic valve and root with coronary artery reimplantation.[138] [139] Furthermore, repair of the mitral valve in patients with acute or healed endocarditis avoids the need for insertion of prosthetic materials and the associated hazards.[140] Although tricuspid valvulectomy without valve replacement has been advocated for treatment of uncontrolled tricuspid valve infection in IV drug abusers at high risk of recidivism and recurrent endocarditis, the likelihood of refractory right-heart failure with time after valvulectomy makes tricuspid valve repair preferable. Cardiac transplantation has been used to salvage an occasional patient with refractory endocarditis. TIMING OF SURGICAL INTERVENTION.

When endocarditis is complicated by valvular regurgitation and significant impairment of cardiac function, surgical intervention before the development of severe intractable hemodynamic dysfunction is recommended, regardless of the duration of antimicrobial therapy.[130] [141] Postoperative mortality correlates with the severity of preoperative hemodynamic dysfunction; consequently, this approach is justified.[94] In patients who have valvular dysfunction and in whom infection is controlled and cardiac function is compensated, surgery may be delayed until antimicrobial therapy has been completed. However, if infection is not controlled, surgery should be performed promptly. Similarly, if a patient who requires valve replacement in the near future has a large vegetation, indicating a high risk for systemic embolization, early cardiac surgery is appropriate. To avoid worsening of neurological status or death in patients who have sustained recent neurological injury, the timing of surgical intervention may require modification. Among patients who have had a nonhemorrhagic embolic stroke, exacerbation of cerebral dysfunction occurs during cardiac surgery in 44 percent of cases when the

interval between the stroke and surgery is 7 days or less, in 17 percent when the interval is 8 to 14 days, and in 10 percent or less when more than 2 weeks has elapsed. After hemorrhagic intracerebral events, the risk for neurological worsening or death with cardiac surgery persists at 20 percent even after 1 month.[142] Thus, when the response of IE to antimicrobial therapy and hemodynamic status permit, delaying cardiac surgery for 2 to 3 weeks after a significant embolic infarct and at least a month after intracerebral hemorrhage (with prior repair of a mycotic aneurysm) has been recommended.[142] [143] In another study of patients with nonhemorrhagic focal cerebral lesions or encephalopathy, those undergoing cardiac surgery without delay experienced no greater mortality or neurological deterioration than did those treated medically. This study suggests that the improved outcomes reported with delayed surgery may simply reflect selection of hardier patients and that more prompt cardiac surgery in patients with nonhemorrhagic cerebral complications, if required, is reasonable and potentially beneficial.[144] Contrast-enhanced cerebral tomography is recommended as the initial study of choice to detect intracerebral hemorrhage with subsequent magnetic resonance angiography or standard cerebral angiography to further evaluate hemorrhagic lesions for a leaking mycotic aneurysm.[143] [145] It is prudent to evaluate the cerebral vasculaturs in patients who have sustained an embolic infarct or who have persistent headaches before cardiac surgery. If a mycotic aneurysm is found, the timing of cardiac surgery should be reconsidered and prostheses that require postoperative anticoagulant therapy should be avoided.[94] DURATION OF ANTIMICROBIAL THERAPY AFTER SURGICAL INTERVENTION.

Inflammatory changes and bacteria are commonly found in vegetations removed from patients who have received most or all of the standard antibiotic therapy recommended for endocarditis caused by the specific microorganism. If valve cultures are negative, this does not indicate that antimicrobial therapy has failed or that a full course of antibiotic therapy is needed postoperatively. The duration of antimicrobial therapy after surgery depends on the length of preoperative therapy, the antibiotic susceptibility of the causative organism, the presence of paravalvular

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invasive infection, and the culture status of the vegetation. In general, for endocarditis caused by relatively antibiotic-resistant organisms with negative cultures of operative specimens, preoperative plus postoperative therapy should at least equal a full course of recommended therapy; for those patients with positive intraoperative cultures, a full course of therapy should be given postoperatively. Patients with PVE should receive a full course of antimicrobial therapy postoperatively when organisms are seen in resected material.[28] Treatment of Extracardiac Complications

SPLENIC ABSCESS.

Three to 5 percent of patients with IE develop a splenic abscess.[80] Although splenic defects can be identified by ultrasonography and computed tomography, these tests usually cannot discriminate between abscess and infarct. Persistent fever and progressive enlargement of the lesion during antimicrobial therapy suggest that it is an abscess; this can be confirmed by percutaneous needle aspiration. Successful therapy of splenic abscesses generally requires drainage, which can often be accomplished by percutaneous placement of a catheter.[84] In patients with endocarditis complicated by numerous splenic abscesses or in whom percutaneous drainage is unsuccessful, splenectomy is required.[84] [94] Splenic abscesses should be effectively treated before valve replacement surgery. If they are not effectively treated before cardiac surgery, splenectomy should be performed as soon thereafter as surgical risks permit. [94] MYCOTIC ANEURYSMS AND SEPTIC ARTERITIS.

From 2 to 10 percent of patients with endocarditis have mycotic aneurysms; in 1 to 5 percent, the aneurysms involve cerebral vessels.[88] Cerebral mycotic aneurysms occur at the branch points in cerebral vessels, are generally located distally over the cerebral cortex, and are found most commonly in branches of the middle cerebral artery. The aneurysms arise either from occlusion of vessels by septic emboli with secondary arteritis and vessel wall destruction or from bacteremic seeding of the vessel wall through the vasa vasorum. S. aureus is commonly implicated in the former and viridans streptococci in the latter.[91] Many patients with mycotic aneurysms or septic arteritis present with devastating intracranial hemorrhage. Focal deficits from embolic events, persistent focal headache, or sterile meningeal irritation (cerebrospinal fluid pleacytosis) may be premonitory symptoms. Cerebral angiography is required to evaluate patients with subarachnoid hemorrhage, and this or magnetic resonance angiography has been recommended for patients experiencing premonitory symptoms, especially if cardiac surgery or anticoagulant therapy is planned.[88] [94] Mycotic aneurysms may resolve during antimicrobial therapy[94] ; however, when anatomically feasible, aneurysms that have ruptured should be repaired surgically. Aneurysms that have not leaked should be monitored angiographically during antimicrobial therapy. Surgery should be considered for a single lesion that enlarges during or after antimicrobial therapy. Anticoagulant therapy should be avoided in patients with a persisting mycotic aneurysm. Although persistent stable aneurysms may rupture after completion of standard antimicrobial therapy, there is no accurate estimation of risk for late rupture, and recommendations for surgical intervention are arbitrary. Nevertheless, prevailing opinion favors, whenever possible without serious neurological injury, the resection of single aneurysms that persist after therapy. The potential existence of occult aneurysms in patients without neurological symptoms or in those who have had a nondiagnostic angiographic evaluation is not considered a contraindication to anticoagulant therapy after completion of antimicrobial therapy. Extracranial mycotic aneurysms should be managed as outlined for cerebral aneurysms. Those that leak, are expanding during therapy, or persist after therapy should be repaired. Particular attention should be given to aneurysms that involve

intraabdominal arteries, rupture of which could result in life-threatening hemorrhage. [94] ANTICOAGULANT THERAPY.

Patients with PVE involving devices that would usually warrant maintenance anticoagulation are continued on anticoagulant therapy.[28] Prothrombin times should be maintained at 1.5 times the control (INR = 3.0). Anticoagulation is not initiated as prophylaxis against thromboembolism in patients with PVE involving devices that do not usually require this therapy. Among patients with NVE, no evidence shows that anticoagulant therapy prevents embolization, and in some instances it may contribute to intracranial hemorrhage, particularly in the presence of a recent cerebral infarct or a mycotic aneurysm.[88] Anticoagulant therapy in patients with NVE is limited to those patients for whom there is a clear indication for this therapy and for whom there is not a known increased risk for intracranial hemorrhage. If central nervous system complications occur in patients who have IE and who are receiving anticoagulant therapy, anticoagulation should be reversed immediately.[28] Response to Therapy and Outcome

Within a week after initiation of effective antimicrobial therapy, almost 75 percent of patients with IE, including those with PVE, are afebrile and 90 percent have defervesced by the end of the second week of treatment. [47] [137] [28] [76] [146] The duration of fever during therapy is longer in patients with IE due to S. aureus, P. aeruginosa, and culture-negative IE as well as IE characterized by microvascular phenomena and major embolic complications.[76] [146] Persistence or recurrence of fever more than 7 to 10 days after initiation of antibiotic therapy identified patients with increased mortality rates and with complications of infection or therapy.[28] [78] [146] Those patients with prolonged or recurrent fever should be evaluated for intracardiac complications, focal extracardiac septic complications, intercurrent nosocomial infections, recurrent pulmonary emboli (patients with right-sided IE), drug-associated fever, additional underlying illnesses, and, if appropriate, in-hospital substance abuse. Blood cultures should be repeated in search of persistent bacteremia or the presence of additional pathogens, e.g., previously unrecognized polymicrobial IE. The antimicrobial susceptibility of the causative organism should be reevaluated, as should the adequacy of antibiotic therapy. Drug reactions have accounted for fever in 17 to 28 percent of these patients.[78] [124] Drug fever attributed to the antimicrobial therapy itself may warrant revision of treatment if a suitable alternative is available. In the absence of effective alternative therapy, treatment can be continued despite drug fever if the antimicrobial is not causing significant end-organ toxicity. In 33 to 45 percent of patients, persistent fever was associated with significant intracardiac complications, many of which required surgical intervention.[76] Many clinical and laboratory features of IE are slow to resolve despite effective antimicrobial therapy. Systemic emboli occur during the early weeks of treatment, although with decreasing frequency.[87] The increased ESR and anemia may not correct until after therapy has been completed.

Mortality rates for large series of NVE treated between 1975 and 1993 range from 16 to 27 percent.[1] [4] [5] [9] [134] Death due to IE has been associated with increased age (>65 to 70 years old), underlying diseases, infection involving the aortic valve, development of CHF, renal failure, and central nervous system complications.[1] [5] The treatment of heart failure due to valve dysfunction by early surgical intervention has decreased the mortality associated with CHF, but subsequently, neurological events and septic complications, e.g., uncontrolled infection and myocardial abscess, have accounted for a larger proportion of deaths and have been associated with high mortality rates.[80] Mortality rates among patients with IE caused by viridans streptococci and S. bovis have ranged from 4 to 16 percent.[1] [4] [9] Higher mortality rates are reported with left-sided NVE caused by other organisms: enterococci, 15 to 25 percent [1] [4] [9] ; S. aureus, 25 to 47 percent[1] [4] [9] [50] [73] ; nonviridans streptococci (groups B, C, and G), 13 to 50 percent[42] [147] ; C. burnetti, 5 to 37 percent[31] [114] [124] ; P. aeruginosa, Enterobacteriaceae, and fungi, greater than 50 percent.[54] [61] In a retrospective study of patients with NVE with either Class III or IV heart failure (New York Heart Association) or invasive uncontrolled infection, only 9 percent of patients treated surgically died, compared with 51 percent of those treated with antibiotics alone.[76] Mortality rates among patients who have NVE, particularly involving the aortic valve, and who were treated surgically have ranged from 5 to 26 percent, with rates toward the high end of this range reported more frequently.[148] [149] [150] Severity of heart failure, abscess, S. aureus infection, and decreased renal function (possibly related to heart failure) have been associated with

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increased postoperative mortality.[150] Nevertheless, survival rates of 85 percent can be achieved when patients with paravalvular abscesses undergo meticulous debridement and reconstructive cardiac surgery.[151] Outcome for patients with PVE, as contrasted with NVE, has been less desirable. Before 1980, mortality rates among patients with onset less than 60 days after surgery and later-onset PVE averaged 70 and 45 percent, respectively. With the recognition that PVE was frequently complicated by invasive infection and that patients would benefit from surgical intervention, mortality rates have decreased to 33 to 45 percent, with lower rates in later-onset cases.[28] [151] Long-term survival was adversely affected by the presence of moderate or severe heart failure at discharge. Survival rates after aggressive surgery for PVE ranged from 75 to 85 percent and were not related to time of onset after cardiac surgery.[29] [139] Among patients with NVE (nonaddicts) discharged after medical or medical-surgical therapy, long-term survival was 88 percent at 5 years and 81 percent at 10 years. [134] Among patients treated surgically for NVE, survival at 5 years ranged from 70 to 80 percent.[138] [149] Among patients with PVE treated surgically, survival rates at 4 to 6 years

range from 50 to 82 percent. [29] [139] RELAPSE AND RECURRENCE.

Relapse of IE usually occurs within 2 months of discontinuing antibiotic treatment. Of patients who have NVE caused by penicillin-susceptible viridans streptococci and who receive a recommended course of therapy, less than 2 percent suffer relapse. From 8 to 20 percent of patients with enterococcal IE experience relapse after standard therapy.[132] Patients with IE caused by S. aureus, Enterobacteriaceae, or fungi are more likely to experience overt failure of therapy rather than relapse; nevertheless, 4 percent of patients with S. aureus IE suffer relapse.[132] Relapse of fungal endocarditis at long intervals after treatment has been reported. Relapse occurs in 10 percent of patients with PVE overall and in 6 to 15 percent of those treated surgically. [131] Among nonaddicts with an initial episode of NVE or PVE, 4.5 to 7 percent experience one or more additional episodes.[132] [134] Among these patients, recurrent IE shares the clinical, microbiological, and response to therapy noted in primary episodes of IE. IV drug abuse is now the most common predisposition for recurrent IE (43 percent of patients). PREVENTION During bacteremia provoked by daily activities, infections, or health care procedures, bacteria adhere to and colonize the platelet fibrin aggregates, NBTE, that have formed on the valve endothelium as a consequence of preexisting congenital or acquired cardiac disease. If the adherence and the subsequent multiplication of bacteria at this site exceed the capacity of host defenses for bacterial eradication, IE results. Although many bacteria enter the bloodstream, those uniquely suited to adhere to NBTE cause the majority of cases of endocarditis. These organisms and the cardiac abnormalities vulnerable to IE are evident from reported cases. Events that predispose to bacteremia by organisms causing endocarditis have been identified. By identifying the patients at risk, the causative bacteria, and the events that induce bacteremia, strategies for prevention of some episodes of IE have been formulated and are routinely recommended even in the absence of supporting clinical trials.[152] [153] [154] Viridans streptococci, the most common cause of NVE and late-onset PVE, are the primary target for prophylaxis used in conjunction with procedures involving the oral cavity, respiratory tract, or esophagus. Procedures involving the genitourinary and gastrointestinal tracts commonly precede the development of enterococcal endocarditis. Accordingly, the prophylaxis for endocarditis used in conjunction with procedures involving these mucosal surfaces is targeted against enterococci. When incision and drainage of infected skin or soft tissue infections are undertaken, prophylaxis is focused on S. aureus. Procedures for which IE prophylaxis is recommended or not recommended have been identified by the American Heart Association and others (Table 47-14) . [152] [153] [154] [155] Although prophylaxis is advised for all at-risk patients who undergo dental procedures

that cause gingival bleeding, extractions TABLE 47-14 -- PROCEDURES FOR WHICH PROPHYLAXIS AGAINST ENDOCARDITIS IS CONSIDERED PROPHYLAXIS PROPHYLAXIS NOT RECOMMENDED RECOMMENDED Dental procedures known to induce gingival or mucosal bleeding, including professional cleaning and scaling

Dental procedures not likely to cause bleeding, such as adjustment of orthodontic appliances and simple fillings above the gum line

Tonsillectomy or adenoidectomy Surgery involving gastrointestinal Intraoral injection or local anesthetic or upper respiratory mucosa (nonintraligamentary) Bronchoscopy with rigid bronchoscope

Shedding of primary teeth

Sclerotherapy for esophageal varices

Tympanostomy tube insertion

Esophageal dilation

Endotracheal tube insertion

Endoscopic retrograde cholangiography with biliary obstruction

Bronchoscopy with flexible bronchoscope, with or without biopsy

Gallbladder surgery Cytoscopy, urethral dilation

Transesophageal echocardiography

Urethral catheterization if urinary Cardiac catheterization, coronary angioplasty infection is present Urinary tract surgery, including prostate surgery

Pacemaker implantation

Incision and drainage of infected Gastrointestinal endoscopy, with or without biopsy tissue* Gastrointestinal endoscopy, with or without biopsy Incision or biopsy of scrubbed skin Cesarean section Vaginal hysterectomy Circumcision

In the absence of infection: urethral catheterization, dilatation and curettage, uncomplicated vaginal delivery, therapeutic abortion, insertion or removal of intrauterine device, sterilization procedures, laparoscopy Adapted from Dajani AS, Taubert KA, Wilson W, et al: Prevention of bacterial endocarditis: Recommendations of the American Heart Association from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young. JAMA 277:1794, 1997; and from Durack DT: Prevention of endocarditis. N Engl J Med 332:38, 1995. In patients at highest risk, physicians may elect to use prophylaxis for these procedures. *Antibiotic prophylaxis should be directed against the most likely endocarditis-associated pathogen(s), often staphylococci.

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TABLE 47-15 -- RELATIVE RISK OF INFECTIVE ENDOCARDITIS ASSOCIATED WITH PREEXISTING CARDIAC DISORDERS RELATIVELY HIGH RISK INTERMEDIATE RISK VERY LOW OR NEGLIGIBLE RISK* Prosthetic heart valves

Mitral valve prolapse with regurgitation (murmur) or thickened valve leaflets

Mitral valve prolapse without regurgitation (murmur) or thickened valve leaflets

Previous infective endocarditis* Cyanotic congenital heart Pure mitral stenosis disease* Patent ductus arteriosus

Tricuspid valve disease

Aortic regurgitation

Pulmonary stenosis

Aortic stenosis

Asymmetrical septal hypertrophy

Trivial valvular regurgitation on echocardiography without structural abnormality


Bicuspid aortic valve or calcific aortic sclerosis with minimal hemodynamic abnormality

Isolated atrial septal defect (secundum)

Mitral stenosis and regurgitation

Arteriosclerotic plaques

Ventricular septal defect

Coronary artery disease

Coarctation of the aorta

Degenerative valvular disease in elderly patients

Cardiac pacemaker, implanted defibrillators

Surgically repaired intracardiac lesion with residual hemodynamic abnormality or prosthetic device

Surgically repaired intracardiac lesions with minimal or no hemodynamic abnormality, less than 6 mo after operation

Surgically repaired intracardiac lesions, with minimal or no hemodynamic abnormality, more than 6 mo after operation (atrial septal defect, ventricular septal defect, patent ductus arteriosus, pulmonary stenosis)

Surgically constructed systemic-pulmonary shunts* Prior coronary bypass graft surgery Prior Kawasaki's disease or rheumatic fever without valvular dysfunction Adapted from Durack DT: Prevention of infective endocarditis. N Engl J Med 332:38, 1995; and Dajani AS, Taubert KA, Wilson W, et al: Prevention of bacterial endocarditis: Recommendations of the American Heart Association from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young. JAMA 277:1794, 1997. Copyright 1997 American Medical Association. *Prophylaxis against endocarditis not recommended. Lesions considered at highest risk for endocarditis.

are the most strongly associated with subsequent IE.[154] Because endocarditis has been reported only rarely in association with other gastrointestinal endoscopic procedures with or without biopsy, prophylaxis is not routinely recommended in this situation. Prophylaxis is not recommended with routine cardiac catheterization or TEE.[152] [155] Based on the frequency of a lesion among patients with endocarditis compared with the general population, lesions have been assigned to high, intermediate, low, and

negligible risk categories (Table 47-15) . [7] [13] [155] [156] [157] [157A] Rheumatic heart disease currently is a less common predisposition for IE in most of the developed countries; however, the attack rate of IE among persons with rheumatic valvular disease approaches that with prosthetic valves and suggests that these lesions entail a high risk also.[158] The risk of IE for patients with mitral valve prolapse and the resulting role of prophylaxis among these patients have been controversial. Mitral valve prolapse has been identified frequently among patients with IE. However, the risk of endocarditis among patients with mitral valve prolapse and a murmur of mitral regurgitation is still relatively low. It is 5- to 10-fold higher than that in the general population but 100-fold less than that among patients with rheumatic valvular heart disease.[158] As a result, mitral valve prolapse with a murmur of mitral regurgitation or mitral valve thickening and prolapse defines a patient with an intermediate risk for IE and one for whom prophylaxis against endocarditis is recommended. GENERAL METHODS.

The incidence of IE can be significantly reduced by total surgical correction of some congenital lesions that otherwise predispose patients to IE, e.g., patent ductus arteriosus, ventricular septal defect, and pulmonary stenosis.[7] [157] The incidence of IE remains high among patients who have undergone surgical correction of other major congenital defects, especially those involving a stenotic aortic valve.[7] Patients with persisting as well as many corrected congenital lesions and those with acquired valvular heart disease who remain at risk for IE should be given written material about their predisposing lesion, their risk for endocarditis, and the recommended antibiotic prophylaxis. Maintenance of attentive oral hygiene which decreases the frequency of bacteremia that accompanies daily activities (chewing, brushing teeth), may be a more important preventive than procedure-focused chemoprophylaxis.[156] Oral hygiene should be addressed before prosthetic valves are placed electively. Among patients at risk for IE, some activities or procedures likely to induce bacteremia should be avoided. Oral irrigating devices, which may produce bacteremia even in patients with normal gingiva, are not recommended. Similarly, the use of central intravascular catheters and urinary catheters should be minimized. Infections associated with bacteremia must be treated promptly and if possible eradicated before the involved tissues are incised or manipulated.[153] CHEMOPROPHYLAXIS.

The widely promulgated recommendations of antimicrobial prophylaxis for endocarditis are based on circumstantial evidence supplemented by studies of prophylaxis using animal models. Studies suggest that prophylactic antibiotics prevent endocarditis by inhibiting growth of the bacteria adherent to NBTE sufficiently to allow their subsequent complete elimination by host defenses.[155] [159] Experimental studies that mimic

single-dose amoxicillin prophylaxis in humans suggest adequate margins of efficacy are present after a single prophylactic dose. Nevertheless, because a more sustained inhibitory effect can be achieved through a postprocedure dose of antibiotics this is recommended for patients in the high-risk group.[152] [160] Clinical studies supporting the efficacy of antibiotic prophylaxis for endocarditis are limited. A retrospective study of patients who had prosthetic valves and who underwent dental and surgical procedures suggested that antibiotic prophylaxis prevented PVE.[161] However, a large case-control study failed to identify dental procedures as a risk for IE among persons with valvular abnormalities and questioned the benefit of antibiotic prophylaxis for these procedures.[162] Additionally, failures of antibiotic prophylaxis unrelated to resistant bacteria have been noted.[155] Risk-benefit and cost-benefit analyses have raised significant questions about antibiotic prophylaxis for patients with mitral valve prolapse. Unless both the cost and risks of prophylaxis are very low, the cost per case of IE prevented is high and mortality or morbidity may not be reduced. From a population perspective, prophylaxis in low-

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TABLE 47-16 -- REGIMENS FOR PROPHYLAXIS AGAINST ENDOCARDITIS: USE WITH GENITOURINARY AND GASTROINTESTINAL (EXCEPT ESOPHAGEAL) PROCEDURES SETTING ANTIBIOTIC REGIMEN* High-risk patients

Ampicillin plus gentamicin

Ampicillin 2.0 gm IV/IM plus gentamicin 1.5 mg/kg within 30 min of procedure, repeat ampicillin 1.0 gm IV/IM or give amoxicillin 1.0 gm PO 6 hr later

High-risk, penicillin-allergic patients

Vancomycin plus gentamicin

Vancomycin 1.0 gm IV over 1-2 hr plus gentamicin 1.5 mg/kg IM/IV infused or injected 30 min before procedure. No second dose recommended

Moderate-risk patients

Amoxicillin or ampicillin

Amoxicillin 2.0 gm PO 1 hr before procedure or ampicillin 2.0 gm IM/IV 30 min before procedure

Moderate-risk, penicillin-allergic patients

Vancomycin

Vancomycin 1.0 gm IV infused over 1-2 hr and completed within 30 min of procedure

Adapted from Dajani AS, Taubert KA, Wilson W, et al: Prevention of bacterial endocarditis: Recommendations by the American Heart Association from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young. JAMA 277:1794-1801, 1997. *Dosing for children: ampicillin 50 mg/kg IV/IM, vancomycin 20 mg/kg IV, gentamicin 1.5 mg/kg IV/IM

(children's doses should not exceed adult doses).

to intermediate-risk settings may not be cost or risk beneficial, and prophylaxis might be reserved for patients who have high-risk cardiac lesions and who are undergoing high-risk procedures.[162] Even if antibiotic prophylaxis is effective as well as safe and inexpensive, only a small percentage of the cases are preventable. For example, only 55 to 75 percent of patients with NVE have preexisting endocarditis-prone valvular disease, and many are not aware of the lesion before the onset of NVE. [4] [5] [155] [156] Additionally, among patients with IE, only a small fraction (5 percent) had both a known valve lesion and a procedure within 30 days of onset of IE that would have warranted prophylaxis.[156] Nevertheless, the morbidity and mortality associated with IE are used to justify prophylaxis (Table 47-16; see Table 43-4) in patients who have high- and intermediate-risk cardiac lesions (see Table 47-15) and who are to undergo bacteremia-inducing procedures (see Table 47-14) . Penicillin-resistant flora may emerge among patients who are receiving continuous penicillin for prevention of rheumatic fever or repetitive courses of antibiotics for serial dental procedures. Consequently, a nonpenicillin prophylaxis regimen is preferred for these patients. Initiation of prophylaxis several days before a procedure encourages the emergence of antibiotic-resistant organisms at the mucosal site and is not recommended.

REFERENCES EPIDEMIOLOGY van der Meer JTM, Thompson J, Valkenburg HA, Michel MF: Epidemiology of bacterial endocarditis in the Netherlands. I. Patient characteristics. Arch Intern Med 152:1863, 1992. 1.

Hogevik H, Olaison L, Andersson R, et al: Epidemiologic aspects of infective endocarditis in an urban population: A 5-year prospective study. Medicine 74:324-339, 1995. 2.

Berlin JA, Abrutyn E, Strom BL, et al: Incidence of infective endocarditis in the Delaware Valley, 1988-1990. Am J Cardiol 76:933-936, 1995. 3.

Watanakunakorn C, Burkert T: Infective endocarditis at a large community teaching hospital, 1980-1990: A review of 210 episodes. Medicine 72:90, 1993. 4.

Kazanjian P: Infective endocarditis: Review of 60 cases treated in community hospitals. Infect Dis Clin Pract 2:41, 1993. 5.

Fernandez-Guerrero ML, Verdejo C, Azofra J, de Gorgolas M: Hospital-acquired infectious endocarditis not associated with cardiac surgery: An emerging problem. Clin Infect Dis 20:16, 1995. 6.

7.

Morris CD, Reller MD, Menashe VD: Thirty-year incidence of infective endocarditis after surgery for

congenital heart defect. JAMA 279:599-603, 1998. van der Meer JTM, van Wijk W, Thompson J, et al: Awareness of need and actual use of prophylaxis: Lack of patient compliance in the prevention of bacterial endocarditis. J Antimicrob Chemother 29:187, 1992. 8.

Sandre RM, Shafran SD: Infective endocarditis: Review of 135 cases over 9 years. Clin Infect Dis 22:276-286, 1996. 9.

PATIENT GROUPS Stull TL, LiPuma JJ: Endocarditis in children. In Kaye D (ed): Infective Endocarditis. 2nd ed. New York, Raven Press, 1992, p 313. 10.

11.

Baltimore RS: Infective endocarditis in children. Pediatr Infect Dis J 11:907, 1992.

Normand J, Bozio A, Etienne J, et al: Changing patterns and prognosis of infective endocarditis in childhood. Eur Heart J 16(Suppl B):28, 1995. 12.

Michel PL, Acar J: Native cardiac disease predisposing to infective endocarditis. Eur Heart J 16(Suppl B):2, 1995. 13.

14.

Stein A, Raoult D: Q fever endocarditis. Eur Heart J 16(Suppl B):19, 1995.

Raoult D, Fournier PE, Drancourt M, et al: Diagnosis of 22 new cases of Bartonella endocarditis. Ann Intern Med 125:646-652, 1996. 15.

Sande MA, Lee BL, Mills J, et al: Endocarditis in intravenous drug users. In Kaye D (ed): Infective Endocarditis. 2nd ed. New York, Raven Press, 1992, p 345. 16.

Levine DP, Crane LR, Zervos MJ: Bacteremia in narcotic addicts at the Detroit Medical Center. II. Infectious endocarditis: A prospective comparative study. Rev Infect Dis 8:374, 1986. 17.

Mathew J, Addai T, Anand A, et al: Clinical features, site of involvement, bacteriologic findings, and outcome of infective endocarditis in intravenous drug users. Arch Intern Med 155:1641-1648, 1995. 18.

Pulvirenti JJ, Kerns E, Benson C, et al: Infective endocarditis in injection drug users: Importance of human immunodeficiency virus serostatus and degree of immunosuppression. Clin Infect Dis 22:40-45, 1996. 19.

Ribera E, Miro JM, Cortes E, et al: Influence of human immunodeficiency virus 1 infection and degree of immunosuppression in the clinical characteristics and outcome of infective endocarditis in intravenous drug users. Arch Intern Med 158:2043-2050, 1998. 20.

Clifford CP, Eykyn SJ, Oakley CM: Staphylococcal tricuspid valve endocarditis in patients with structurally normal hearts and no evidence of narcotic abuse. Q J Med 87:755, 1994. 21.

Rutledge R, Kim J, Applebaum RE: Actuarial analysis of the risk of prosthetic valve endocarditis in 1,598 patients with mechanical and bioprosthetic valves. Arch Surg 120:469, 1985. 22.

23.

Ivert TSA, Dismukes WE, Cobbs CG, et al: Prosthetic valve endocarditis. Circulation 69:223, 1984.

Arvay A, Lengyel M: Incidence and risk factors of prosthetic valve endocarditis. Eur J Cardiothorac Surg 2:340, 1988. 24.

Calderwood SB, Swinski LA, Waternaux CM, et al: Risk factors for the development of prosthetic valve endocarditis. Circulation 72:31, 1985. 25.

Agnihotri AK, McGiffin DC, Galbraith AJ, O'Brien MF: Surgery for acquired heart disease. J Thorac Cardiovasc Surg 110:1708-1724, 1995. 26.

Horskotte D, Piper C, Niehues R, et al: Late prosthetic valve endocarditis. Eur Heart J 16(Suppl B):39, 1995. 27.

Karchmer AW, Gibbons GW: Infections of prosthetic heart valves and vascular grafts. In Bisno AL, Waldvogel FA (eds): Infections Associated with Indwelling Devices. 2nd ed. Washington, DC, American Society for Microbiology, 1994, p 213. 28.

Lytle BW, Priest BP, Taylor PC, et al: Surgery for acquired heart disease: Surgical treatment of prosthetic valve endocarditis. J Thorac Cardiovasc Surg 111:198-210, 1996. 29.

Fernicola DJ, Roberts WC: Frequency of ring abscess and cuspal infection in active infective endocarditis involving bioprosthetic valves. Am J Cardiol 72:314-323, 1993. 30.

Chastre J, Trouillet JL: Early infective endocarditis on prosthetic valves. Eur Heart J 16(Suppl B):32, 1995. 31.

Douglas JL, Cobbs CG: Prosthetic valve endocarditis. In Kaye D (ed): Infective Endocarditis. 2nd ed. New York, Raven Press, 1992, p 375. 32.

Sobel JD: Nosocomial infective endocarditis. In Kaye D (ed): Infective Endocarditis, 2nd ed. New York, Raven Press, 1992, p 361. 33.

34.

Jernigan JA, Farr BM: Short-course therapy of catheter-related Staphylococcus 1746

aureus bacteremia: A meta-analysis. Ann Intern Med 119:304, 1993. Fowler VG Jr, Li J, Corey GR, et al: Role of echocardiography in evaluation of patients with Staphylococcus aureus bacteremia: Experience in 103 patients. J Am Coll Cardiol 30:1072-1078, 1997. 35.

Raad II, Sabbagh MF: Optimal duration of therapy for catheter-related Staphylococcus aureus bacteremia: A study of 55 cases and review. Clin Infect Dis 14:75, 1992. 36.

Fang G, Keys TF, Gentry LO, et al: Prosthetic valve endocarditis resulting from nosocomial bacteremia: A prospective, multicenter study. Ann Intern Med 119:560, 1993. 37.

Etiologic Microorganisms Douglas CWI, Heath J, Hampton KK, Preston FE: Identity of viridans streptococci isolated from cases of infective endocarditis. J Med Microbiol 39:179, 1993. 38.

Bouvet A: Human endocarditis due to nutritionally variant streptococci: Streptococcus adjacens and Streptococcus defectivus. Eur Heart J 16(Suppl B):24, 1995. 39.

Doern GV, Ferraro MJ, Brueggeman AB, Ruoff KL: Emergence of high rates of antimicrobial resistance among viridans group streptococci in the United States. Antimicrob Agents Chemother 40:891-894, 1996. 40.

Ballet M, Gevigney G, Gare JP, et al: Infective endocarditis due to Streptococcus bovis: A report of 53 cases. Eur Heart J 16:1975-1980, 1995. 41.

Baddour LM, Infectious Diseases Society of America Emerging Infections Network: Infective endocarditis caused by beta-hemolytic streptococci. Clin Infect Dis 26:66-71, 1998. 42.

Aronin SI, Mukherjee SK, West JC, Cooney EL: Review of pneumococcal endocarditis in adults in the penicillin era. Clin Infect Dis 26:165-171, 1998. 43.

Whitby S, Pallera A, Schaberg DR, Bronze MS: Infective endocarditis caused by Streptococcus pneumoniae with high-level resistance to penicillin and cephalosporin. Clin Infect Dis 23:1176-1177, 1996. 44.

Eliopoulos, GM: Enterococcal endocarditis. In Kaye, D. (ed.): Infective Endocarditis. 2nd ed. New York, Raven Press, 1992, p. 209. 45.

Eliopoulos GM: Aminoglycoside resistant enterococcal endocarditis. Infect Dis Clin North Am 7:117, 1993. 46.

Chuard C, Vaudaux P, Waldvogel FA, Lew DP: Susceptibility of Staphylococcus aureus growing on fibronectin-coated surfaces to bactericidal antibiotics. Antimicrob Agents Chemother 37:625, 1993. 47.

Anwar H, Strap JL, Costerton JW: Establishment of aging biofilms: Possible mechanism of bacterial resistance to antimicrobial therapy. Antimicrob Agents Chemother 36:1347, 1992. 48.

Karchmer AW: Staphylococcal endocarditis. In Kaye D (ed): Infective Endocarditis. 2nd ed. New York, Raven Press, 1992, p 225. 49.

Whitener C, Caputo GM, Weitekamp MR, Karchmer AW: Endocarditis due to coagulase-negative staphylococci: Microbiologic, epidemiologic, and clinical considerations. Infect Dis Clin North Am 7:81, 1993. 50.

Roder BL, Wandall DA, Frimodt-Moller N, et al: Clinical features of Staphylococcus aureus endocarditis: A 10-year experience in Denmark. Arch Intern Med 159:462-469, 1999. 51.

Fowler VG Jr, Sanders LL, Kong LK, et al: Infective endocarditis due to Staphylococcus aureus: 59 prospectively identified cases with follow-up. Clin Infect Dis 28:106-114, 1999. 52.

Vandenesch F, Etienne J, Reverdy ME, Eykyn SJ: Endocarditis due to Staphylococcus lugdunensis: Report of 11 cases and review. Clin Infect Dis 17:871, 1993. 53.

Hessen MT, Abrutyn E: Gram-negative bacterial endocarditis. In Kaye D (ed): Infective Endocarditis. 2nd ed. New York, Raven Press, 1992, p 251. 54.

55.

Siller KA, Johnson WD Jr: Unusual bacterial causes of endocarditis. In Kaye D (ed): Infective

Endocarditis. 2nd ed. New York, Raven Press, 1992, p 265. Berbari EF, Cockerill FR III, Steckelberg J: Infective endocarditis due to unusual or fastidious microorganisms. Mayo Clin Proc 72:532-542, 1997. 56.

Petit AIC, Bok JW, Thompson J, et al: Native-valve endocarditis due to CDC coryneform group ANF-3: Report of a case and review of corynebacterial endocarditis. Clin Infect Dis 19:897, 1994. 57.

Drancourt M, Mainardi JL, Brouqui P, et al: Bartonella (Rochalimaea) quintana endocarditis in three homeless men. N Engl J Med 332:419, 1995. 58.

Spach DH, Kanter AS, Daniels NA, et al: Bartonella (Rochalimaea) species as a cause of apparent "culture-negative" endocarditis. Clin Infect Dis 20:1044, 1995. 59.

Gubler JGH, Kuster M, Dutly F, et al: Whipple endocarditis without overt gastrointestinal disease: Report of four cases. Ann Intern Med 131:112-116, 1999. 60.

61.

Rubinstein E, Lang R: Fungal endocarditis. Eur Heart J 16(Suppl B):84, 1995.

Moyer DV, Edwards JE Jr: Fungal endocarditis. In Kaye D (ed): Infective Endocarditis. 2nd ed. New York, Raven Press, 1992, p 299. 62.

Melgar GR, Nasser RM, Gordon SM, et al: Fungal prosthetic valve endocarditis in 16 patients. An 11 year experience in a tertiary care hospital. Medicine 76:94-103, 1997. 63.

Gilbert HM, Peters ED, Lang SJ, Hartman BJ: Successful treatment of fungal prosthetic valve endocarditis: Case report and review. Clin Infect Dis 22:348-354, 1996. 64.

Weinstein L, Schlesinger JJ: Pathoanatomic, pathophysiologic and clinical correlations in endocarditis (first of two parts). N Engl J Med 291:832, 1974. 65.

Livornese LL Jr, Korzeniowski OM: Pathogenesis of infective endocarditis. In Kaye D (ed): Infective Endocarditis. 2nd ed. New York, Raven Press, 1992, p 19. 66.

Weinstein L, Schlesinger JJ: Pathoanatomic, pathophysiologic and clinical correlations in endocarditis (second of two parts). N Engl J Med 291:1122, 1974. 67.

Dankert J, van der Werff J, Zaat SAJ, et al: Involvement of bactericidal factors from thrombin-stimulated platelets in clearance of adherent viridans streptococci in experimental infective endocarditis. Infect Immun 63:663, 1995. 68.

Bayer AS, Cheng D, Yeaman MR, et al: In vitro resistance to thrombin-induced platelet microbicidal protein among clinical bacteremic isolates of Staphylococcus aureus correlates with an endovascular infectious source. Antimicrob Agents Chemother 42:3169-3172, 1998. 69.

Sullam PM, Frank U, Yeaman MR, et al: Effect of thrombocytopenia on the early course of streptococcal endocarditis. J Infect Dis 168:910, 1993. 70.

Yeaman MR, Puentes SM, Norman DC, Bayer AS: Partial characterization and staphylocidal activity of thrombin-induced platelet microbicidal protein. Infect Immun 60:1202, 1992. 71.

72.

Moreillon P, Entenza J, Francioli P, et al: Role of Staphylococcus aureus coagulase and clumping

factor in pathogenesis of experimental endocarditis. Infect Immun 63:4738-4743, 1995. Shiro H, Muller E, Gutierrez N, et al: Transposition mutants of Staphylococcus epidermidis deficient in elaboration of capsular polysaccharide/adhesin and slime are avirulent in a rabbit model of endocarditis. J Infect Dis 169:1042, 1994. 73.

Herzberg MC, MacFarlane GD, Gong K, et al: The platelet interactivity phenotype of Streptococcus sanguis influences the course of experimental endocarditis. Infect Immun 60:4809, 1992. 74.

Bancsi MJLMF, Thompson J, Bertina RM: Stimulation and monocyte tissue expression in an in vitro model of bacterial endocarditis. Infect Immun 52:5669, 1994. 75.

Croft CH, Woodward W, Elliott A, et al: Analysis of surgical versus medical therapy in active complicated native valve infective endocarditis. Am J Cardiol 51:1650, 1983. 76.

Watanabe G, Haverich A, Speier R, et al: Surgical treatment of active infective endocarditis with paravalvular involvement. J Thorac Cardiovasc Surg 107:171, 1994. 77.

Blumberg EA, Robbins N, Adimora A, Lowy FD: Persistent fever in association with infective endocarditis. Clin Infect Dis 15:983, 1992. 78.

Douglas JL, Dismukes WE: Surgical therapy of infective endocarditis on natural valves. In Kaye D (ed): Infective Endocarditis. 2nd ed. New York, Raven Press, 1992, p 397. 79.

Mansur AJ, Grinberg M, Lamos da Luz P, Bellotti G: The complications of infective endocarditis: A reappraisal in the 1980's. Arch Intern Med 152:2428, 1992. 80.

Steckelberg JM, Murphy JG, Wilson WR: Management of complications of infective endocarditis. In Kaye D (ed): Infective Endocarditis. 2nd ed. New York, Raven Press, 1992, p 435. 81.

Aragam JR, Weyman AE: Echocardiographic findings in infective endocarditis. In Weyman AE, (ed): Principles and Practice of Echocardiography. 2nd ed. Philadelphia, Lea & Febiger, 1994, p 1178. 82.

Rohman S, Erbel R, George G, et al: Clinical relevance of vegetation localization by transesophageal echocardiography in infective endocarditis. Eur Heart J 13:446-452, 1992. 83.

Allan JD Jr: Splenic abscess: Pathophysiology, diagnosis, and management. In Remington JS, Swartz MN (eds): Current Clinical Topics in Infectious Diseases. Boston, Blackwell Scientific Publications, 1994, p 23. 84.

CLINICAL FEATURES Werner GS, Schulz R, Fuchs JB, et al: Infective endocarditis in the elderly in the era of transesophageal echocardiography: Clinical features and prognosis compared with younger patients. Am J Med 100:90-97, 1996. 85.

Bush LM, Johnson CC: Clinical syndrome and diagnosis. In Kaye D (ed): Infective Endocarditis. 2nd ed. New York, Raven Press, 1992, p 99. 86.

Steckelberg JM, Murphy JG, Ballard D, et al: Emboli in infective endocarditis: The prognostic value of echocardiography. Ann Intern Med 114:635, 1991. 87.

88.

Kanter MC, Hart RG: Neurologic complications of infective endocarditis. Neurology 41:1015, 1991.

Roder BL, Wandall DA, Espersen F, et al: Neurologic manifestations in Staphylococcus aureus endocarditis: A review of 260 bacteremic cases in nondrug addicts. Am J Med 102:379-386, 1997. 89.

Gagliardi JP, Nettles RE, McCarty DE, et al: Native valve infective endocarditis in elderly and younger adult patients: Comparison of clinical features and outcomes with use of the Duke criteria and the Duke endocarditis data base. Clin Infect Dis 26:1165-1168, 1998. 90.

Masuda J, Yutani C, Waki R, et al: Histopathological analysis of the mechanisms of intracranial hemorrhage complicating infective endocarditis. Stroke 23:843, 1992. 91.

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DIAGNOSIS Durack DT, Lukes AS, Bright DK: New criteria for diagnosis of infective endocarditis: Utilization of specific echocardiographic findings. Am J Med 96:200, 1994. 92.

Mortara LA, Bayer AS: Staphylococcus aureus bacteremia and endocarditis: New diagnostic and therapeutic concepts. Infect Dis Clin North Am 7:53, 1993. 93.

Bayer AS, Bolger AF, Taubert KA, et al: Diagnosis and management of infective endocarditis and its complications. Circulation 98:2936-2948, 1998. 94.

Lindner JR, Case RA, Dent JM, et al: Diagnostic value of echocardiography in suspected endocarditis: An evaluation based on the pretest probability of disease. Circulation 93:730, 1996. 95.

Sekeres MA, Abrutyn E, Berlin JA, et al: An assessment of the usefulness of the Duke criteria for diagnosis of active infective endocarditis. Clin Infect Dis 24:1185-1190, 1997. 96.

Mugge A: Echocardiographic detection of cardiac valve vegetations and prognostic implications. Infect Dis Clin North Am 7:877, 1993. 97.

Sochowski RA, Chan KL: Implication of negative results on a monoplane transesophageal echocardiographic study in patients with suspected infective endocarditis. J Am Coll Cardiol 21:216, 1993. 98.

Hoen B, Selton-Suty C, Lacassin F, et al: Infective endocarditis in patients with negative blood cultures: Analysis of 88 cases from a one-year nationwide survey in France. Clin Infect Dis 20:501, 1995. 99.

Shapiro DS, Kenney SC, Johnson M, et al: Brief report: Chlamydia psittaci endocarditis diagnosed by blood culture. N Engl J Med 326:1192, 1992. 100.

Goldenberger D, Kunzli A, Vogt P, et al: Molecular diagnosis of bacteria endocarditis by broad-range PCR amplification and direct sequencing. J Clin Microbiol 35:2733-2739, 1992. 101.

Kaye KM, Kaye D: Laboratory findings including blood cultures. In Kaye D (ed): Infective Endocarditis. 2nd ed. New York, Raven Press, 1992, p 117. 102.

103.

Daniel WG, Mugge A: Transesophageal echocardiography. N Engl J Med 332:1268, 1995.

Vered Z, Mossinson D, Peleg E, et al: Echocardiographic assessment of prosthetic valve endocarditis. Eur Heart J 16(Suppl B):63, 1995. 104.

Morguet AJ, Werner GS, Andreas S, Kreuzer H: Diagnostic value of transesophageal compared with transthoracic echocardiography in suspected prosthetic valve endocarditis. Herz 20:390-398, 1995. 105.

Heidenreich PA, Masoudi FA, Maini B, et al: Echocardiography in patients with suspected endocarditis: A cost-effectiveness analysis. Am J Med 107:198, 1999. 105A.

Daniel WG, Mugge A, Grote J, et al: Comparison of transthoracic and transesophageal echocardiography for detection of abnormalities of prosthetic and bioprosthetic valves in the mitral and aortic positions. Am J Cardiol 71:210, 1993. 106.

Vuille C, Nidorf M, Weyman AE, Picard MH: Natural history of vegetations during successful medical treatment of endocarditis. Am Heart J 128:1200, 1994. 107.

Karalis DG, Bansal RC, Hauck AJ, et al: Transesophageal echocardiographic recognition of subaortic complications in aortic valve endocarditis: Clinical and surgical implications. Circulation 86:353, 1992. 108.

Sokil AB: Cardiac imaging in infective endocarditis. In Kaye D (ed): Infective Endocarditis. 2nd ed. New York, Raven Press, 1992, p 125. 109.

TREATMENT Scheld WM, Sande MA: Endocarditis and intravascular infections. In Mandell GL, Bennett JE, Dolin R (eds): Mandel, Douglas and Bennett's Principles and Practice of Infectious Diseases. 4th ed. New York, Churchill Livingstone, 1995, p 740. 110.

Entenza JM, Caldelari I, Glauser MP, et al: Importance of genotypic and phenotypic tolerance in the treatment of experimental endocarditis due to Streptococcus gordonii. J Infect Dis 175:70-76, 1997. 111.

Enzler MJ, Fluckiger U, Glauser MP, Moreillon P: Antibiotic treatment of experimental endocarditis due to methicillin-resistant Staphylococcus epidermidis. J Infect Dis 170:100-109, 1994. 112.

Wilson WR, Karchmer AW, Dajani AS, et al: Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, staphylococci, and HACEK microorganisms. JAMA 274:1706, 1995. 113.

Antimicrobial Therapy Roberts SA, Lang SDR, Ellis-Pegler RB: Short-course treatment of penicillin-susceptible viridans streptococcal infective endocarditis with penicillin and gentamicin. Infect Dis Clin Pract 2:191, 1993. 114.

Francioli P, Ruch W, Stamboulian D: The International Infective Endocarditis Study Treatment of streptococcal endocarditis with a single daily dose of ceftriaxone and netilmicin for 14 days: A prospective multicenter study. Clin Infect Dis 21:1406-1410, 1995. 115.

Sexton DJ, Tenenbaum MJ, Wilson WR, et al: Ceftriaxone once daily for four weeks compared with ceftriaxone plus gentamicin once daily for two weeks for treatment of endocarditis due to penicillin-susceptible streptococci. Clin Infect Dis 27:1470-1474, 1998. 116.

Chuard C, Herrmann M, Vaudaux P, et al: Successful therapy of experimental chronic foreign-body infection due to methicillin-resistant Staphylococcus aureus by antimicrobial combinations. Antimicrob Agents Chemother 35:2611, 1991. 117.

Torres-Tortosa M, de Cueto M, Vergara A, et al: Prospective evaluation of a two-week course of intravenous antibiotics in intravenous drug addicts with infective endocarditis. Eur J Clin Microbiol Infect Dis 13:559, 1994. 118.

Markowitz N, Quinn EL, Saravolatz LD: Trimethoprim-sulfamethoxazole compared with vancomycin for the treatment of Staphylococcus aureus infection. Ann Intern Med 117:390, 1992. 119.

Mainardi JL, Shlaes DM, Goering RV, et al: Decreased teicoplanin susceptibility of methicillin-resistant strains of Staphylococcus aureus. J Infect Dis 171:1646, 1995. 120.

Sett SS, Hudon MPJ, Jamieson WRE, Chow AW: Prosthetic valve endocarditis: Experience with porcine bioprostheses. J Thorac Cardiovasc Surg 105:428, 1993. 121.

John MVD, Hibberd PL, Karchmer AW, et al: Staphylococcus aureus prosthetic valve endocarditis: Optimal management and risk factors for death. Clin Infect Dis 26:1302-1309, 1998. 122.

Venditti M, DeBernardis F, Micozzi A, et al: Fluconazole treatment of catheter-related right-sided endocarditis caused by Candida albicans and associated endophthalmitis and folliculitis. Clin Infect Dis 14:422, 1992. 123.

Nguyen MH, Nguyen ML, Yu VL, et al: Candida prosthetic valve endocarditis: Prospective study of six cases and review of the literature. Clin Infect Dis 22:262-267, 1996. 124.

125.

Muehrcke DD: Fungal prosthetic valve endocarditis. Sem Thor Cardiovasc Surg 7:20, 1995.

Nasser RM, Melgar GR, Longworth DL, Gordon SM: Incidence and risk of developing fungal prosthetic valve endocarditis after nosocomial candidemia. Am J Med 103:25, 1997. 126.

Raoult D, Houpikian P, Tissot Dupont H, et al: Treatment of Q fever endocarditis: Comparison of 2 regimens containing doxycycline and ofloxacin or hydroxychloroquine. Arch Intern Med 159:167-173, 1999. 127.

128.

Tunkel AR, Kaye D: Endocarditis with negative blood cultures. N Engl J Med 326:1215, 1992.

Olaison L, Berlin L, Hogevik H, Alestig K: Incidence of beta-lactam-induced delayed hypersensitivity and neutropenia during treatment of infective endocarditis. Arch Intern Med 159:607-615, 1999. 129.

Surgical Treatment of Intracardiac Complications Alsip SG, Blackstone EH, Kirklin JW, Cobbs CG: Indications for cardiac surgery in patients with active infective endocarditis. Am J Med 78(Suppl 6B):138, 1985. 130.

Al Jubair K, Al Fagih M, Ashmeg A, et al: Cardiac operations during active endocarditis. J Thorac Cardiovasc Surg 104:487, 1992. 131.

Santoro J, Ingerman M: Response to therapy: Relapses and reinfections. In Kaye D (ed): Infective Endocarditis. 2nd ed. New York, Raven Press, 1992, p 423. 132.

Karchmer AW: Infections of prosthetic valves and intravascular devices. In Mandell GL, Bennett JE, Dolin R (eds): Principles and Practice of Infectious Diseases. New York, Churchill Livingstone, 2000. 133.

Tornos MP, Permanyer-Miralda G, Olona M, et al: Long-term complications of native valve infective endocarditis in non-addicts: A 15-year follow-up study. Ann Intern Med 117:567, 1992. 134.

Blumberg EA, Karalis DA, Chandrasekaran K, et al: Endocarditis-associated paravalvular abscess. Do clinical parameters predict the presence of abscess? Chest 107:898-903, 1995. 135.

Hecht SR, Berger M: Right-sided endocarditis in intravenous drug users: Prognostic features in 102 episodes. Ann Intern Med 17:560, 1992. 136.

Davenport J, Hart RG: Prosthetic valve endocarditis 1976-1987: Antibiotics, anticoagulation, and stroke. Stroke 21:993, 1990. 137.

McGiffin DC, Galbraith AJ, McLachian GJ, et al: Aortic valve infection: Risk factors for death and recurrent endocarditis after aortic valve replacement. J Thorac Cardiovasc Surg 104:511, 1992. 138.

Jault F, Gandjbakheh I, Chastre JC, et al: Prosthetic valve endocarditis with ring abscesses: Surgical management and long-term results. J Thorac Cardiovasc Surg 105:1106, 1993. 139.

Hendren WG, Morris AS, Rosenkranz ER, et al: Mitral valve repair for bacterial endocarditis. J Thorac Cardiovasc Surg 103:124, 1992. 140.

Reinhartz O, Herrmann M, Redling F, Zerkowski HR: Timing of surgery in patients with acute infective endocarditis. J Cardiovasc Surg 37:397-400, 1996. 141.

Eishi K, Kawazoe K, Kuriyama Y, et al: Surgical management of infective endocarditis associated with cerebral complications: Multicenter retrospective study in Japan. J Thorac Cardiovasc Surg 110:1745-1755, 1995. 142.

Gillinov AM, Shah RV, Curtis WE, et al: Valve replacement in patients with endocarditis and acute neurologic deficit. Ann Thorac Surg 61:1125-1130, 1996. 143.

Parrino PE, Kron IL, Ross SD, et al: Does a focal neurologic deficit contraindicate operation in a patient with endocarditis? Ann Thorac Surg 67:59-64, 1999. 144.

Huston JH III, Nichols DA, Luetmer PH, et al: Blinded prospective evaluation of sensitivity of MR angiography to known intracranial aneurysms: Importance of aneurysm size. Am J Neuroradiol 15:1607-1614, 1994. 145.

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RESPONSE TO THERAPY AND OUTCOME Lederman MM, Sprague L, Wallis RS, Ellner JJ: Duration of fever during treatment of infective endocarditis. Medicine 71:52, 1992. 146.

Roberts RB: Streptococcal endocarditis: The viridans and beta hemolytic streptococci. In Kaye D (ed): Infective Endocarditis. 2nd ed. New York, Raven Press, 1992, p 191. 147.

Acar J, Michel PL, Varenne O, et al: Surgical treatment of infective endocarditis. Eur Heart J 16(Suppl B):94, 1995. 148.

Amrani M, Schoevaerdts JC, Eucher P, et al: Extension of native aortic valve endocarditis: Surgical considerations. Eur Heart J 16(Suppl B):103, 1995. 149.

Mullany CJ, Chua YL, Schaff HV, et al: Early and late survival after surgical treatment of culture-positive active endocarditis. Mayo Clin Proc 70:517, 1995. 150.

d'Udekem Y, David TE, Feindel CM, et al: Long-term results of operation for paravalvular abscess. Ann Thorac Surg 62:48-53, 1996. 151.

PREVENTION Dajani AS, Taubert KA, Wilson W, et al: Prevention of bacterial endocarditis: Recommendations by the American Heart Association, from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Diseases in the Young. JAMA 277:1794-1801, 1997. 152.

Leport C, Horstkotte D, Burckhardt D, Group of Experts of the International Society for Chemotherapy: Antibiotic prophylaxis for infective endocarditis from an international group of experts towards a European consensus. Eur Heart J 16(Suppl B):126, 1995. 153.

Hay DR, Chambers ST, Ellis-Pegler RB, et al: Prevention of infective endocarditis associated with dental treatment and other medical interventions. N Z Med J 105:192, 1992. 154.

155.

Durack DT: Prevention of infective endocarditis. N Engl J Med 332:38, 1995.

van der Meer JTM, Thompson J, Valkenburg HA, Michel MF: Epidemiology of bacterial endocarditis in the Netherlands. II. Antecedent procedures and use of prophylaxis. Arch Intern Med 152:1869, 1992. 156.

DeGevigney G, Pop C, Delahaye JP: The risk of infective endocarditis after cardiac surgical and interventional procedures. Eur Heart J 16(Suppl B):7, 1995. 157.

Spirito P, Rapezzi C, Bellone P, et al: Infective endocarditis hypertrophic cardiomyopathy. Circulation 99:2132, 1999. 157A.

Steckelberg JM, Wilson WR: Risk factors for infective endocarditis. Infect Dis Clin North Am 7:9, 1993. 158.

Blatter M, Francioli P: Endocarditis prophylaxis: From experimental models to human recommendation. Eur Heart J 16(Suppl B):107, 1995. 159.

Fluckiger U, Moreillon P, Blaser J, et al: Simulation of amoxicillin pharmacokinetics in humans for the prevention of streptococcal endocarditis in rats. Antimicrob Agents Chemother 38:2846, 1994. 160.

Horstkotte D, Friedrichs W, Pippert H, et al: Nutzen der endokarditisprophylaxe bei patienten mit prothetischen herzklappen. Kardiologie 75:8, 1986. 161.

Strom BL, Abrutyn E, Berlin JA, et al: Dental and cardiac risk factors for infective endocarditis: A population-based, case-control study. Ann Intern Med 129:761-769, 1998. 162.




GUIDELINES PREVENTION, EVALUATION, AND MANAGEMENT OF INFECTIVE ENDOCARDITIS

THOMAS H. LEE Guidelines for antibiotic prophylaxis were issued by the American Heart Association (AHA) in 1997.[1] These guidelines represented a major departure from prior recommendations by emphasizing that most cases are not attributable to an invasive procedure. According to these guidelines, patients with preexisting cardiac disease should be divided into high-, moderate-, and negligible-risk categories on the basis of their potential outcomes if endocarditis were to develop (see Table 47-15) . For dental work, for example, antibiotic prophylaxis is recommended only for patients who have high- and moderate-risk cardiac conditions and who are undergoing high-risk procedures (Table 47-G-1) . For nondental procedures, endocarditis prophylaxis is recommended only for high-risk patients undergoing high-risk procedures (see Table 47-15) ; this strategy is considered optional for medium-risk patients. Antibiotic regimens are described in Table 47-16 . The 1998 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for patients with valvular heart disease[2] endorse the earlier guidelines from the AHA, with a few caveats (Table 47-G-2) . The ACC/AHA guidelines recommend antibiotic prophylaxis for patients with hypertrophic cardiomyopathy only when latent or resting obstruction is a factor. In addition, the ACC/AHA committee expressed concern that an increased risk for endocarditis may exist for some patients with mitral valve prolapse without regurgitation; hence, this group was not willing to state that antibiotic prophylaxis was inappropriate for such patients. Instead, the ACC/AHA guidelines indicate that this issue must be addressed by using clinical judgment in individual cases.

Finally, the ACC/AHA guidelines specified that antibiotic prophylaxis was not necessary for patients with physiological mitral regurgitation in the absence of a murmur.

INDICATIONS FOR ECHOCARDIOGRAPHY Echocardiography is strongly supported in virtually all patients with suspected or known infective endocarditis, but the 1997 ACC/AHA guidelines on echocardiography3 do not recommend transesophageal echocardiography (TEE) as the initial test of choice in the diagnosis of native valve endocarditis (see Table 47-G-2) . Instead, the guidelines urge use of TEE when specific questions are not adequately addressed by the initial transthoracic echocardiography (TTE) evaluation, such as when the TTE study is of poor quality, when the TTE is nondiagnostic despite a high clinical suspicion of endocarditis, when a prosthetic valve is involved, when there is a high suspicion such as in TABLE 47--G-1 -- DENTAL PROCEDURES AND ENDOCARDITIS PROPHYLAXIS[1] Endocarditis Prophylaxis Recommended for Patients with High- and Moderate-Risk Cardiac Conditions (see Table 47-1) Dental extractions Periodontal procedures including surgery, scaling and root planing, probing, and recall maintenance Dental implant placement and reimplantation of avulsed teeth Endodontic (root canal) instrumentation or surgery only beyond the apex Subgingival placement of antibiotic fibers or strips Initial placement of orthodontic bands but not brackets Intraligamentary local anesthetic injections Prophylactic cleaning of teeth or implants where bleeding is anticipated Endocarditis Prophylaxis Not Recommended Restorative dentistry* (operative and prosthodontic) with or without retraction cord Local anesthetic injections (nonintraligamentary) Intracanal endodontic treatment; post placement and buildup Placement of rubber dams Postoperative suture removal Placement of removable prosthodontic or orthodontic appliances Taking of oral impressions Fluoride treatments Taking of oral radiographs

Orthodontic appliance adjustment Shedding of primary teeth From Dajani AS, Taubert KA, Wilson W, et al: Prevention of bacterial endocarditis: Recommendations by the American Heart Association. Circulation 96:358-366, 1997. *This includes restoration of decayed teeth (filling cavities) and replacement of missing teeth. Clinical judgment may indicate antibiotic use in selected circumstances that may create significant bleeding.

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TABLE 47--G-2 -- ACC/AHA GUIDELINES FOR PREVENTION, EVALUATION, AND TREATMENT OF ENDOCARDITIS[2] [3] Indication Class I* Class IIa Class IIb Class III§ Antibiotic endocarditis prophylaxis for patients with mitral valve prolapse undergoing procedures associated with bacteremia

1. Patients with characteristic systolic click-murmur complex 2. Patients with isolated systolic click and echocardiographic evidence of MVP and MR

1. Patients with isolated systolic click, echocardiographic evidence of high-risk MVP

1. Patients with isolated systolic click and equivocal or no evidence of MVP

Echocardiography in infective endocarditis: Native valves (from 3)

1. Detection and characterization of valvular lesions, their hemodynamic severity, and/or ventricular compensation¶ 2. Detection of vegetations and characterization of lesions in patients with congenital heart disease in whom infective endocarditis is suspected 3. Detection of associated abnormalities (e.g., abscesses, shunts)¶ 4. Reevaluation studies in complex endocarditis (e.g., virulent organism, severe hemodynamic lesion, aortic valve involvement, persistent fever or bacteremia, clinical change, or symptomatic deterioration) 5. Evaluation of patients with high clinical suspicion of culture-negative endocarditis¶

1. Evaluation of bacteremia without a known source¶ 2. Risk stratification in established endocarditis¶

1. Routing reevaluation in uncomplicated endocarditis during antibiotic therapy

1. Evaluation of fever and nonpathological murmur without evidence of bacteremia

Echocardiography in infective endocarditis: Prosthetic valves (from 3)

1. Detection and characterization of valvular lesions, their hemodynamic severity, and/or ventricular compensation¶ 2. Detection of associated abnormalities (e.g., abscesses, shunts)¶ 3. Reevaluation in complex endocarditis (e.g., virulent organism, severe hemodynamic lesion, aortic valve involvement, persistent fever or bacteremia, clinical change, or symptomatic deterioration) 4. Evaluation of suspected endocarditis and negative cultures¶ 5. Evaluation of bacteremia without a known source¶

1. Evaluation of persistent fever without evidence of bacteremia or new murmur¶

1. Routine reevaluation in uncomplicated endocarditis during antibiotic therapy¶

1. Evaluation of transient fever without evidence of bacteremia or new murmur

Surgery for native valve endocarditis (criteria also apply to repaired mitral and aortic allograft or autograft valves)

1. Acute AF or MR with heart failure 2. Acute AF with tachycardia and early closure of the mitral valve 3. Fungal endocarditis 4. Evidence of annular or aortic abscess, sinus or aortic true or false aneurysm 5. Evidence of valve dysfunction and persistent infection after a prolonged period (7 to 10 days) of appropriate antibiotic therapy, as indicated by presence of fever, leukocytosis, and bacteremia, provided there are no noncardiac causes of infection

1. Recurrent emboli after appropriate antibiotic therapy 2. Infection with gram-negative organisms or organisms with a poor response to antibiotics in patients with evidence of valve dysfunction

1. Mobile vegetations >10 mm

1. Early infections of the mitral valve that can likely be repaired 2. Persistent pyrexia and leukocytosis with negative blood cultures

Surgery for prosthetic valve endocarditis (criteria exclude repaired mitral and aortic allograft or autograft valves)

1. Early prosthetic valve endocarditis (first 2 months or less after surgery) 2. Heart failure with prosthetic valve dysfunction 3. Fungal endocarditis 4. Staphylococcal endocarditis not responding to antibiotic therapy 5. Evidence of paravalvular leak, annular or aortic abscess, sinus or aortic true or false aneurysm, fistula formation, or new-onset conduction disturbances 6. Infection with gram-negative organisms or organisms with a poor response to antibiotics

1. Persistent bacteremia after a prolonged course (7 to 10 days) of appropriate antibiotic therapy without noncardiac causes of bacteremia 2. Recurrent peripheral embolus despite therapy

1. Vegetation of any size on or near the prosthesis

AF=atrial fibrillation; MR=mitral regurgitation; MVP=mitral valve prolapse. *Procedure or treatment is beneficial, useful, and effective. Weight of evidence in favor of usefulness/efficacy. Usefulness/efficacy less well established. §Procedure or treatment not considered useful or effective. ¶Transesophageal echocardiography may provide incremental value in addition to information obtained by transthoracic imaging.

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a patient with staphylococcus bacteremia, or in an elderly patient with valvular abnormalities that make diagnosis difficult. Diagnosis of prosthetic valve endocarditis with TTE is more difficult than diagnosis of

endocarditis of native valves. Thus, the ACC/AHA guidelines suggest a lower threshold for performance of TEE in patients with prosthetic valves and suspected endocarditis (see Table 47-G-2) .

SURGERY FOR ACTIVE ENDOCARDITIS The ACC/AHA guidelines for valvular heart disease support performance of surgery for patients with life-threatening congestive heart failure or cardiogenic shock due to active endocarditis. Indications for surgery for patients with stable endocarditis are considered less clear (see Table 47-G-2) .

REFERENCES Dajani AS, Taubert KA, Wilson W, et al: Prevention of bacterial endocarditis: Recommendations by the American Heart Association. Circulation 96:358-366, 1997. 1.

Bonow RO, Carabello B, de Leon AC Jr, et al: ACC/AHA guidelines for the management of patients with valvular heart disease: Executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease). Circulation 98:1949-1984, 1998. 2.

Cheitlin MD, Alpert JS, Armstrong WF, et al: ACC/AHA guidelines for the clinical application of echocardiography: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Clinical Application of Echocardiography). Circulation 95:1686-1744, 1997. 3.




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Chapter 48 - The Cardiomyopathies and Myocarditides JOSHUA WYNNE EUGENE BRAUNWALD

The cardiomyopathies constitute a group of diseases in which the dominant feature is direct involvement of the heart muscle itself. They are distinctive because they are not the result of pericardial, hypertensive, congenital, valvular, or ischemic diseases. Although the diagnosis of cardiomyopathy requires the exclusion of these etiological factors, the features of cardiomyopathy are often sufficiently distinctive--both clinically and hemodynamically--to allow a definitive diagnosis to be made.[1] With increasing awareness of this condition, along with improvements in diagnostic techniques, cardiomyopathy is being recognized as a significant cause of morbidity and mortality.[2] Whether the result of improved recognition or of other factors, the incidence and prevalence of cardiomyopathy appear to be increasing.[2] Although coronary artery disease is the most common cause of congestive heart failure (accounting for about two thirds of all cases), we avoid using the term cardiomyopathy in this setting, because the primary problem is in the coronary arteries and not the heart muscle itself. TABLE 48-1 -- CLASSIFICATION OF THE CARDIOMYOPATHIES DISORDER DESCRIPTION

Dilated cardiomyopathy Dilatation and impaired contraction of the left or both ventricles. Caused by familial/genetic, viral and/or immune, alcoholic/toxic, or unknown factors, or is associated with recognized cardiovascular disease. Hypertrophic cardiomyopathy

Left and/or right ventricular hypertrophy, often asymmetrical, which usually involves the interventricular septum. Mutations in sarcoplasmic proteins cause the disease in many patients.

Restrictive cardiomyopathy

Restricted filling and reduced diastolic size of either or both ventricles with normal or near-normal systolic function. Is idiopathic or associated with other disease (e.g., amyloidosis, endomyocardial disease).

Arrhythmogenic right ventricular cardiomyopathy

Progressive fibrofatty replacement of the right, and to some degree left, ventricular myocardium. Familial disease is common.

Unclassified cardiomyopathy

Diseases that do not fit readily into any category. Examples include systolic dysfunction with minimal dilatation, mitochondrial disease, and fibroelastosis.

Specific Cardiomyopathies Ischemic cardiomyopathy

Presents as dilated cardiomyopathy with depressed ventricular function not explained by the extent of coronary artery obstructions or ischemic damage.

Valvular cardiomyopathy

Presents as ventricular dysfunction that is out of proportion to the abnormal loading conditions produced by the valvular stenosis and/or regurgitation.

Hypertensive cardiomyopathy

Presents with left ventricular hypertrophy with features of cardiac failure due to systolic or diastolic dysfunction.

Inflammatory cardiomyopathy

Cardiac dysfunction as a consequence of myocarditis.

Metabolic cardiomyopathy

Includes a wide variety of causes, including endocrine abnormalities, glycogen storage disease, deficiencies (such as hypokalemia), and nutritional disorders.

General systemic disease

Includes connective tissue disorders and infiltrative diseases such as sarcoidosis and leukemia.

Muscular dystrophies

Includes Duchenne, Becker-type, and myotonic dystrophies.

Neuromuscular disorders

Includes Friedreich ataxia, Noonan syndrome, and lentiginosis.

Sensitivity and toxic reactions

Includes reactions to alcohol, catecholamines, anthracyclines, irradiation, and others.

Peripartal cardiomyopathy

First becomes manifest in the peripartum period, but it is likely a heterogeneous group.

Derived from Richardson P, McKenna W, Bristow M, et al: Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies. Circulation 93:841, 1996. Copyright 1996, American Heart Association.

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Figure 48-1 Diagram comparing three morphologic types of cardiomyopathies of unknown cause. Ao = aorta; LA = left atrium; LV = left ventricle. (From Waller BF: Pathology of the cardiomyopathies. J Am Soc Echocardiogr 1:4, 1988.)

Figure 48-2 Gross pathology of dilated cardiomyopathy. Prominent ventricular dilatation is apparent in this heart, which has been opened so that the interior of the left ventricle can be seen. Wall thickness is normal, but the shape of the heart has become more globular. (From Kasper EK, Hruban RH, Baughman KL: Idiopathic dilated cardiomyopathy. \i\In\r\ Abelmann WH, Braunwald E ;obeds.;cb: Atlas of Heart Diseases. Vol 2. Cardiomyopathies, Myocarditis, and Pericardial Disease. Philadelphia, Current Medicine, 1995, pp 3.1-3.18.)

A variety of schemes have been proposed for classifying the cardiomyopathies. The most widely recognized classification is that promulgated jointly by the World Health Organization (WHO) and the International Society and Federation of Cardiology (ISFC) (Table 48-1) .[3] In the WHO/ISFC classification, the cardiomyopathies are classified based on their predominant pathophysiological features; other diseases that affect the myocardium that are associated with a specific cardiac disorder or are part of a generalized systemic disorder are termed specific cardiomyopathies (in the previous WHO/ISFC classification, they were termed specific heart muscle diseases).[3] Three basic types of functional impairment have been described (Fig. 48-1; Table 48-2) : (1) dilated (DCM, formerly called congestive), the most common form, accounting for 60 percent of all cardiomyopathies[4] and characterized by ventricular dilatation, contractile dysfunction, and often symptoms of congestive heart failure (Fig. 48-2) ; (2) hypertrophic (HCM), recognized by inappropriate left ventricular hypertrophy, often with asymmetrical involvement of the interventricular septum, with preserved or enhanced contractile function until late in the course; and (3) restrictive (RCM), the least common form in western countries, marked by impaired diastolic filling and in some cases with endocardial scarring of the ventricle. Two other forms of cardiomyopathy are recognized: arrhythmogenic right ventricular cardiomyopathy and unclassified; the latter includes fibroelastosis, systolic dysfunction with minimal dilatation, and mitochondrial involvement.[3] The distinction TABLE 48-2 -- FUNCTIONAL CLASSIFICATION OF THE CARDIOMYOPATHIES DILATED RESTRICTIVE HYPERTROPHIC

Symptoms

Physical Examination

Congestive heart failure, particularly left sided

Dyspnea, fatigue

Dyspnea, angina pectoris

Fatigue and weakness

Right-sided congestive heart failure

Fatigue, syncope, palpitations

Systemic or pulmonary emboli

Signs and symptoms of systemic disease: amyloidosis, iron storage disease, etc.

Moderate to severe cardiomegaly: S3 and S4

Mild to moderate Mild cardiomegaly cardiomegaly: S3 or S4 Apical systolic thrill and heave; brisk carotid upstroke

Atrioventricular valve regurgitation, especially mitral

Chest Roentgenogram

S4 common Systolic murmur that increases with Valsalva maneuver

Moderate to marked Mild cardiac cardiac enlargement enlargement, especially left ventricular

Mild to moderate cardiac enlargement

Pulmonary venous hypertension

Pulmonary venous hypertension

Left atrial enlargement

Low voltage


Electrocardiogram Sinus tachycardia

Atrial and ventricular Intraventricular arrhythmias conduction defects

ST segment and T wave abnormalities

ST segment and T wave abnormalities

Abnormal Q waves

Intraventricular conduction defects Echocardiogram

Atrioventricular valve regurgitation; inspiratory increase in venous pressure (Kussmaul sign)

Left ventricular dilatation and dysfunction

Atrioventricular conduction defects

Atrial and ventricular arrhythmias Increased left Asymmetrical septal ventricular wall hypertrophy (ASH) thickness and mass

Abnormal diastolic mitral valve motion secondary to abnormal compliance and filling pressures

Radionuclide Studies

Cardiac Catheterization

Left ventricular dilatation and dysfunction (RVG)

Small or normal-sized left ventricular cavity

Narrow left ventricular outflow tract

Normal systolic function

Systolic anterior motion (SAM) of the mitral valve

Pericardial effusion

Small or normal-sized left ventricle

Infiltration of Small or 201 myocardium ( Tl) normal-sized left ventricle (RVG) Small or normal-sized left ventricle (RVG)

Vigorous systolic function (RVG)

Normal systolic function (RVG)

Asymmetrical septal hypertrophy (RVG or 201 Tl)

Left ventricular enlargement and dysfunction

Diminished left ventricular compliance

Diminished left ventricular compliance

Mitral and/or tricuspid regurgitation

"Square root sign" Mitral regurgitation in ventricular pressure recordings Vigorous systolic function

Elevated left- and often right-sided filling pressures

Preserved systolic function Elevated left- and right-sided filling pressures

Diminished cardiac output RVG=Radionuclide ventriculogram; 201 Tl=thallium-201.

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Dynamic left ventricular outflow gradient

TABLE 48-3 -- CLINICAL INDICATIONS FOR ENDOMYOCARDIAL BIOPSY DEFINITE Monitoring of cardiac allograft rejection Monitoring of anthracycline cardiotoxicity POSSIBLE Detection and monitoring of myocarditis Diagnosis of secondary cardiomyopathies Differentiation between restrictive and constrictive heart disease UNCERTAIN Unexplained, life-threatening ventricular tachyarrhythmias Acquired immunodeficiency syndrome Formulation of prognosis in idiopathic dilated cardiomyopathy From Mason JW, O'Connell JB: Clinical merit of endomyocardial biopsy. Circulation 79:971, 1989. Copyright 1989, American Heart Association. between the three major functional categories is not absolute, and often there is overlap; in particular, patients with HCM also have increased wall stiffness (as a consequence of the myocardial hypertrophy) and thus present some of the features of an RCM.[3] Late in their course, ventricular dilation and systolic heart failure, bearing some resemblance to DCM, may occur. Examples of specific cardiomyopathies include ischemic cardiomyopathy, valvular cardiomyopathy, hypertensive cardiomyopathy, and inflammatory cardiomyopathy (myocarditis with cardiac dysfunction) (see Table 48-1 ). [3] Most forms of specific cardiomyopathy are characterized by the DCM pattern. The term ischemic cardiomyopathy (see Chap. 37 ) has been used to describe the condition in which coronary artery disease causes multiple infarctions, diffuse fibrosis, and/or severe ischemia that leads to left ventricular dilatation with congestive heart failure; it may or may not be associated with angina pectoris.[5] Endomyocardial Biopsy

Evaluation of some patients suspected of suffering from a cardiomyopathy has been facilitated by the use of endomyocardial biopsy.[6] Using a flexible bioptome, the clinician may obtain tissue samples from the right ventricle (and left ventricle when required) through a transvenous (or transarterial) approach with ease and safety (see Chap. 11 ). The availability of disposable transfemoral bioptomes has further facilitated endomyocardial biopsy. Two-dimensional echocardiography may help guide the placement of the bioptome and reduce or eliminate radiation exposure.[7] Endomyocardial biopsy results in a small tissue sample (average size 1 to 2 mm), and multiple samples (usually four or more) are required because pronounced topographical variations may be found within the myocardium. Which patients should be subjected to

biopsy remains controversial, but there is general agreement that biopsy may be of benefit in certain specific situations (Table 48-3) . [6] There is little debate as to its clinical utility in detecting infiltrative disorders of the myocardium and in monitoring for anthracycline cardiotoxicity and cardiac transplant rejection. Although on occasion endomyocardial biopsy may identify a specific etiological agent in an individual patient with cardiac disease of uncertain cause (Table 48-4) , the clinical utility of routine biopsy in cardiomyopathy is limited (particularly because no definitive pattern has been found in DCM) (Fig. 48-3) .[8] [9] It has been estimated that a specific etiological diagnosis is obtained by biopsy in fewer than 10 percent of patients with cardiomyopathy and a treatable disease is found in only about 2 percent.[6] DALLAS CRITERIA.

Interpretation of biopsy specimens had been plagued by a high degree of interobserver variability; the adoption of a generally accepted set of histological definitions, the Dallas criteria, has improved agreement.[10] It is hoped that newer immunohistochemical and molecular biological techniques (such as the polymerase chain reaction or in situ hybridization techniques to detect viral infection of the heart) may expand further the diagnostic utility of endomyocardial biopsy.[10] [11] [12] TABLE 48-4 -- SPECIFIC DIAGNOSES THAT CAN BE CONFIRMED BY MYOCARDIAL BIOPSY Cardiac allograft Fabry disease of the heart Henoch-Schonlein purpura rejection Myocarditis

Carcinoid disease

Rheumatic carditis

Giant cell myocarditis

Irradiation injury

Chagasic cardiomyopathy

Doxorubicin cardiotoxicity

Glycogen storage disease

Chloroquine cardiomyopathy

Cardiac amyloidosis

Cardiac tumors of cardiac origin

Lyme carditis

Cardiac sarcoidosis

Cardiac tumors of noncardiac Carnitine deficiency origin cardiomyopathy

Cardiac hemochromatosis

Kearns-Sayre syndrome

Right ventricular lipomatosis

Endocardial fibrosis

Cytomegalovirus infection

Hypereosinophilic syndrome

Endocardial fibroelastosis

Toxoplasmosis

From Mason JW, O'Connell JB: Clinical merit of endomyocardial biopsy. Circulation 79:971, 1989. Copyright 1989, American Heart Association.

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Figure 48-3 Histological specimens obtained by right ventricular endomyocardial biopsy. A, Idiopathic dilated cardiomyopathy with varying degrees of interstitial fibrosis and myocyte hypertrophy (trichrome stain, 210×). B, Myocarditis with dense focal area of mononuclear cell infiltrate adjacent to necrotic and degenerating myocytes, with irregular myocytic hypertrophy and dense interstitial fibrosis (hematoxylin-eosin, 210×). (From Dec GW, Fuster V: Idiopathic dilated cardiomyopathy. N Engl J Med 331:1564, 1994. Copyright 1994, Massachusetts Medical Society.)

Dilated Cardiomyopathy IDIOPATHIC DILATED CARDIOMYOPATHY Dilated cardiomyopathy is a syndrome characterized by cardiac enlargement and impaired systolic function of one or both ventricles (see Fig. 48-2 ). Although it was formerly called congestive cardiomyopathy, the term dilated cardiomyopathy is now preferred because the earliest abnormality usually is ventricular enlargement and systolic contractile dysfunction, with the signs and symptoms of congestive heart failure often (but not invariably) developing later. In an occasional patient, the predominant finding is that of contractile dysfunction with only a mildly dilated left ventricle. In the WHO/ISFC classification scheme, this variant of DCM is placed in the unclassified cardiomyopathy group. Conversely, apparently normal elite athletes may demonstrate considerable ventricular enlargement with normal systolic performance. It is presumed that this is a physiological adaptation to intense athletic training and does not appear to represent a disease state, although the long-term consequences are not fully known.[13] The incidence of DCM is reported to be 5 to 8 cases per 100,000 population per year and appears to be increasing, although the true figure likely is higher as a consequence of underreporting of mild or asymptomatic cases. [14] It occurs almost three times more frequently in blacks and males as in whites and females, and this difference does not appear to be related solely to differing degrees of hypertension, cigarette smoking, or alcohol use.[2] [15] [16] Survival in blacks and males appears to be worse than in whites and females.[17] Although the cause is not definable in many cases, more than 75 specific diseases of heart muscle can produce the clinical manifestations of DCM. It is likely that this condition represents a final common pathway that is the end result of myocardial damage produced by a variety of cytotoxic, metabolic, immunological, familial, and infectious mechanisms. Alcohol, for example, may lead to severe cardiac dysfunction and may produce clinical, hemodynamic, and pathological findings identical to those present in idiopathic DCM (see p. 1758 ). NATURAL HISTORY.

The natural history of DCM is not well established. Many patients have minimal or no symptoms, and the progression of the disease in these patients is unclear, although there is some evidence that the long-term prognosis is not good. [18] Nevertheless, in symptomatic patients the course usually is one of progressive deterioration, with one quarter of newly diagnosed patients referred to major medical centers dying within a year and half dying within 5 years, although a minority improve, with a reduction in cardiac size and longer survival.[14] Recent data suggest that in patients with mild dilatation not referred to a medical center the prognosis may be more favorable, no doubt reflecting at least in part earlier diagnosis and perhaps more effective treatment options now available in the community.[1] [19] [20] About a fourth of patients with recent-onset DCM improve spontaneously, even some sick enough initially to be considered for cardiac transplantation.[21] In some patients clinical and functional improvement may occur years after initial presentation. PROGNOSIS.

A variety of clinical predictors of patients at enhanced risk of dying of DCM have been identified, including the presence of a protodiastolic (S3 ) gallop, ventricular arrhythmias, advanced age, and specific endomyocardial biopsy features.[22] However, the predictive reliability of any single feature is not high,[23] and it may be difficult to predict with any accuracy the clinical course and outcome in an individual patient.[14] [20] Nevertheless, greater ventricular enlargement and worse dysfunction tend to correlate with poorer prognosis,[16] [22] [24] particularly if the right ventricle is dilated and dysfunctional as well.[25] Cardiopulmonary exercise testing also can provide prognostic information (see Chap. 6 ). Marked limitation of exercise capacity manifested by reduced maximal systemic oxygen uptake (especially when below 10 to 12 ml/kg/min) is a reliable predictor of mortality and is used widely as an indicator for consideration of cardiac transplantation.[14] [16] It has been suggested that specific endomyocardial biopsy morphological findings (such as loss of intracellular myofilaments) may offer some predictive information regarding prognosis.[14] [26]

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Pathology MACROSCOPIC EXAMINATION.

This reveals enlargement and dilatation of all four cardiac chambers; the ventricles are more dilated than the atria (see Fig. 48-2 ). Although the thickness of the ventricular wall is increased in some cases, the degree of hypertrophy often is less than might be expected given the severe dilatation present.[14] The development of left ventricular hypertrophy appears to have a protective or beneficial role in DCM, presumably because it reduces systolic wall stress and thus protects against further cavity dilatation. The cardiac valves are intrinsically normal, and intracavitary thrombi, particularly in the

ventricular apex, are common.[14] The coronary arteries usually are normal. The right ventricle is preferentially involved in some cases of DCM, sometimes on a familial basis. HISTOLOGICAL EXAMINATION.

Microscopic study reveals extensive areas of interstitial and perivascular fibrosis, particularly involving the left ventricular subendocardium (see Fig. 48-3 ). Small areas of necrosis and cellular infiltrate are seen on occasion, but these typically are not prominent features. There is marked variation in myocyte size; some myocardial cells are hypertrophied, and others are atrophied. No viruses or other etiological agents have been identified with any regularity in tissue from patients with DCM. Particularly disappointing has been the failure to identify any immunological, histochemical, morphological, ultrastructural, or microbiological marker that might be used to establish the diagnosis of idiopathic DCM or to clarify its cause. Etiology

About a fourth of the cases of congestive heart failure in the United States are due to idiopathic DCM[27] ; most of the remainder are caused by the sequelae of coronary artery or hypertensive heart disease. It is likely that idiopathic DCM represents a common expression of myocardial damage that has been produced by a variety of as yet unestablished myocardial insults. Although the cause(s) remain unclear, interest has centered on three possible basic mechanisms of damage: (1) familial and genetic factors; (2) viral myocarditis and other cytotoxic insults; and (3) immunological abnormalities (Figs. 48-4 and 48-5) .[14] [28] Familial linkage of DCM occurs more commonly than often is appreciated. In 20 percent or more of patients, a first-degree relative also shows evidence of DCM, suggesting that familial transmission is relatively frequent.[20] [29] [30] [31] [32] [33] [299A] Some asymptomatic relatives of patients with DCM have subclinical left ventricular enlargement and/or dysfunction that may progress to overt symptomatic DMC.[29] Most familial cases demonstrate autosomal dominant transmission; six chromosomal loci have been identified, and more are likely to be found.[34] However, the disease is genetically quite heterogeneous[32] and autosomal recessive [35] and X-linked inheritance[36] have been found. One form of familial X-linked DCM is due to a deletion in the promoter region and the first exon of the gene that codes for the protein dystrophin, a component of the cytoskeleton of myocytes.[37] [38] This has fueled speculation that a resulting deficiency of cardiac dystrophin is the cause of the associated DCM (see also Chap. 21 ). Mutations involving mitochondrial DNA have been reported as well. [39] [40] [41] Whether any of the patients without apparent familial linkage has a genetic predisposition to DCM remains un

Figure 48-4 Diagram showing the cardiac myocyte and the molecules that have been implicated in dilated cardiomyopathy. The actin cytoskeleton is linked to the extracellular matrix by dystrophin and the dystrophin-associated glycoprotein complex. Linkage of the actin cytoskeleton to the contractile

apparatus is hypothesized to occur through the muscle LIM (Lin-11, Isl-1, Mec-3) protein (MLP). A nuclear transcription factor, cyclic AMP response-element binding protein (CREB), is shown binding to a cyclic AMP response element in the myocyte DNA. Mutations in dystrophin and other members of the dystrophin-associated glycoprotein complex, as well as in MLP and CREB, have all been shown to result in dilated cardiomyopathy in mice or humans. (From Leiden JD: The genetics of dilated cardiomyopathy: Emerging clues to the puzzle. N Engl J Med 337:1080, 1997. Copyright 1997, Massachusetts Medical Society.)

Figure 48-5 Hypotheses to explain the pathogenesis of dilated cardiomyopathy. MHC=myosin heavy chain. (From Mestroni L, Krajinovic M, Severini GM, et al: Familial dilated cardiomyopathy. Br Heart J 72:S35, 1994.)

known. There is great interest in using molecular genetic techniques to identify markers of disease susceptibility in asymptomatic carriers at risk for the eventual development of overt clinical DCM.[36] [42] An example of such a marker may be the angiotensin-converting enzyme DD genotype that is found with increased frequency in DCM patients.[43] One intriguing familial metabolic deficiency is that of carnitine, with improvement occurring in the myopathy with carnitine repletion.[44] SEQUELA OF VIRAL MYOCARDITIS.

Wide speculation exists that an episode of subclinical viral myocarditis initiates an autoimmune reaction that culminates in the development of full-blown DCM.[27] [45] Although this hypothesis is inviting, it remains largely unsupported[46] ; it has been estimated that only about 15 percent of patients with myocarditis progress to DCM. In some patients who exhibit the clinical features of DCM, endomyocardial biopsy reveals evidence of an inflammatory myocarditis (see Fig. 48-3 B). The reported frequency of evidence of an inflammatory infiltrate in DCM varies widely and undoubtedly depends largely on patient selection and the criteria used for diagnosis; using rigorous criteria, only about 10 percent (or less) of patients with DCM have biopsy evidence of myocarditis.[6] Other evidence favoring the concept that DCM is a postviral disorder includes the presence of high antibody viral titers, viral-specific RNA sequences, and apparent viral particles in patients with "idiopathic" DCM.[47] On the other hand, the more rigorous technique of polymerase chain reaction generally has not confirmed the presence of viral remnants in the myocardium of most cardiomyopathy patients,[48] although data are conflicting.[49] [50] AUTOIMMUNITY.

Abnormalities of both humoral and cellular immunity have been found in patients with DCM,[28] [51] [52] although the findings have not been completely reproducible. There is speculation that antibodies might be the result of myocardial damage, rather than the cause.[53] There appears to be an association with specific HLA Class II antigens (particularly DR4), suggesting that abnormalities of immunoregulation may play a role in DCM.[31] [54] Circulating antimyocardial antibodies to a variety of antigens (including the myosin heavy chain, the beta adrenoreceptor, the muscarinic receptor, laminin, and mitochondrial proteins) have been identified.[28] [55] [56] [57] Additional evidence for the

significance of circulating antimyocardial antibodies comes from the demonstration of short-term clinical improvement in the manifestations of heart failure in a small number of patients treated with immunoadsorption and elimination of anti-beta1 -adrenergic receptor antibodies. [58] [58A] [58B] Abnormalities of various T cells, including cytotoxic T cells, suppressor T lymphocytes, and natural killer cells, have been found in some studies.[14] [59] These immunological abnormalities may be the consequence of prior viral myocarditis.[59] It has been postulated that viral components may be incorporated into the cardiac sarcolemma, only to serve as an antigenic source that directs the immune response to attack the myocardium. Nevertheless, the precise

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role of either humoral or cellular immunomodulation in the pathogenesis of DCM remains unestablished.[14] PROINFLAMMATORY CYTOKINES.

A variety of proinflammatory cytokines such as tumor necrosis factor-alpha (and the related tumor necrosis factor-alpha converting enzyme) are expressed in DCM and may play a role in producing contractile dysfunction; whether viral infection, autoimmune abnormalities, or other factors induce their expression is unknown.[60] [61] Similarly, the vasoconstrictor peptide endothelin is increased in decompensated DCM and has been implicated as a cause of the heightened vascular tone that accompanies congestive heart failure.[62] OTHER POTENTIAL CAUSES.

A variety of other possible causes have been proposed, although none is accepted as the cause of DCM. Thus, endocrine abnormalities as well as the effects of chemicals or toxins have been suggested as possible etiological factors. It has been suggested that microvascular hyperreactivity (spasm) may lead to myocellular necrosis and scarring, with resultant heart failure, although this remains speculative.[5] Apoptosis, or programmed cell death, has been demonstrated in the hearts of patients with DCM and arrhythmogenic right ventricular cardiomyopathy, although there is some controversy regarding the veracity of these findings in DCM.[63] Even if true, the significance of this finding, and whether it is a primary or secondary event in the development of cardiomyopathy, remains unclear. From a clinical standpoint, the more important causes of nonidiopathic DCM include alcohol and cocaine abuse, human immunodeficiency virus (HIV) infection[64] (see Chap. 68 ), metabolic abnormalities, and the cardiotoxicity of anticancer drugs (especially doxorubicin). ABNORMALITIES OF THE SYMPATHETIC NERVOUS SYSTEM.

Several abnormalities of the sympathetic nervous system have been demonstrated in DCM, but they appear to be the result rather than the cause of the disease.[14] [65] A

reduction in density of membrane-associated beta adrenoreceptors[66] is believed to be a consequence of the development of anti-beta-adrenoreceptor autoantibodies. An alteration in the signal transmission pathway by which the beta adrenoreceptors stimulate the contractile apparatus (the G-protein system) has been found as well. Inhibition of this system is enhanced in DCM patients, perhaps accounting for their depressed contractile function. An increase of the subunits of the inhibitory guanine nucleotide-binding protein (Gi ) has been reported to occur in the membranes of myocytes from failing hearts.[67] This increase in Gi is associated with a striking reduction of basal adenylate cyclase activity and of the positive inotropic effects of isoproterenol and the phosphodiesterase inhibitor milrinone. These findings suggest that the increase of Gi might contribute to the reduced effects of endogenous catecholamines in DCM. The precise cause of contractile dysfunction at the cellular level in patients with DCM remains speculative. Although there are demonstrable abnormalities of cellular metabolism and calcium handling by cardiomyopathic tissue,[5] [68] [69] [70] the significance of these findings is not yet clear.[62] Clinical Manifestations HISTORY.

Symptoms usually develop gradually in patients with DCM. Some patients are asymptomatic and yet have left ventricular dilatation for months or even years. This dilatation may be recognized clinically only later when symptoms develop or when routine chest roentgenography demonstrates cardiomegaly. A relatively small number of patients develop symptoms of heart failure for the first time after recovery from what appears to be a systemic viral infection. In still others, severe heart failure develops acutely during an episode of myocarditis; although some recovery occurs, chronic manifestations of diminished cardiac reserve persist and heart failure reappears months or years later. It is important to question the patient and family carefully about alcohol consumption, because excessive alcohol consumption is a major cause of DCM, and its cessation may result in substantial clinical improvement.[14] Although patients of any age may be affected, the disease is most common in middle age and is more frequent in men than in women. The most striking symptoms of DCM are those of left ventricular failure. Fatigue and weakness due to diminished cardiac output are common. Right-sided heart failure is a late and ominous sign and is associated with a particularly poor prognosis. Chest pain occurs in about one third of patients and may suggest concomitant ischemic heart disease.[1] [14] The demonstrated reduction in the vasodilator reserve of the coronary microvasculature in DCM suggests that subendocardial ischemia may play a role in the genesis of chest pain that occurs despite angiographically normal coronary arteries.[71] Chest pain secondary to pulmonary embolism and abdominal pain secondary to congestive hepatomegaly are frequent in the late stages of illness. PHYSICAL EXAMINATION (See also Chaps. 4 and 17 ).

Examination usually reveals variable degrees of cardiac enlargement and findings of

congestive heart failure. The systolic blood pressure is usually normal or low, and the pulse pressure is narrow, reflecting a diminished stroke volume. Pulsus alternans (see Fig. 17-5 ) is common when severe left ventricular failure is present. Cheyne-Stokes breathing may be present and is associated with a poor prognosis.[72] The jugular veins are distended when right-sided heart failure appears, but on initial presentation most patients do not have evidence of this.[14] Prominent a and v waves may be visible. Grossly pulsatile jugular veins with prominent regurgitant waves indicate the presence of tricuspid valvular regurgitation; this is usually a late and often ominous finding. The liver may be engorged and pulsatile. Peripheral edema and ascites are present when right-sided heart failure is advanced. The precordium usually reveals left and, occasionally, right ventricular impulses, but the heaves are not sustained as they are in patients with ventricular hypertrophy. The apical impulse is usually displaced laterally, reflecting left ventricular dilatation. A presystolic a wave may be palpable on occasion and is generated in a similar manner as a presystolic (S4 ) gallop heard on auscultation. The second heart sound (S2 ) is usually normally split, although paradoxical splitting may be detected in the presence of left bundle branch block, an electrocardiographic (ECG) finding that is not unusual in DCM. If pulmonary hypertension is present, the pulmonary component of S 2 may be accentuated and the splitting may be narrow. Presystolic gallop sounds (S4 ) are almost universally present and often precede the development of overt congestive heart failure.[14] Ventricular gallops (S3 ) are the rule once cardiac decompensation occurs, and a summation gallop is heard when there is concomitant tachycardia. Systolic murmurs are common and are usually due to mitral or, less commonly, tricuspid valvular regurgitation.[14] Mitral regurgitation results from enlargement and abnormal motion of the mitral annulus; ventricular dilatation with resultant distortion of the geometry of the subvalvular apparatus ("papillary muscle dysfunction") plays a lesser role. Gallop sounds and regurgitant murmurs can often be elicited or intensified by isometric handgrip exercise with its attendant enhancement of systemic vascular resistance and impedance to left ventricular outflow. Systemic emboli resulting from dislodgement of intracardiac thrombi from the left atrium and ventricle and pulmonary emboli that originate in the venous system of the legs are common late complications. NONINVASIVE LABORATORY EXAMINATIONS.

To identify potentially reversible causes of DCM, several basic screening biochemical tests are indicated, including determination of levels of serum phosphorus (hypophosphatemia), serum calcium (hypocalcemia), and serum creatinine and urea nitrogen (uremia), thyroid function studies (hypothyroidism and hyperthyroidism), and iron studies (hemochromatosis). It is prudent to test for HIV as well, because this infection is an important and often unrecognized cause of congestive heart failure [64] (see Chap. 68 ). The chest roentgenogram usually reveals generalized cardiomegaly and pulmonary vascular redistribution; interstitial and alveolar edema are less common on initial presentation.[14] Pleural effusions may be present, and the azygos vein and superior vena cava may be dilated when right-sided heart failure supervenes.

Electrocardiography.

The ECG often shows sinus tachycardia when heart failure is present. The entire spectrum of atrial and ventricular tachyarrhythmias may be

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seen. Poor R wave progression and intraventricular conduction abnormalities, especially left bundle branch block, are common.[14] Anterior Q waves may be present when there is extensive left ventricular fibrosis, even without a discrete myocardial scar or evidence of coronary artery disease.[14] ST segment and T wave abnormalities are common, as are P wave changes, especially left atrial abnormality. Ambulatory monitoring demonstrates the ubiquity of ventricular arrhythmias, with about half of monitored patients with DCM exhibiting nonsustained ventricular tachycardia.[14] There is no consensus that complex or frequent ventricular arrhythmias predict sudden (presumably arrhythmic) death, although they do appear to predict total mortality. [73] Perhaps ventricular arrhythmias as detected on ambulatory monitoring are a marker for the extent of myocardial damage in DCM and therefore are associated with sudden death without necessarily being its cause. In occasional cases, particularly in children, recurrent and/or incessant supraventricular or ventricular tachyarrhythmias may actually be the cause (rather than the result) of ventricular dysfunction.[74] [75] In those cases, restoration of sinus rhythm or slowing of the heart rate may reverse the cardiomyopathy.[76] [77] Echocardiography.

Two-dimensional and Doppler forms of echocardiography are useful in assessing the degree of impairment of left ventricular function and for excluding concomitant valvular or pericardial disease (see Fig. 7-99 ). [20] In addition to examining all four cardiac valves for evidence of structural or functional abnormalities, echocardiography allows evaluation of the size of the ventricular cavity and thickness of the ventricular walls. A pericardial effusion may be demonstrated on occasion. Doppler studies are useful in delineating the severity of mitral (and tricuspid) regurgitation. Patients with a pattern of left ventricular filling on Doppler studies that simulates that seen with RCM appear to have more advanced disease.[78] Combining echocardiography with dobutamine infusion may identify patients with left ventricular dysfunction due to coronary artery disease by demonstrating provocable differences in regional wall motion and thus distinguish them from patients with idiopathic DCM.[79] It has been suggested that thallium-201 imaging may be helpful in distinguishing left ventricular enlargement caused by DCM from that caused by coronary artery disease,[80] although there is not complete agreement on this point.[14] [81] Scanning with gallium or antimyosin antibody (see Chap. 9 ) may help to identify patients more likely to have evidence of myocarditis on biopsy, although whether this finding is useful clinically is not yet established.[14] [82]

Radionuclide Ventriculography.

Like echocardiography, radionuclide ventriculography reveals increased end-diastolic and end-systolic left ventricular volumes, reduced ejection fraction in one or both ventricles, and wall motion abnormalities (see Chap. 9 ); it is used most commonly when echocardiography is technically suboptimal.[14] Like echocardiography, it may demonstrate segmental wall motion abnormalities in DCM even in the absence of coronary artery disease, the disease process that most commonly produces regional dysfunction. In most patients it is not necessary to carry out serial studies or batteries of noninvasive tests to follow patients with DCM and evaluate their response to treatment; adjustments in pharmacological therapies usually are made based on routine bedside clinical features and symptomatic response. CARDIAC CATHETERIZATION AND ANGIOCARDIOGRAPHY.

Only certain patients with DCM require cardiac catheterization (particularly those with chest pain and a suspicion of ischemic disease or patients thought to have a treatable systemic disease such as sarcoidosis or hemochromatosis, where myocardial biopsy is an important part of the catheterization procedure).[14] When cardiac catheterization is carried out, the left ventricular end-diastolic, left atrial, and pulmonary artery wedge pressures usually are elevated. Modest degrees of pulmonary arterial hypertension are common. Advanced cases may demonstrate right ventricular dilatation and failure as well, with resultant elevation of the right ventricular end-diastolic, right atrial, and central venous pressures. Left ventriculography demonstrates enlargement of this chamber, typically with diffuse reduction in wall motion. Segmental wall motion abnormalities are not uncommon and may simulate the angiographic findings in ischemic heart disease. However, prominent localized wall motion disturbances are more characteristic of ischemic heart disease, whereas diffuse global dysfunction is more typical of DCM. The ejection fraction is reduced and the end-systolic volume is increased as a result of the impairment of left ventricular contractility. Sometimes left ventricular thrombi may be visualized within the left ventricle as intracavitary filling defects. Mild mitral regurgitation is often present. On occasion, it may be difficult to distinguish left ventricular dilatation secondary to severe mitral regurgitation due to intrinsic mitral valve disease from DCM with secondary mitral regurgitation. Coronary arteriography usually reveals normal vessels, although coronary vasodilatory capacity may be impaired[83] [84] ; in some cases this may relate to marked elevation of the left ventricular filling pressures.[85] This examination may be of particular value in excluding coronary artery disease in patients with abnormal Q waves on the ECG or regional left ventricular wall motion abnormalities on noninvasive evaluation (although noninvasive testing, including electron-beam computed tomography [CT], may be sufficiently reliable to exclude important coronary artery disease without resorting to arteriography).[86] Coronary arteriography, when necessary, thus helps to distinguish between myocardial infarction as a result of obstructive coronary artery disease and extensive localized myocardial fibrosis secondary to severe DCM in the absence of

coronary artery obstruction. Management

Because the cause of idiopathic DCM, by definition, is unknown, specific therapy is not possible.[27] Treatment, therefore, is for heart failure, as discussed in Chapters 18 and 21 . Many of the therapeutic approaches are directed at modifying the results of the long-term activation of two interrelated neurohormonal/autocrine-paracrine systems, the adrenergic and renin-angiotensin systems.[87] Physical, dietary, and pharmacological interventions may help to control symptoms; regular physical exercise (as tolerated) increases exercise capacity by improving endothelial dysfunction and augmenting blood flow in skeletal muscles.[88] Only cardiac transplantation (see Chap. 20 ) and specific pharmacological therapy (the vasodilators enalapril or hydralazine plus nitrates, the beta-adrenoceptor blocker carvedilol, and the aldosterone receptor blocker spironolactone) have been shown to prolong life.[14] [27] [89] [90] [91] BETA-ADRENERGIC RECEPTOR BLOCKADE.

Because of evidence that activation of the adrenergic system may have deleterious cardiac effects (rather than being an important compensatory mechanism as traditionally thought), beta-adrenoceptor blockade has been suggested as treatment for DCM (see Chaps. 18 and 21 ). [78] [92] Results to date generally have been favorable, with evidence of improved symptoms, exercise capacity, and left ventricular function and a suggestion that survival has been improved.[14] [93] [94] [95] [96] [97] [97A] Beta-adrenoceptor blockade has been surprisingly well tolerated, with infrequent aggravation of heart failure (which, on occasion, may be profound). The mechanism of beneficial action of beta-adrenoceptor blockers is unknown but may relate to (1) negative chronotropic effect with reduced myocardial oxygen demand, (2) reduced myocardial damage due to catecholamines, (3) improved diastolic relaxation (both early active and late passive properties), (4) inhibition of sympathetically mediated vasoconstriction, (5) increase ("upregulation") in myocardial beta-adrenoceptor density, (6) improved calcium handling at slower heart rates, (7) modulation of postreceptor inhibitory G proteins, and/or (7) a direct effect on myocyte and interstitial growth, with attendant inhibition of the remodeling process (remodeling refers to the change in ventricular shape, size, and geometry that occurs after myocyte dysfunction).[90] [92] [98] [99] [100] Modulation of the remodeling process has also

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been implicated in the successful use of growth hormone in a small number of patients with DCM.[101] Beta-adrenergic blocker therapy is now accepted as part of the four-drug approach (along with digoxin, vasodilators and diuretics) advocated for all suitable patients with

symptomatic congestive heart failure (see Chap. 21 ). Patients with advanced heart failure or in a decompensated state should not ordinarily be given a beta-adrenergic blocker for fear of worsening the failure.[102] Recent data indicate that carvedilol (a beta-adrenoceptor blocker with alpha-adrenoceptor blocking and antioxidant effects) substantially reduces mortality in DCM.[90] It remains unestablished whether carvedilol has additional clinical benefits beyond those found with the other beta-adrenergic blockers, although some patients appear to respond more favorably.[103] [104] CALCIUM ANTAGONISTS.

Because of the possible link between DCM, microvascular circulatory abnormalities, and abnormal myocardial calcium handling, there has been interest in the use of calcium antagonists. These agents have generally been well tolerated when used in DCM patients, although myocardial depression is an important potential side effect of the calcium antagonists as a group. Unfortunately, combining a calcium antagonist with traditional standard therapy (digoxin, diuretics, and vasodilator) does not appear to have substantial clinical benefit, nor does it reduce further the mortality in DCM.[105] At present, the routine use of calcium antagonists in DCM is considered nonstandard and not first-line therapy.[106] ANTIARRHYTHMICS.

Although there is no definitive evidence that antiarrhythmic agents prolong life or prevent sudden death in DCM,[14] [73] [107] it may be appropriate to use them in the treatment of symptomatic arrhythmias. Because of the adverse effects of most available agents, many of which depress myocardial contractility and have a proarrhythmic effect (see Chap. 23 ), treatment should be individualized, with both efficacy and toxicity carefully monitored. Unfortunately, electrophysiological testing is of limited utility in DCM because it is positive in a minority of patients at risk,[14] [108] the lack of inducibility of ventricular tachyarrhythmias does not identify a low-risk group, and pharmacological suppression of provoked arrhythmias does not necessarily predict freedom from recurrences.[109] The recording of late potentials by the signal-averaged ECG has appeared to be of benefit in assessing the risk of death in some studies, although this has not been a universal finding and awaits further confirmation.[110] [111] The implantable cardioverter-defibrillator (ICD) (see Chap. 24 ) should be considered in appropriate candidates with symptomatic ventricular tachyarrhythmias.[112] [113] Even patients with unexplained syncope and no demonstrated tachyarrhythmia (even during electrophysiological testing) may profit from the insertion of an ICD. ANTICOAGULANTS.

There is a lack of agreement as to the appropriateness and usefulness of chronic anticoagulant therapy in DCM to protect against pulmonary and especially systemic emboli.[114] [115] Even in the absence of controlled clinical trials demonstrating their efficacy,[116] we believe that the available observational data support the use of anticoagulants in good-risk patients with DCM and heart failure.[114] [117] There is general agreement that anticoagulants should be used in the presence of atrial fibrillation, if the patient has previously had a stroke, and when there is visible thrombus on

echocardiography. Oral warfarin is used to achieve a prolongation of the prothrombin time of 2.0 to 3.0 international normalized ratio. IMMUNOSUPPRESSIVES.

In those patients with chronic heart failure secondary to DCM and lymphocytic infiltrate on myocardial biopsy, treatment with corticosteroids and immunosuppressive agents had been advocated in the past. Unfortunately, such therapy does not appear to have a clinically important effect on symptoms, exercise performance, or ejection fraction (in more than just the short term) and may be associated with significant complications.[118] Routine clinical use of immunosuppressive therapy thus cannot be recommended at present. DUAL CHAMBER PACING.

This has been used in some patients with DCM and intact atrioventricular conduction in an attempt to change the sequence of ventricular depolarization, reduce functional mitral regurgitation, and thus improve clinical status; some symptomatic and hemodynamic improvement has been reported, especially in patients with intraventricular conduction delay or those with disturbed timing of atrioventricular mechanical activation.[119] [120] In a small number of patients followed short term, biventricular or left ventricular pacing appeared to be preferable to traditional right ventricular pacing.[120A] However, the data to date are largely anecdotal and equivocal, and demonstration of long-term benefit is lacking.[109] [121] SURGICAL TREATMENT.

Mitral annuloplasty or replacement of regurgitant valves has been attempted in some patients with DCM and prominent atrioventricular valvular regurgitation. The results of operation are usually less than satisfactory because of the degree of preexisting cardiac dysfunction and damage, although some patients have shown some degree of symptomatic improvement, at least over the intermediate term.[122] In appropriately selected patients, cardiac transplantation (see Chap. 20 ) may be an attractive alternative to medical therapy, with a 5-year survival rate of about 75 percent. Surgical translocation of the latissimus dorsi muscle to wrap around the heart and augment cardiac performance (dynamic cardiomyoplasty) appears to have benefited some patients who are not otherwise suitable candidates for cardiac transplantation.[53] [123] Excision of part of the left ventricle (partial ventriculotomy) has been proposed as an additional surgical alternative to cardiac transplantation[124] ; the lack of a randomized control trial demonstrating efficacy has limited the widespread adoption of the procedure. ALCOHOLIC CARDIOMYOPATHY Chronic excessive consumption of alcohol may be associated with congestive heart failure, hypertension, cerebrovascular accidents, arrhythmias, and sudden death; it is the major cause of secondary, nonischemic DCM in the western world and accounts for

upward of one third of all cases of DCM.[125] It is estimated that two thirds of the adult population use alcohol to some extent, and more than 10 percent are heavy users. [126] Therefore, it is not surprising that alcoholic cardiomyopathy is a major problem. Ceasing alcohol consumption early in the course of alcoholic cardiomyopathy may halt the progression of or even reverse left ventricular contractile dysfunction, unlike nonalcoholic cardiomyopathy, which often is marked by progressive clinical deterioration.[9] [127] The consumption of alcohol may result in myocardial damage by three basic mechanisms: (1) a presumed direct toxic effect of alcohol or its metabolites; (2) nutritional effects, most commonly in association with thiamine deficiency that leads to beriberi heart disease (see Chap. 17 ); and (3) rarely, toxic effects due to additives in the alcoholic beverage (cobalt) (see p. 1759 ). [9] [128] There had been speculation that alcohol caused myocardial damage only through dietary deficiencies, but it is now clear that alcoholic cardiomyopathy occurs in the absence of nutritional deficiencies.[125] [126] [129]

Typical Oriental beriberi (see Chap. 17 ) may coexist with alcoholic cardiomyopathy, although it is no longer noted with any frequency.[130] The distinguishing features of each include peripheral vasodilatation and high-output heart failure, often right sided, in the former and reduced contractility with typically left-sided low-output failure in the latter. [125] [130]

Alcohol results in acute as well as chronic depression of myocardial contractility and may produce reversible cardiac dysfunction even when ingested by normal nonalcoholic individuals. What is responsible for the transition from the reversible acute effects to permanent myocardial damage remains unclear.[126] The precise mechanisms of cardiac depression produced by alcohol are undetermined, but a direct toxic effect on striated muscle is likely (particularly because alcoholics often demonstrate concomitant skeletal myopathy and cardiomyopathy).[125] [126] In acute studies, alcohol and its metabolite acetaldehyde have been shown to interfere with a number of membrane and cellular functions that involve the transport and binding of calcium, mitochondrial respiration, myocardial lipid metabolism, myocardial protein synthesis, and signal transduction.[126] Studies in isolated ferret papillary muscles have shown that ethanol in concentrations similar to those occurring in intoxicated humans depresses myocardial contractility by interfering with excitation-contraction coupling through inhibition of the interaction between calcium and the myofilaments.[126] There are data supporting the role of free radical damage and defects in protein synthesis in the genesis of alcohol-induced myocardial damage.[126] The role that other associated electrolyte imbalances (hypokalemia, hypophosphatemia, hypomagnesemia) may play in alcohol-mediated damage has not been settled. PATHOLOGY.

The gross and microscopic pathological findings are nonspecific and similar to those observed in idiopathic DCM, with interstitial fibrosis, myocytolysis, evidence of small vessel coronary artery disease, and myocyte hypertrophy. [125] [131] Electron microscopy

shows enlarged and disorganized mitochondria, with large glycogen-containing vacuoles.[126] Clinical Manifestations

Alcoholic cardiomyopathy most commonly occurs in men 30 to 55 years of age who have been heavy consumers of whisky, wine, or beer, usually for more than 10 years. Female alcoholics who develop cardiomyopathy appear to have a lower cumulative lifetime dose of alcohol than men.[127] Although alcoholic cardiomyopathy may be observed

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in the homeless, malnourished, "skid row" alcoholic man, many patients are well-nourished individuals of middle and even upper socioeconomic status without liver disease or peripheral neuropathy. Accordingly, unless a high index of suspicion is maintained, it may be easy to miss a history of alcohol abuse.[132] Persistent questioning of the patient and particularly the relatives of patients with unexplained cardiomegaly or cardiomyopathy is often required to elicit a history of alcoholism. It is frequently possible to demonstrate mild depression of cardiac function in chronic alcoholics even before cardiac dysfunction becomes clinically manifest. Abnormalities of both systolic function (reduced ejection fraction) and diastolic function (increased myocardial wall stiffness) have been demonstrated in alcoholic patients without cardiac symptoms by a variety of invasive and noninvasive techniques.[132A] Although overt alcoholic liver disease and cardiac involvement usually do not occur together, even cirrhotic patients without signs or symptoms of heart disease have demonstrable evidence of asymptomatic myocardial disease. The development of symptoms may be insidious, although some patients have acute and florid left-sided congestive heart failure. A paroxysm of atrial fibrillation is a relatively frequent initial presenting finding. More advanced cases demonstrate findings of biventricular failure, with left ventricular dysfunction usually dominating. Dyspnea, orthopnea, and paroxysmal nocturnal dyspnea frequently are observed. Palpitations may be present and usually are due to supraventricular tachyarrhythmias. Syncope may be seen as well and may be the result of supraventricular, or more likely ventricular, tachyarrhythmias. Angina pectoris does not occur unless there is concomitant coronary artery disease or aortic stenosis, although atypical chest pain may be seen. PHYSICAL EXAMINATION.

The cardiac findings resemble those seen in idiopathic DCM (see p. 1756 ). Examination usually reveals a narrow pulse pressure, often with an elevated diastolic pressure secondary to excessive peripheral vasoconstriction. There is cardiomegaly, and protodiastolic (S3 ) and presystolic (S4 ) gallop sounds are common. An apical

systolic murmur of mitral regurgitation often is found. The severity of right-sided heart failure varies, but jugular venous distention and peripheral edema are common. A concomitant skeletal muscle myopathy involving the shoulder and pelvic girdle is a frequent finding, and the degree of muscle weakness and histological abnormality in the skeletal muscles parallels that in the heart.[125] LABORATORY EXAMINATION.

The chest roentgenogram in advanced cases demonstrates considerable cardiac enlargement, pulmonary congestion, and pulmonary venous hypertension (see Chap. 8 ). Pleural effusions often are seen. ECG abnormalities are common and frequently are the only indication of alcoholic heart disease during the preclinical phase. Alcoholic patients without other evidence of heart disease often are seen after developing palpitations, chest discomfort, or syncope, typically after a binge of alcohol consumption on a weekend, particularly during the year-end holiday season. This is dubbed the "holiday heart syndrome." The most common arrhythmia observed is atrial fibrillation, followed by atrial flutter and frequent ventricular premature contractions. Alcohol consumption may predispose to atrial flutter or fibrillation, even in nonalcoholics. Hypokalemia may play a role in the genesis of some of these arrhythmias. Supraventricular arrhythmias are also frequently observed in patients with overt alcoholic cardiomyopathy. Sudden unexpected death is not uncommon in young adult alcoholics, and it is likely that ventricular fibrillation is responsible. Atrioventricular conduction disturbances (most commonly first-degree heart block), bundle branch block, left ventricular hypertrophy, poor R wave progression across the precordium, and repolarization abnormalities are common ECG findings. Prolongation of the QT interval is noted frequently. ST segment and T wave changes are often restored to normal within several days after cessation of alcohol consumption. The hemodynamic findings observed at cardiac catheterization and the assessment of left ventricular function by noninvasive methods (echocardiography and isotope angiography) resemble those found in idiopathic DCM. MANAGEMENT.

The natural history of alcoholic cardiomyopathy depends on the drinking habits of the patient. Total abstinence in the early stages of the disease may lead to resolution of the manifestations of congestive heart failure and a return of heart size toward normal, although patients with severe heart failure may show no improvement in function or prognosis.[9] [133] Continued alcohol consumption leads to further myocardial damage and fibrosis, with the development of refractory congestive heart failure. Death may be due to arrhythmia, heart block, or systemic or pulmonary embolism, in addition to myocardial failure. The key to the long-term treatment of alcoholic cardiomyopathy is immediate and total abstinence as early in the course of the disease as possible. This may be quite effective in improving the signs and symptoms of congestive heart failure. [133] The reversibility of

alcoholic myocardial depression is supported by the demonstration of a reduction of myocardial uptake of labeled monoclonal antimyosin antibodies (a marker of myocyte damage) in alcoholics who stop drinking.[82] The prognosis in patients who continue to drink is poor, particularly if they have been symptomatic for a long time. Prolonged bed rest is thought to result in functional improvement, although its major benefit may simply be the decreased alcohol consumption. The management of acute episodes of congestive heart failure is similar to that of idiopathic DCM (see p. 1757 ). For patients with severe congestive heart failure, it is prudent to administer thiamine on the chance that beriberi may be contributing to the heart failure.[130] Whether to use chronic anticoagulation (as is often considered in idiopathic DCM) is a difficult question; we usually do not prescribe warfarin unless there are unequivocal and pressing indications because of the risk of bleeding due to noncompliance, trauma, and over-anticoagulation due to hepatic dysfunction. COBALT CARDIOMYOPATHY

A previously unrecognized syndrome of severe congestive heart failure appeared in the mid 1960s, first in Canada and subsequently in the United States and Europe.[129] The disease was found in people who drank a particular brand of beer to which cobalt sulfate had been added as a foam stabilizer. Since cobalt was removed from the process, no more cases of the disease have been reported. On very rare occasions occupational exposure to cobalt may result in myocardial damage and attendant congestive heart failure.[129] [134] ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY (See also Chap. 25 ) This unique cardiomyopathy (which is also called arrhythmogenic right ventricular dysplasia [ARVD]) is marked by myocardial cell loss with partial or total replacement of right ventricular muscle by adipose and fibrous tissue; apoptosis appears to be a principal cause of the cell death (Fig. 48-6) .[135] [136] ARVD is associated with reentrant ventricular tachyarrhythmias of right ventricular origin (producing a left bundle branch block configuration of the QRS complex) and the risk of sudden death.[137] [138] In about one third of the cases there is autosomal dominant inheritance of the disease, and several distinct genetic mutations have been reported.[137] [139] One variant, found on the Greek island

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Figure 48-6 Top left, Postmortem pathological section of heart (four-chamber) in a patient with right ventricular cardiomyopathy (arrhythmogenic right ventricular dysplasia) and biventricular involvement. Severe widespread fatty infiltration of right ventricular (RV) wall is present; an apical aneurysm is present at the left ventricular level (arrow). \i\Top right,\r\ Histological section at level of RV inflow (hematoxylin-eosin, ;ts 2.5). Severe transmural fibrofatty infiltration of RV wall is present, compatible with

RV dysplasia. \i\Bottom,\r\ Histological section at the level of the left ventricle (outflow) (hematoxylin-eosin, ;ts2.5) shows focal severe [chfibrofatty infiltration with myo[chcellular atrophy, compatible with left ventricular involvement. (From Pinamonti B, Pagnan L, Bussani R, et al: Right ventricular dysplasia with biventricular involvement. Circulation 98:1943\en\1945, 1998. Copyright 1998, American Heart Association.)

of Naxos, is inherited as a recessive trait but with a high degree of penetrance.[138] ARVD appears to be distinct from Uhl disease, which is marked by extreme thinning of the ventricular wall.[138] [140] The diagnosis is based on a constellation of clinical, ECG, histological, and echocardiographic findings.[137] Typical clinical features include male predominance, normal physical examination, inverted T waves in the right precordial ECG leads, symptoms of palpitations and syncope, and a risk of sudden death. [137] [141] [142] In some patients with ventricular arrhythmias of no evident cause, clinically subtle right ventricular dysplasia may be etiological.[143] Noninvasive and invasive evaluation demonstrate a dilated, poorly contractile right ventricle, usually with a normal left ventricle, although some degree of left ventricular dysfunction has been seen.[138] [141] [144] Magnetic resonance imaging (MRI) shows promise for identifying patients with this condition.[145] Antiarrhythmic therapy, especially with beta-adrenoceptor blockers, sotalol, or amiodarone, often is effective in controlling the arrhythmias.[140] The arrhythmias may be related to abnormalities of regional right ventricular sympathetic innervation, or impaired presynaptic catecholamine reuptake, as has been demonstrated by noninvasive scintigraphy.[146] Cryo- or catheter-based radiofrequency ablation of the presumed arrhythmogenic focus has been successful in resolving the ventricular arrhythmia in some patients unresponsive to or intolerant of antiarrhythmic drug therapy.[147] [148] Insertion of an ICD or cardiac transplantation is reserved for recalcitrant cases.[140]




Hypertrophic Cardiomyopathy Although first described over a century ago, the unique features of HCM were not studied systematically until the late 1950s.[148] [149] [150] [151] [152] [153] [154] The characteristic finding was inappropriate myocardial hypertrophy that occurred in the absence of an obvious cause for the hypertrophy (e.g., aortic stenosis or systemic hypertension), often predominantly involving the interventricular septum of a nondilated left ventricle that showed hyperdynamic systolic function ( Fig. 48-7; see also Fig. 48-13 (Figure Not Available) ).[152] [153] A distinctive clinical feature was soon recognized in some patients with HCM--a dynamic pressure gradient in the subaortic area that divided the left ventricle into a high-pressure apical region and a lower-pressure subaortic region (Fig. 48-8) . Although subsequent studies have shown that only a minority of patients (perhaps a fourth)[155] demonstrate this outflow gradient, its unique features attracted much attention and led to a myriad of terms (more than 75) used to describe the disease (among the more popular terms were idiopathic hypertrophic subaortic stenosis [IHSS] and muscular subaortic stenosis).[156] The term hypertrophic cardiomyopathy (HCM) is now preferred because most patients do not have an outflow gradient or "stenosis" of the left ventricular outflow tract.[153] Because hypertrophy typically occurs in the absence of a pressure gradient, the characteristic distinguishing feature of HCM is myocardial hypertrophy that is out of proportion to the hemodynamic load.

Figure 48-7 A, Pathological findings in a patient with hypertrophic cardiomyopathy who had a left ventricular outflow tract gradient during life. The heart is opened in the longitudinal plane. This patient had mitral regurgitation that was due partially to abnormal insertion of an anomalous papillary muscle (arrow) onto the ventricular surface of the anterior mitral leaflet. (Modified from Wigle ED, Sasson Z, Henderson MA, et al: Hypertrophic cardiomyopathy: The importance of the site and the extent of hypertrophy. A review. Prog Cardiovasc Dis 28:1, 1985.) B, Histological specimen of a patient with hypertrophic cardiomyopathy showing myofibrillar disarray. In the central area the myofibrils cross each other in a

disorganized manner, but in adjacent areas on each side the appearance is more normal, with parallel arrays of myofibrils. (PTHA stain, 240×.) (From Davies MJ, McKenna WJ: Hypertrophic cardiomyopathy: An introduction to pathology and pathogenesis. Br Heart J 72:S2, 1994.) C, Diagrammatic representation showing usual location of myocyte disarray in interventricular septum in hypertrophic cardiomyopathy. This explains why disarray is usually deep or absent in septectomy specimen, and why endomyocardial biopsy (3-mm maximum dimension) is also unlikely to sample a zone of disarray. RV=right ventricle, LV=left ventricle. (From Tazelaar HD, Billingham ME: The surgical pathology of hypertrophic cardiomyopathy. Arch Pathol Lab Med 111:257, 1987.)

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Figure 48-8 Left-sided heart pressures in various conditions. In each horizontal panel there is an idealized depiction of the pressure tracing that would be obtained as a catheter is withdrawn from the left ventricular body through the left ventricular outflow tract into the proximal aortic root. On the far right is a superimposition of the pressures in the left ventricular body and in the aorta. The vertical lines bound the regional catheter position within the heart during withdrawal. All forms of discrete stenosis (supravalvular, valvular, and subvalvular) have delayed aortic upstroke rates downstream from the stenosis. Only in hypertrophic cardiomyopathy is the aortic upstroke rate rapid and parallel to the left ventricular pressure. L.V. = left ventricular; Out = outflow tract. (From Criley JM, Siegel RJ: Subaortic stenosis revisited: The importance of the dynamic pressure gradient. Medicine 72:412, 1993.)

The physiological characteristics of HCM differ substantially from those of DCM (Table 48-5) . The most characteristic pathophysiological abnormality in HCM is diastolic rather than systolic dysfunction (see Chap. 15) . Thus, HCM is characterized by abnormal stiffness of the left ventricle with resultant impaired ventricular filling. This abnormality in diastolic relaxation produces increased left ventricular end-diastolic pressure with resulting pulmonary congestion and dyspnea, the most common symptoms in HCM, despite typically hyperdynamic left ventricular systolic function. The overall prevalence of HCM is low, although probably higher than thought previously; it is found in about 0.2 percent (1 in 500) of the general population and in 0.5 percent of unselected patients referred for an echocardiographic examination.[152] It may be the most common genetically transmitted cardiac disorder.[153] Pathology MACROSCOPIC EXAMINATION.

This typically discloses a marked increase in myocardial mass, and the ventricular cavities are small (see Fig. 48-7 A).[157] [158] The left ventricle is usually more involved in the hypertrophic process than is the right. The atria are dilated and often hypertrophied, reflecting the high resistance to filling of the ventricles caused by diastolic dysfunction and the effects of atrioventricular valve regurgitation. The pattern and extent of left ventricular hypertrophy in HCM vary greatly from patient to patient, and a characteristic feature is heterogeneity in the amount of hypertrophy evident in different regions of the left ventricle.[153] [157] [158] A feature found in most patients with HCM is disproportionate involvement of the interventricular septum and anterolateral wall compared with the posterior segment of the free wall of the left ventricle. [153] [157] When hypertrophy is

largely localized to the anterior septum, the process has been called asymmetrical septal hypertrophy (ASH). A wide variety of other patterns of hypertrophy may be seen, and about 30 percent of patients show only localized and relatively mild hypertrophy in a single region of the ventricle.[153] The differentiation of the "physiological" hypertrophy that occurs in some highly trained male athletes from that seen in HCM may be difficult; athletes may demonstrate left ventricular wall thicknesses up to 16 mm in the absence of HCM (normal or = 65 years of age. Am J Cardiol 73:1105, 1994. 167.

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Wilmshurst PT, Katritsis D: Restrictive and hypertrophic cardiomyopathies in Noonan syndrome: The overlap syndromes. Heart 75:94, 1996. 168.

Carvalho JS, Matthews EE, Leonard JV, et al: Cardiomyopathy of glycogen storage disease type III. Heart Vessels 8:155, 1993. 169.

Maron BJ, Wolfson JK, Roberts WC: Relation between extent of cardiac muscle cell disorganization and left ventricular wall thickness in hypertrophic cardiomyopathy. Am J Cardiol 70:785, 1992. 170.

171.

Clark AL, Coats AJ: Screening for hypertrophic cardiomyopathy. BMJ 306:409, 1993.

Mogensen J, Klausen IC, Pedersen AK, et al: Alpha-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy. J Clin Invest 103:39R, 1999. 172.

Watkins H, Thierfelder L, Hwang DS, et al: Sporadic hypertrophic cardiomyopathy due to de novo myosin mutations. J Clin Invest 90:1666, 1992. 173.

Keating M: The devil's in the details: Progress in familial hypertrophic cardiomyopathy. J Clin Invest 93:2, 1994. 174.

Jarcho JA, McKenna W, Pare JA, et al: Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14ql. N Engl J Med 321:1372, 1989. 175.

Fananapazir L: Advances in molecular genetics and management of hypertrophic cardiomyopathy. JAMA 281:1746, 1999. 176.

Moolman JA, Reith S, Uhl K, et al: A newly created splice donor site in exon 25 of the MyBP-C gene is responsible for inherited hypertrophic cardiomyopathy with incomplete disease penetrance. Circulation 101:1396, 2000. 176A.

177.

MacRae CA, Ghaisas N, Kass S, et al: Familial hypertrophic cardiomyopathy with

Wolff-Parkinson-White syndrome maps to a locus on chromosome 7q3. J Clin Invest 96:1216, 1995. Watkins H, McKenna WJ, Thierfelder L, et al: Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med 332:1058, 1995. 178.

Okamoto S, Ozaki M, Konishi T, et al: A case report of siblings with hypertrophic cardiomyopathy that progressed to dilated cardiomyopathy--case reports. Angiology 44:406, 1993. 179.

Solomon SD, Wolff S, Watkins H, et al: Left ventricular hypertrophy and morphology in familial hypertrophic cardiomyopathy associated with mutations of the beta-myosin heavy chain gene. J Am Coll Cardiol 22:498, 1993. 180.

Hecht GM, Klues HG, Roberts WC, et al: Coexistence of sudden cardiac death and end-stage heart failure in familial hypertrophic cardiomyopathy. J Am Coll Cardiol 22:489, 1993. 181.

Anan R, Shano H, Kisanuki A, et al: Patients with familial hypertrophic cardiomyopathy caused by a PhellOIle missense mutation in the cardiac troponin T gene have variable cardiac morphologies and a favorable prognosis. Circulation 98:391, 1998. 182.

Tardiff JC, Factor SM, Tompkins BD, et al: A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy. J Clin Invest 101:2800, 1998. 183.

Anan R, Greve G, Thierfelder L, et al: Prognostic implications of novel beta cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy. J Clin Invest 93:280, 1994. 184.

Sherrid MV, Chu CK, Delia E, et al: An echocardiographic study of the fluid mechanics of obstruction in hypertrophic cardiomyopathy. J Am Coll Cardiol 22:816, 1993. 185.

Betocchi S, Hess OM, Losi MA, et al: Regional left ventricular mechanics in hypertrophic cardiomyopathy. Circulation 88:2206, 1993. 186.

Losi MA, Betocchi S, Grimaldi M, et al: Heterogeneity of left ventricular filling dynamics in hypertrophic cardiomyopathy. Am J Cardiol 73:987, 1994. 187.

Gwathmey JK, Warren SE, Briggs GM, et al: Diastolic dysfunction in hypertrophic cardiomyopathy: Effect on active force generation during systole. J Clin Invest 87:1023, 1991. 188.

Factor SM, Butany J, Sole MJ, et al: Pathologic fibrosis and matrix connective tissue in the subaortic myocardium of patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 17:1343, 1991. 189.

Lazzeroni E, Picano E, Morozzi L, et al: Dipyridamole-induced ischemia as a prognostic marker of future adverse cardiac events in adult patients with hypertrophic cardiomyopathy. Circulation 96:4268, 1997. 190.

Perrone-Filardi P, Bacharach SL, Dilsizian V, et al: Regional systolic function, myocardial blood flow and glucose uptake at rest in hypertrophic cardiomyopathy. Am J Cardiol 72:199, 1993. 191.

Takemura G, Takatsu Y, Fujiwara H: Luminal narrowing of coronary capillaries in human hypertrophic hearts: An ultrastructural morphometrical study using endomyocardial biopsy specimens. Heart 79:78, 1998. 192.

193.

Kyriakidis MK, Dernellis JM, Androulakis AE, et al: Changes in phasic coronary blood flow velocity

profile and relative coronary flow reserve in patients with hypertrophic obstructive cardiomyopathy. Circulation 96:834, 1997. Kyriakidis M, Triposkiadis F, Dernellis J, et al: Effects of cardiac versus circulatory angiotensin-converting enzyme inhibition on left ventricular diastolic function and coronary blood flow in hypertrophic obstructive cardiomyopathy. Circulation 97:1342, 1998. 194.

Yetman AT, McCrindle BW, MacDonald C, et al: Myocardial bridging in children with hypertrophic cardiomyopathy--a risk factor for sudden death. N Engl J Med 339:1201, 1998. 195.

Clinical Manifestations Frank S, Braunwald E: Idiopathic hypertrophic subaortic stenosis: Clinical analysis of 126 patients with emphasis on the natural history. Circulation 37:759, 1968. 196.

Chikamori T, Counihan PJ, Doi YL, et al: Mechanisms of exercise limitation in hypertrophic cardiomyopathy. J Am Coll Cardiol 19:507, 1992. 197.

Nienaber CA, Hiller S, Spielmann RP, et al: Syncope in hypertrophic cardiomyopathy: Multivariate analysis of prognostic determinants. J Am Coll Cardiol 15:948, 1990. 198.

Kar AK, Roy S, Panja M: Aortic regurgitation in hypertrophic cardiomyopathy. J Assoc Physicians India 41:576, 1993. 199.

Etchells E, Bell C, Robb K: Does this patient have an abnormal systolic murmur? JAMA 277:564, 1997. 200.

Ryan MP, Cleland JG, French JA, et al: The standard electrocardiogram as a screening test for hypertrophic cardiomyopathy. Am J Cardiol 76:689, 1995. 201.

Maron BJ, Mathenge R, Casey SA, et al: Clinical profile of hypertrophic cardiomyopathy identified de novo in rural communities. J Am Coll Cardiol 33:1590, 1999. 202.

Usui M, Inoue H, Suzuki J, et al: Relationship between distribution of hypertrophy and electrocardiographic changes in hypertrophic cardiomyopathy. Am Heart J 126:177, 1993. 203.

Shibata M, Yamakado T, Imanaka-Yoshida K, et al: Familial hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome progressing to ventricular dilation. Am Heart J 131:1223, 1996. 204.

Tamura M, Harada K, Ito T, et al: Abrupt aggravation of atrioventricular block and syncope in hypertrophic cardiomyopathy. Arch Dis Child 73:536, 1995. 205.

Maki S, Ikeda H, Muro A, et al: Predictors of sudden cardiac death in hypertrophic cardiomyopathy. Am J Cardiol 82:774, 1998. 206.

Stewart JT, McKenna WJ: Management of arrhythmias in hypertrophic cardiomyopathy. Cardiovasc Drugs Ther 8:95, 1994. 207.

Fananapazir L, Chang AC, Epstein SE, et al: Prognostic determinants in hypertrophic cardiomyopathy: Prospective evaluation of a therapeutic strategy based on clinical, Holter, hemodynamic, and electrophysiological findings. Circulation 86:730, 1992. 208.

Spirito P, Lakatos E, Maron BJ: Degree of left ventricular hypertrophy in patients with hypertrophic cardiomyopathy and chronic atrial fibrillation. Am J Cardiol 69:1217, 1992. 209.

Robinson K, Frenneaux MP, Stockins B, et al: Atrial fibrillation in hypertrophic cardiomyopathy: A longitudinal study. J Am Coll Cardiol 15:1279, 1990. 210.

Kulakowski P, Counihan PJ, Camm AJ, et al: The value of time and frequency domain, and spectral temporal mapping analysis of the signal-averaged electrocardiogram in identification of patients with hypertrophic cardiomyopathy at increased risk of sudden death. Eur Heart J 14:941, 1993. 211.

Counihan PJ, Fei L, Bashir Y, et al: Assessment of heart rate variability in hypertrophic cardiomyopathy: Association with clinical and prognostic features. Circulation 88:1682, 1993. 212.

Sneddon JF, Slade A, Seo H, et al: Assessment of the diagnostic value of head-up tilt testing in the evaluation of syncope in hypertrophic cardiomyopathy. Am J Cardiol 73:601, 1994. 213.

Klues HG, Roberts WC, Maron BJ: Morphological determinants of echocardiographic patterns of mitral valve systolic anterior motion in obstructive hypertrophic cardiomyopathy. Circulation 87:1570, 1993. 214.

Naito J, Masuyama T, Tanouchi J, et al: Analysis of transmural trend of myocardial integrated ultrasound backscatter for differentiation of hypertrophic cardiomyopathy and ventricular hypertrophy due to hypertension. J Am Coll Cardiol 24:517, 1994. 215.

Vitale DF, Bonow RO, Calabro R, et al: Myocardial ultrasonic tissue characterization in pediatric and adult patients with hypertrophic cardiomyopathy. Circulation 94:2826, 1996. 216.

Klues HG, Proschan MA, Dollar AL, et al: Echocardiographic assessment of mitral valve size in obstructive hypertrophic cardiomyopathy: Anatomic validation from mitral valve specimen. Circulation 88:548, 1993. 217.

Grigg LE, Wigle ED, Williams WG, et al: Transesophageal Doppler echocardiography in obstructive hypertrophic cardiomyopathy: Clarification of pathophysiology and importance in intraoperative decision making. J Am Coll Cardiol 20:42, 1992. 218.

Schwammenthal E, Nakatani S, He S, et al: Mechanism of mitral regurgitation in hypertrophic cardiomyopathy: Mismatch of posterior to anterior leaflet length and mobility. Circulation 98:856, 1998. 219.

Levine RA, Vlahakes GJ, Lefebvre X, et al: Papillary muscle displacement causes systolic anterior motion of the mitral valve: Experimental validation and insights into the mechanism of subaortic obstruction. Circulation 91:1189, 1995. 220.

Lin CS, Chen KS, Lin MC, et al: The relationship between systolic anterior motion of the mitral valve and the left ventricular outflow tract Doppler in hypertrophic cardiomyopathy. Am Heart J 122:1671, 1991. 221.

Kramer CM, Reichek N, Ferrari VA, et al: Regional heterogeneity of function in hypertrophic cardiomyopathy. Circulation 90:186, 1994. 222.

Dong SJ, MacGregor JH, Crawley AP, et al: Left ventricular wall thickness and regional systolic function in patients with hypertrophic cardiomyopathy: A three-dimensional tagged magnetic resonance imaging study. Circulation 90:1200, 1994. 223.

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Marwick TH, Nakatani S, Haluska B, et al: Provocation of latent left ventricular outflow tract gradients with amyl nitrite and exercise in hypertrophic cardiomyopathy. Am J Cardiol 75:805, 1995. 224.

Cannon RO III, Dilsizian V, O'Gara PT, et al: Myocardial metabolic, hemodynamic, and electrocardiographic significance of reversible thallium-201 abnormalities in hypertrophic cardiomyopathy. Circulation 83:1660, 1991. 225.

Dilsizian V, Bonow RO, Epstein SE, et al: Myocardial ischemia detected by thallium scintigraphy is frequently related to cardiac arrest and syncope in young patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 22:796, 1993. 226.

Chikamori T, Dickie S, Poloniecki JD, et al: Prognostic significance of radionuclide-assessed diastolic function in hypertrophic cardiomyopathy. Am J Cardiol 65:478, 1990. 227.

Hemodynamics Fananapazir L, McAreavey D: Therapeutic options in patients with obstructive hypertrophic cardiomyopathy and severe drug-refractory symptoms. J Am Coll Cardiol 31:259, 1998. 228.

Maron BJ, McIntosh CL, Klues HG, et al: Morphologic basis for obstruction to right ventricular outflow in hypertrophic cardiomyopathy. Am J Cardiol 71:1089, 1993. 229.

Kizilbash AM, Heinle SK, Grayburn PA: Spontaneous variability of left ventricular outflow tract gradient in hypertrophic obstructive cardiomyopathy. Circulation 97:461, 1998. 230.

Brockenbrough EC, Braunwald E, Morrow AG: A hemodynamic technic for the detection of hypertrophic subaortic stenosis. Circulation 23:189, 1961. 231.

Paz R, Jortner R, Tunick PA, et al: The effect of the ingestion of ethanol on obstruction of the left ventricular outflow tract in hypertrophic cardiomyopathy. N Engl J Med 335:938, 1996. 232.

Akasaka T, Yoshikawa J, Yoshida K, et al: Phasic coronary flow characteristics in patients with hypertrophic cardiomyopathy: A study by coronary Doppler catheter. J Am Soc Echocardiogr 7:9, 1994. 233.

Vassalli G, Seiler C, Hess OM: Risk stratification in hypertrophic cardiomyopathy. Curr Opin Cardiol 9:330, 1994. 234.

Maron BJ, Spirito P: Impact of patient selection biases on the perception of hypertrophic cardiomyopathy and its natural history. Am J Cardiol 72:970, 1993. 235.

Cannan CR, Reeder GS, Bailey KR, et al: Natural history of hypertrophic cardiomyopathy: A population-based study, 1976 through 1990. Circulation 92:2488, 1995. 236.

Cecchi F, Olivotto I, Montereggi A, et al: Hypertrophic cardiomyopathy in Tuscany: Clinical course and outcome in an unselected regional population. J Am Coll Cardiol 26:1529, 1995. 237.

Seiler C, Jenni R, Vassalli G, et al: Left ventricular chamber dilatation in hypertrophic cardiomyopathy: Related variables and prognosis in patients with medical and surgical therapy. Br Heart J 74:508, 1995. 238.

Maron BJ, Spirito P: Implications of left ventricular remodeling in hypertrophic cardiomyopathy. Am J Cardiol 81:1339, 1998. 239.

240.

Watkins H: Sudden death in hypertrophic cardiomyopathy. N Engl J Med 342:422, 2000.

Doevendans PA: Hypertrophic cardiomyopathy: Do we have the algorithm for life and death? Circulation 101:1224, 2000. 240A.

Yoshida N, Ikeda H, Wada T, et al: Exercise-induced abnormal blood pressure responses are related to subendocardial ischemia in hypertrophic cardiomyopathy. J Am Coll Cardiol 32:1938, 1998. 241.

Borggrefe M, Breithardt G: Is the implantable defibrillator indicated in patients with hypertrophic cardiomyopathy and aborted sudden death? J Am Coll Cardiol 31:1086, 1998. 242.

Atiga WL, Fananapazir L, McAreavey D, et al: Temporal repolarization lability in hypertrophic cardiomyopathy caused by beta-myosin heavy-chain gene mutations. Circulation 101:1237, 2000. 242A.

Almendral JM, Ormaetxe J, Martinez-Alday, JD, et al: Treatment of ventricular arrhythmias in patients with hypertrophic cardiomyopathy. Eur Heart J 14::71, 1993. 243.

Olivotto I, Maron BJ, Montereggi A, et al: Prognostic value of systemic blood pressure response during exercise in a community-based patient population with hypertrophic cardiomyopathy. J Am Coll Cardiol 33:2044, 1999. 244.

Botvinick EH, Dae MW, Krishnan R, et al: Hypertrophic cardiomyopathy in the young: Another form of ischemic cardiomyopathy? J Am Coll Cardiol 22:805, 1993. 245.

Nienaber CA, Gambhir SS, Mody FV, et al: Regional myocardial blood flow and glucose utilization in symptomatic patients with hypertrophic cardiomyopathy. Circulation 87:1580, 1993. 246.

Counihan PJ, Frenneaux MP, Webb DJ, et al: Abnormal vascular responses to supine exercise in hypertrophic cardiomyopathy. Circulation 84:686, 1991. 247.

Maron BJ, Kogan J, Proschan MA, et al: Circadian variability in the occurrence of sudden cardiac death in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 23:1405, 1994. 248.

Maron BJ, Thompson PD, Puffer JC, et al: Cardiovascular preparticipation screening of competitive athletes: A statement for health professionals from the Sudden Death Committee (Clinical Cardiology) and Congenital Cardiac Defects Committee (Cardiovascular Disease in the Young), American Heart Association. Circulation 94:850, 1996. 249.

Maron BJ, Klues HG: Surviving competitive athletics with hypertrophic cardiomyopathy. Am J Cardiol 73:1098, 1994. 250.

Maron BJ, Shen WK, Link MS, et al: Efficacy of implantable cardioverterdefibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med 342:365, 2000. 251.

252.

Takagi E, Yamakado T, Nakano T: Prognosis of completely asymptomatic adult patients with

hypertrophic cardiomyopathy. J Am Coll Cardiol 33:206, 1999. Gilligan DM, Chan WL, Stewart R, et al: Cardiac responses assessed by echocardiography to changes in preload in hypertrophic cardiomyopathy. Am J Cardiol 73:312, 1994. 253.

Management Gilligan DM, Chan WL, Joshi J, et al: A double-blind, placebo-controlled crossover trial of nadolol and verapamil in mild and moderately symptomatic hypertrophic cardiomyopathy. J Am Coll Cardiol 21:1672, 1993. 254.

Wikman-Coffelt J, Stefenelli T, Wu ST, et al: [Ca2+]i transients in the cardiomyopathic hamster heart. Circ Res 68:45, 1991. 255.

Gistri R, Cecchi F, Choudhury L, et al: Effect of verapamil on absolute myocardial blood flow in hypertrophic cardiomyopathy. Am J Cardiol 74:363, 1994. 256.

Betocchi S, Piscione F, Losi M, et al: Effects of diltiazem on left ventricular systolic and diastolic function in hypertrophic cardiomyopathy. Am J Cardiol 78:451, 1996. 257.

Dimitrow PP, Dubiel JS: Effects on left ventricular function of pindolol added to verapamil in hypertrophic cardiomyopathy. Am J Cardiol 71:313, 1993. 258.

Fifer MA, O'Gara PT, McGovern BA, et al: Effects of disopyramide on left ventricular diastolic function in hypertrophic cardiomyopathy. Am J Cardiol 74:405, 1994. 259.

Matsubara H, Nakatani S, Nagata S, et al: Salutary effect of disopyramide on left ventricular diastolic function in hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol 26:768, 1995. 260.

Cecchi F, Olivotto I, Montereggi A, et al: Prognostic value of non-sustained ventricular tachycardia and the potential role of amiodarone treatment in hypertrophic cardiomyopathy: Assessment in an unselected non-referral based patient population. Heart 79:331, 1998. 261.

Tendera M, Wycisk A, Schneeweiss A, et al: Effect of sotalol on arrhythmias and exercise tolerance in patients with hypertrophic cardiomyopathy. Cardiology 82:335, 1993. 262.

Maron BJ, Cecchi F, McKenna WJ: Risk factors and stratification for sudden cardiac death in patients with hypertrophic cardiomyopathy. Br Heart J 72:S13, 1994. 263.

Spirito P, Rapezzi C, Bellone P, et al: Infective endocarditis in hypertrophic cardiomyopathy: Prevalence, incidence, and indications for antibiotic prophylaxis. Circulation 99:2132, 1999. 264.

Fananapazir L, Cannon RO III, Tripodi D, et al: Impact of dual-chamber permanent pacing in patients with obstructive hypertrophic cardiomyopathy with symptoms refractory to verapamil and beta-adrenergic blocker therapy. Circulation 85:2149, 1992. 265.

266.

Kappenberger L: Pacing for obstructive hypertrophic cardiomyopathy. Br Heart J 73:107, 1995.

Maron BJ, Nishimura RA, McKenna WJ, et al: Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy: A randomized, double-blind, crossover study (M-PATHY). Circulation 99:2927, 1999. 267.

Nagueh SF, Lakkis NM, Middleton KJ, et al: Changes in left ventricular diastolic function 6 months after nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy. Circulation 99:344, 1999. 268.

Nishimura RA, Trusty JM, Hayes DL, et al: Dual-chamber pacing for hypertrophic cardiomyopathy: A randomized, double-blind, crossover trial. J Am Coll Cardiol 29:435, 1997. 269.

Maron BJ: Appraisal of dual-chamber pacing therapy in hypertrophic cardiomyopathy: Too soon for a rush to judgment? J Am Coll Cardiol 27:431, 1996. 270.

Linde C, Gadler F, Kappenberger L, et al: Placebo effect of pacemaker implantation in obstructive hypertrophic cardiomyopathy. Am J Cardiol 83:903, 1999. 271.

Erwin JP 3rd, Nishimura RA, Lloyd MA, et al: Dual chamber pacing for patients with hypertrophic obstructive cardiomyopathy: A clinical perspective in 2000. Mayo Clin Proc 75:173, 2000. 271A.

Cannon RO III, Tripodi D, Dilsizian V, et al: Results of dual-chamber pacing in symptomatic nonobstructive hypertrophic cardiomyopathy. Am J Cardiol 73:571, 1994. 272.

Elliott PM, Sharma S, Varnava A, et al: Survival after cardiac arrest or sustained ventricular tachycardia in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 33:1596, 1999. 273.

Primo J, Geelen P, Brugada J, et al: Hypertrophic cardiomyopathy: Role of the implantable cardioverter-defibrillator. J Am Coll Cardiol 31:1081, 1998. 274.

Seggewiss H, Gleichmann U, Faber L, et al: Percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy: Acute results and 3-month follow-up in 25 patients. J Am Coll Cardiol 31:252, 1998. 275.

Kim JJ, Lee CW, Park SW, et al: Improvement in exercise capacity and exercise blood pressure response after transcoronary alcohol ablation therapy of septal hypertrophy in hypertrophic cardiomyopathy. Am J Cardiol 83:1220, 1999. 276.

1802

Delahaye F, Jegaden O, de Gevigney G, et al: Postoperative and long-term prognosis of myotomy-myomectomy for obstructive hypertrophic cardiomyopathy: Influence of associated mitral valve replacement. Eur Heart J 14:1229, 1993. 277.

Nakatani S, Schwammenthal E, Lever HM, et al: New insights into the reduction of mitral valve systolic anterior motion after ventricular septal myectomy in hypertrophic obstructive cardiomyopathy. Am Heart J 131:294, 1996. 278.

Morrow AG, Lambrew CT, Braunwald E: Idiopathic subaortic stenosis: II. Operative treatment and the results of pre- and postoperative hemodynamic evaluations. Circulation 30(Suppl 4):120, 1964. 279.

Schulte HD, Bircks WH, Loesse B, et al: Prognosis of patients with hypertrophic obstructive cardiomyopathy after transaortic myectomy: Late results up to twenty-five years. J Thorac Cardiovasc Surg 106:709, 1993. 280.

Brunner-La Schonbeck MH, Rocca HP, Vogt PR, et al: Long-term follow-up in hypertrophic obstructive cardiomyopathy after septal myectomy. Ann Thorac Surg 65:1207, 1998. 281.

Robbins RC, Stinson EB: Long-term results of left ventricular myotomy and myectomy for obstructive hypertrophic cardiomyopathy. J Thorac Cardiovasc Surg 111:586, 1996. 282.

Cannon RO III, Dilsizian V, O'Gara PT, et al: Impact of surgical relief of outflow obstruction on thallium perfusion abnormalities in hypertrophic cardiomyopathy. Circulation 85:1039, 1992. 283.

Nishimura RA, Danielson GK: Dual chamber pacing for hypertrophic obstructive cardiomyopathy: Has its time come? Br Heart J 70:301, 1993. 284.

McCully RB, Nishimura RA, Tajik AJ, et al: Extent of clinical improvement after surgical treatment of hypertrophic obstructive cardiomyopathy. Circulation 94:467, 1996. 285.

Heric B, Lytle BW, Miller DP, et al: Surgical management of hypertrophic obstructive cardiomyopathy: Early and late results. J Thorac Cardiovasc Surg 110:195, 1995. 286.

Brown PS Jr, Roberts CS, McIntosh CL, et al: Aortic regurgitation after left ventricular myotomy and myectomy. Ann Thorac Surg 51:585, 1991. 287.

Schwammenthal E, Levine RA: Dynamic subaortic obstruction: A disease of the mitral valve suitable for surgical repair? J Am Coll Cardiol 28:203, 1996. 288.

Joyce FS, Lever HM, Cosgrove DM III: Treatment of hypertrophic cardiomyopathy by mitral valve repair and septal myectomy. Ann Thorac Surg 57:1025, 1994. 289.

Shirani J, Maron BJ, Cannon RO III, et al: Clinicopathologic features of hypertrophic cardiomyopathy managed by cardiac transplantation. Am J Cardiol 72:434, 1993. 290.

RESTRICTIVE AND INFILTRATIVE CARDIOMYOPATHIES 291.

Kushwaha SS, Fallon JT, Fuster V: Restrictive cardiomyopathy. N Engl J Med 336:267, 1997.

292.

Spyrou N, Foale R: Restrictive cardiomyopathies. Curr Opin Cardiol 9:344, 1994.

293.

Benson MD: Hereditary amyloidosis and cardiomyopathy. Am J Med 93:1, 1992.

Keren A, Popp RL: Assignment of patients into the classification of cardiomyopathies. Circulation 86:1622, 1992. 294.

Garcia MJ, Rodriguez L, Ares M, et al: Differentiation of constrictive pericarditis from restrictive cardiomyopathy: Assessment of left ventricular diastolic velocities in longitudinal axis by Doppler tissue imaging. J Am Coll Cardiol 277:108, 1996. 295.

Angelini A, Calzolari V, Thiene G, et al: Morphologic spectrum of primary restrictive cardiomyopathy. Am J Cardiol 80:1046, 1997. 296.

Masui T, Finck S, Higgins CB: Constrictive pericarditis and restrictive cardiomyopathy: Evaluation with MR imaging. Radiology 182:369, 1992. 297.

Gasperetti CM, Sarembock IJ, Feldman MD: Usefulness of dynamic hand exercise for developing maximal separation of left and right ventricular pressures at end-diastole and usefulness in distinguishing restrictive cardiomyopathy from constrictive pericardial disease. Am J Cardiol 69:1508, 1992. 298.

Klein AL, Cohen GI, Pietrolungo JF, et al: Differentiation of constrictive pericarditis from restrictive cardiomyopathy by Doppler transesophageal echocardiographic measurements of respiratory variations in pulmonary venous flow. J Am Coll Cardiol 22:1935, 1993. 299.

Felker GM, Thompson RE, Hare JM, et al: Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 342:1077, 2000. 299A.

Amyloidosis Hesse A, Altland K, Linke RP, et al: Cardiac amyloidosis: A review and report of a new transthyretin (prealbumin) variant. Br Heart J 70:111, 1993. 300.

Booth DR, Tan SY, Hawkins PN, et al: A novel variant of transthyretin, 59Thr Lys, associated with autosomal dominant cardiac amyloidosis in an Italian family. Circulation 91:962, 1995. 301.

302.

Kyle RA: Amyloidosis. Circulation 91:1269, 1995.

Jacobson DR, Pastore RD, Yaghoubian R, et al: Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med 336:466, 1997. 303.

Gertz MA, Kyle RA, Noel P: Primary systemic amyloidosis: A rare complication of immunoglobulin M monoclonal gammopathies and Waldenstrom's macroglobulinemia. J Clin Oncol 11:914, 1993. 304.

Gertz MA, Kyle RA, Thibodeau SN: Familial amyloidosis: A study of 52 North American-born patients examined during a 30-year period. Mayo Clin Proc 67:428, 1992. 305.

Dubrey S, Pollak A, Skinner M, et al: Atrial thrombi occurring during sinus rhythm in cardiac amyloidosis: Evidence for atrial electromechanical dissociation. Br Heart J 74:541, 1995. 306.

Chamarthi B, Dubrey SW, Cha K, et al: Features and prognosis of exertional syncope in light chain-associated AL cardiac amyloidosis. Am J Cardiol 80:1242, 1997. 307.

Reisinger J, Dubrey SW, LaValley M, et al: Electrophysiologic abnormalities in AL (primary) amyloidosis with cardiac involvement. J Am Coll Cardiol 30:1046, 1997. 308.

Simons M, Isner JM: Assessment of relative sensitivities of noninvasive tests for cardiac amyloidosis in documented cardiac amyloidosis. Am J Cardiol 69:425, 1992. 309.

Tei C, Dujardin KS, Hodge DO, et al: Doppler index combining systolic and diastolic myocardial performance: Clinical value in cardiac amyloidosis. J Am Coll Cardiol 28:658, 1996. 310.

Fattori R, Rocchi G, Celletti F, et al: Contribution of magnetic resonance imaging in the differential diagnosis of cardiac amyloidosis and symmetric hypertrophic cardiomyopathy. Am Heart J 136:824, 1998. 311.

Tanaka M, Hongo M, Kinoshita O, et al: Iodine-123 metaiodobenzylguanidine scintigraphic assessment of myocardial sympathetic innervation in patients with familial amyloid polyneuropathy. J Am 312.

Coll Cardiol 29:168, 1997. Lekakis J, Dimopoulos M, Nanas J, et al: Antimyosin scintigraphy for detection of cardiac amyloidosis. Am J Cardiol 80:963, 1997. 313.

Kyle RA, Spittell PC, Gertz MA, et al: The premortem recognition of systemic senile amyloidosis with cardiac involvement. Am J Med 101:395, 1996. 314.

Kyle RA, Gertz MA, Greipp PR, et al: A trial of three regimens for primary amyloidosis: Colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med 336:1202, 1997. 315.

Dubrey S, Mendes L, Skinner M, et al: Resolution of heart failure in patients with AL amyloidosis. Ann Intern Med 125:481, 1996. 316.

Pollak A, Falk RH: Left ventricular systolic dysfunction precipitated by verapamil in cardiac amyloidosis. Chest 104:618, 1993. 317.

Mathew V, Olson LJ, Gertz MA, et al: Symptomatic conduction system disease in cardiac amyloidosis. Am J Cardiol 80:1491, 1997. 318.

Kyle RA: High-dose therapy in multiple myeloma and primary amyloidosis: An overview. Semin Oncol 26:74, 1999. 319.

Pelosi F Jr, Capehart J, Roberts WC: Effectiveness of cardiac transplantation for primary (AL) cardiac amyloidosis. Am J Cardiol 79:532, 1997. 320.

Inherited Infiltrative Disorders Causing Restrictive Cardiomyopathy Eng CM, Resnick-Silverman LA, Niehaus DJ, et al: Nature and frequency of mutations in the alpha-galactosidase A gens that cause Fabry disease. Am J Hum Genet 53:1186, 1993. 321.

Nakao S, Takenaka T, Maeda M, et al: An atypical variant of Fabry's disease in men with left ventricular hypertrophy. N Engl J Med 333:288, 1995. 322.

Pochis WT, Litzow JT, King BG, et al: Electrophysiologic findings in Fabry's disease with a short PR interval. Am J Cardiol 74:203, 1994. 323.

Mester SW, Weston MW: Cardiac tamponade in a patient with Gaucher's disease. Clin Cardiol 15:766, 1992. 324.

Starzl TE, Demetris AJ, Trucco M, et al: Chimerism after liver transplantation for type IV glycogen storage disease and type 1 Gaucher's disease. N Engl J Med 328:745, 1993. 325.

Liu P, Olivieri N: Iron overload cardiomyopathies: New insights into an old disease. Cardiovasc Drugs Ther 8:101, 1994. 326.

Porter J, Cary N, Schofield P: Haemochromatosis presenting as congestive cardiac failure. Br Heart J 73:73, 1995. 327.

Westra WH, Hruban RH, Baughman KL, et al: Progressive hemochromatotic cardiomyopathy despite reversal of iron deposition after liver transplantation. Am J Clin Pathol 99:39, 1993. 328.

Wang TL, Chen WJ, Liau CS, et al: Sick sinus syndrome as the early manifestation of cardiac hemochromatosis. J Electrocardiol 27:91, 1994. 329.

Strobel JS, Fuisz AR, Epstein AE, et al: Syncope and inducible ventricular fibrillation in a woman with hemochromatosis. J Interv Card Electrophysiol 3:225, 1999. 330.

Cecchetti G, Binda A, Piperno A, et al: Cardiac alterations in 36 consecutive patients with idiopathic haemochromatosis: Polygraphic and echocardiographic evaluation. Eur Heart J 12:224, 1991. 331.

Waxman S, Eustace S, Hartnell GG: Myocardial involvement in primary hemochromatosis demonstrated by magnetic resonance imaging. Am Heart J 128:1047, 1994. 332.

Politi A, Sticca M, Galli M: Reversal of haemochromatotic cardiomyopathy in beta thalassaemia by chelation therapy. Br Heart J 73:486, 1995. 333.

Coleman RA, Winter HS, Wolf B, et al: Glycogen storage disease type III (glycogen debranching enzyme deficiency): Correlation of biochemical defects with myopathy and cardiomyopathy. Ann Intern Med 116:896, 1992. 334.

1803

Tse HF, Shek TW, Tai YT, et al: Case report: Lysosomal glycogen storage disease with normal acid maltase: An unusual form of hypertrophic cardiomyopathy with rapidly progressive heart failure. Am J Med Sci 312:182, 1996. 335.

Myocardial Sarcoidosis 336.

Sharma OP: Myocardial sarcoidosis: A wolf in sheep's clothing. Chest 106:988, 1994.

Yazaki Y, Isobe M, Hiramitsu S, et al: Comparison of clinical features and prognosis of cardiac sarcoidosis and idiopathic dilated cardiomyopathy. Am J Cardiol 82:537, 1998. 337.

Pisani B, Taylor DO, Mason JW: Inflammatory myocardial diseases and cardiomyopathies. Am J Med 102:459, 1997. 338.

339.

Bohle W, Schaefer HE: Predominant myocardial sarcoidosis. Pathol Res Pract 190: 212, 1994.

340.

Mitchell DN, du Bois RM, Oldershaw PJ: Cardiac sarcoidosis. BMJ 314:320, 1997.

Angomachalelis N, Hourzamanis A, Salem N, et al: Pericardial effusion concomitant with specific heart muscle disease in systemic sarcoidosis. Postgrad Med J 70:S8, 1994. 341.

Le Guludec D, Menad F, Faraggi M, et al: Myocardial sarcoidosis: Clinical value of technetium-99m sestamibi tomoscintigraphy. Chest 106:1675, 1994. 342.

Tawarahara K, Kurata C, Okayama K, et al: Thallium-201 and gallium-67 single photon emission computed tomographic imaging in cardiac sarcoidosis. Am Heart J 124:1383, 1992. 343.

Okayama K, Kurata C, Tawarahara K, et al: Diagnostic and prognostic value of myocardial scintigraphy with thallium-201 and gallium-67 in cardiac sarcoidosis. Chest 107:330, 1995. 344.

Chandra M, Silverman ME, Oshinski J, et al: Diagnosis of cardiac sarcoidosis aided by MRI. Chest 110:562, 1996. 345.

Hirose Y, Ishida Y, Hayashida K, et al: Myocardial involvement in patients with sarcoidosis: An analysis of 75 patients. Clin Nucl Med 19:522, 1994. 346.

Knapp WH, Bentrup A, Ohlmeier H: Indium-111-labelled antimyosin antibody imaging in a patient with cardiac sarcoidosis. Eur J Nucl Med 20:80, 1993. 347.

Shammas RL, Movahed A: Successful treatment of myocardial sarcoidosis with steroids. Sarcoidosis 11:37, 1994. 348.

Paz HL, McCormick DJ, Kutalek SP, et al: The automated implantable cardiac defibrillator: Prophylaxis in cardiac sarcoidosis. Chest 106:1603, 1994. 349.

Endomyocardial Disease Kutty; VR, Abraham S, Kartha CC: Geographical distribution of endomyocardial fibrosis in south Kerala. Int J Epidemiol 25:1202, 1996. 350.

Rashwan MA, Ayman M, Ashour S, et al: Endomyocardial fibrosis in Egypt: An illustrated review. Br Heart J 73:284, 1995. 351.

Ribeiro PA, Muthusamy R, Duran CM: Right-sided endomyocardial fibrosis with recurrent pulmonary emboli leading to irreversible pulmonary hypertension. Br Heart J 68:326, 1992. 352.

353.

Kartha CC: Endomyocardial fibrosis, a case for the tropical doctor. Cardiovasc Res 30:636, 1995.

354.

Weller PF, Bubley GJ: The idiopathic hypereosinophilic syndrome. Blood 83:2759, 1994.

355.

Felice PV, Sawicki J, Anto J: Endomyocardial disease and eosinophilia. Angiology 44:869, 1993.

356.

Shaper AG: What's new in endomyocardial fibrosis? Lancet 342:255, 1993.

357.

Valiathan MS: Endomyocardial fibrosis. Natl Med J India 6:212, 1993.

Barbosa MM, Lamounier JA, Oliveira EC, et al: Short report: Endomyocardial fibrosis and cardiomyopathy in an area endemic for schistosomiasis. Am J Trop Med Hyg 58:26, 1998. 358.

Andy JJ, Ogunowo PO, Akpan NA, et al: Helminth associated hypereosinophilia and tropical endomyocardial fibrosis (EMF) in Nigeria. Acta Trop 69:127, 1998. 359.

Kumari KT, Ravikumar A, Kurup PA: Accumulation of glycosaminoglycans associated with hypomagnesaemia in endomyocardial fibrosis in Kerala: Possible involvement of dietary factors. Indian Heart J 49:49, 1997. 360.

361.

Butterfield JH, Gleich GJ: Interferon-alpha treatment of six patients with the idiopathic

hypereosinophilic syndrome. Ann Intern Med 121:648, 1994. 362.

Parrillo JE: Heart disease and the eosinophil. N Engl J Med 323:1560, 1990.

De Cock C, Lemaitre J, Deuvaert FE: Loeffler endomyocarditis: A clinical presentation as right ventricular tumor. J Heart Valve Dis 7:668, 1998. 363.

Rutakingirwa M, Ziegler JL, Newton R, et al: Poverty and eosinophilia are risk factors for endomyocardial fibrosis (EMF) in Uganda. Trop Med Int Health 4:229, 1999. 364.

D'Silva SA, Kohli A, Dalvi BV, et al: MRI in right ventricular endomyocardial fibrosis. Am Heart J 123:1390, 1992. 365.

Saraclar M, Ozer S, Oztunc F, et al: Echocardiographic findings in endomyocardial fibrosis. Turk J Pediatr 34:47, 1992. 366.

Mady C, Barretto AC, Mesquita ET, et al: Maximal functional capacity in patients with endomyocardial fibrosis. Eur Heart J 14:240, 1993. 367.

Barretto AC, Mady C, Nussbacher A, et al: Atrial fibrillation in endomyocardial fibrosis is a marker of worse prognosis. Int J Cardiol 67:19, 1998. 368.

Moraes F, Lapa C, Hazin S, et al: Surgery for endomyocardial fibrosis revisited. Eur J Cardiothorac Surg 15:309, 1999. 369.

Schneider U, Jenni R, Turina J, et al: Long-term follow-up of patients with endomyocardial fibrosis: Effects of surgery. Heart 79:362, 1998. 370.

Uva MS, Jebara VA, Acar C, et al: Mitral valve repair in patients with endomyocardial fibrosis. Ann Thorac Surg 54:89, 1992. 371.

Carcinoid Heart Disease Pellikka PA, Tajik AJ, Khandheria BK, et al: Carcinoid heart disease: Clinical and echocardiographic spectrum in 74 patients. Circulation 87:1188, 1993. 372.

Waltenberger J, Lundin L, Oberg K, et al: Involvement of transforming growth factor-beta in the formation of fibrotic lesions in carcinoid heart disease. Am J Pathol 142:71, 1993. 373.

374.

Kulke MH, Mayer RJ: Carcinoid tumors. N Engl J Med 340:858, 1999.

Robiolio PA, Rigolin VH, Wilson JS, et al: Carcinoid heart disease: Correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization and echocardiography. Circulation 92:790, 1995. 375.

Robiolio PA, Rigolin VH, Harrison JK, et al: Predictors of outcome of tricuspid valve replacement in carcinoid heart disease. Am J Cardiol 75:485, 1995. 376.

Connolly HM, Nishimura RA, Smith HC, et al: Outcome of cardiac surgery for carcinoid heart disease. J Am Coll Cardiol 25:410, 1995. 377.

378.

Yun D, Heywood JT: Metastatic carcinoid disease presenting solely as high-output heart failure. Ann

Intern Med 120:45, 1994. Onate A, Alcibar J, Inguanzo R, et al: Balloon dilation of tricuspid and pulmonary valves in carcinoid heart disease. Tex Heart Inst J 20:115, 1993. 379.

Grant SC, Scarffe JH, Levy RD, et al: Failure of balloon dilatation of the pulmonary valve in carcinoid pulmonary stenosis. Br Heart J 67:450, 1992. 380.

MYOCARDITIS Olinde KD, O'Connell JB: Inflammatory heart disease: Pathogenesis, clinical manifestations, and treatment of myocarditis. Annu Rev Med 45:481, 1994. 381.

Seko Y, Matsuda H, Kato K, et al: Expression of intercellular adhesion molecule-1 in murine hearts with acute myocarditis caused by coxsackievirus B3. J Clin Invest 91:1327, 1993. 382.

Wessely R, Henke A, Zell R, et al: Low-level expression of a mutant coxsackieviral cDNA induces a myocytopathic effect in culture: An approach to the study of enteroviral persistence in cardiac myocytes. Circulation 98:450, 1998. 383.

Herskowitz A, Ahmed-Ansari A, Neumann DA, et al: Induction of major histocompatibility complex antigens within the myocardium of patients with active myocarditis: A nonhistologic marker of myocarditis. J Am Coll Cardiol 15:624, 1990. 384.

385.

Rose NR, Neumann DA, Herskowitz A: Coxsackievirus myocarditis. Adv Intern Med 37: 411, 1992.

Knowlton KU, Badorff C: The immune system in viral myocarditis: Maintaining the balance. Circ Res 85:559, 1999. 386.

Brown CS, Bertolet BD: Peripartum cardiomyopathy: A comprehensive review. Am J Obstet Gynecol 178:409, 1998. 387.

388.

Hyypia T: Etiological diagnosis of viral heart disease. Scand J Infect Dis 88:25, 1993.

Friedrich MG, Strohm O, Schulz-Menger J, et al: Contrast media-enhanced magnetic resonance imaging visualizes myocardial changes in the course of viral myocarditis. Circulation 97:1802, 1998. 389.

Ino T, Okubo M, Akimoto K, et al: Corticosteroid therapy for ventricular tachycardia in children with silent lymphocytic myocarditis. J Pediatr 126:304, 1995. 390.

McCarthy RE 3rd, Boehmer JP, Hruban RH, et al: Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis. N Engl J Med 342:690, 2000. 390A.

Davies MJ, Ward DE: How can myocarditis be diagnosed and should it be treated? Br Heart J 68:346, 1992. 391.

Friedman RA, Kearney DL, Moak JP, et al: Persistence of ventricular arrhythmia after resolution of occult myocarditis in children and young adults. J Am Coll Cardiol 24:780, 1994. 392.

Dec GW Jr, Waldman H, Southern J, et al: Viral myocarditis mimicking acute myocardial infarction. J Am Coll Cardiol 20:85, 1992. 393.

Galiuto L, Enriquez-Sarano M, Reeder GS, et al: Eosinophilic myocarditis manifesting as myocardial infarction: Early diagnosis and successful treatment. Mayo Clin Proc 72:603, 1997. 394.

Chida K, Ohkawa S, Esaki Y: Clinicopathologic characteristics of elderly patients with persistent ST segment elevation and inverted T waves: Evidence of insidious or healed myocarditis? J Am Coll Cardiol 25:1641, 1995. 395.

Matsuura H, Palacios IF, Dec GW, et al: Intraventricular conduction abnormalities in patients with clinically suspected myocarditis are associated with myocardial necrosis. Am Heart J 127:1290, 1994. 396.

Smith SC, Ladenson JH, Mason JW, et al: Elevations of cardiac troponin I associated with myocarditis: Experimental and clinical correlates. Circulation 95:163, 1997. 397.

1804

James KB, Lee K, Thomas JD, et al: Left ventricular diastolic dysfunction in lymphocytic myocarditis as assessed by Doppler echocardiography. Am J Cardiol 73:282, 1994. 398.

Matsouka H, Hamada M, Honda T, et al: Evaluation of acute myocarditis and pericarditis by Gd-DTPA enhanced magnetic resonance imaging. Eur Heart J 15:283, 1994. 399.

400.

Mason JW: Myocarditis. Adv Intern Med 44:293, 1999.

401.

Huber SA: Viral myocarditis--a tale of two diseases. Lab Invest 66:1, 1992.

Akhtar N, Ni J, Stromberg D, et al: Tracheal aspirate as a substrate for polymerase chain reaction detection of viral genome in childhood pneumonia and myocarditis. Circulation 99:2011, 1999. 402.

Frustaci A, Chimenti C, Maseri A: Global biventricular dysfunction in patients with asymptomatic coronary artery disease may be caused by myocarditis. Circulation 99:1295, 1999. 403.

Popovic Z, Miric M, Vasiljevic J, et al: Acute hemodynamic effects of metoprolol +/- nitroglycerin in patients with biopsy-proven lymphocytic myocarditis. Am J Cardiol 81:801, 1998. 404.

Maisch B, Schonian U, Crombach M, et al: Cytomegalovirus associated inflammatory heart muscle disease. Scand J Infect Dis 88:135, 1993. 405.

Mason JW, O'Connell JB, Herskowitz A, et al: A clinical trial of immunosuppressive therapy for myocarditis: The Myocarditis Treatment Trial Investigators. N Engl J Med 333:269, 1995. 406.

Drucker NA, Colan SD, Lewis AB, et al: Gamma-globulin treatment of acute myocarditis in the pediatric population. Circulation 89:252, 1994. 407.

McNamara DM, Rosenblum WD, Janosko KM, et al: Intravenous immune globulin in the therapy of myocarditis and acute cardiomyopathy. Circulation 95:2476, 1997. 408.

Rezkalla SH, Raikar S, Kloner RA: Treatment of viral myocarditis with focus on captopril. Am J Cardiol 77:634, 1996. 409.

Yamamoto N, Shibamori M, Ogura M, et al: Effects of intranasal administration of recombinant murine interferon-gamma on murine acute myocarditis caused by encephalomyocarditis virus. Circulation 97:1017, 1998. 410.

Nishio R, Matsumori A, Shioi T, et al: Treatment of experimental viral myocarditis with interleukin-10. Circulation 100:1102, 1999. 411.

Viral Myocarditis Nakamura H, Yamamura T, Umemoto S, et al: Autoimmune response in chronic ongoing myocarditis demonstrated by heterotopic cardiac transplantation in mice. Circulation 94:3348, 1996. 412.

413.

Hingorani AD: Postinfectious myocarditis. BMJ 304:1676, 1992.

Frustaci A, Maseri A: Localized left ventricular aneurysms with normal global function caused by myocarditis. Am J Cardiol 70:1221, 1992. 414.

415.

Gowrishankar K, Rajajee S: Varied manifestations of viral myocarditis. Indian J Pediatr 61:75, 1994.

Remes J, Helin M, Vaino P, et al: Clinical outcome and left ventricular function 23 years after acute coxsackievirus myopericarditis. Eur Heart J 11:182, 1990. 416.

Lowry RW, Adam E, Hu C, et al: What are the implications of cardiac infection with cytomegalovirus before heart transplantation? J Heart Lung Transplant 13:122, 1994. 417.

Partanen J, Nieminen MS, Krogerus L, et al: Cytomegalovirus myocarditis in transplanted heart verified by endomyocardial biopsy. Clin Cardiol 14:847, 1991. 418.

Schindler JM, Neftel KA: Simultaneous primary infection with HIV and CMV leading to severe pancytopenia, hepatitis, nephritis, perimyocarditis, myositis, and alopecia totalis. Klin Wochenschr 68:237, 1990. 419.

Kabra SK, Juneja R, Madhulika, et al: Myocardial dysfunction in children with dengue haemorrhagic fever. Natl Med J India 11:59, 1998. 420.

Wali JP, Biswas A, Chandra S, et al: Cardiac involvement in dengue haemorrhagic fever. Int J Cardiol 64:31, 1998. 421.

422.

Ursell PC, Habib A, Sharma P, et al: Hepatitis B virus and myocarditis. Hum Pathol 15:481, 1984.

Okabe M, Fukuda K, Arakawa K, et al: Chronic variant of myocarditis associated with hepatitis C virus infection. circulation 96:22, 1997. 423.

Prati D, Poli F, Farma E, et al: Multicenter study on hepatitis C virus infection in patients with dilated cardiomyopathy. J Med Virol 58:116, 1999. 424.

Dalekos GN, Achenbach K, Christodoulou D, et al: Idiopathic dilated cardiomyopathy: Lack of association with hepatitis C virus infection. Heart 80:270, 1998. 425.

Hebert MM, Yu C, Towbin JA, et al: Fatal Epstein-Barr virus myocarditis in a child with repetitive myocarditis. Pediatr Pathol Lab Med 15:805, 1995. 426.

Craver RD, Sorrells K, Gohd R: Myocarditis with influenza B infection. Pediatr Infect Dis J 16:629, 1997. 427.

McGregor D, Henderson S: Myocarditis, rhabdomyolysis and myoglobinuric renal failure complicating influenza in a young adult. NZ Med J 110:237, 1997. 428.

Cummins D, Bennett D, Fisher-Hoch SP, et al: Electrocardiographic abnormalities in patients with Lassa fever. J Trop Med Hyg 92:350, 1989. 429.

430.

Ozkutlu S, Soylemezoglu O, Calikoglu AS, et al: Fatal mumps myocarditis. Jpn Heart J 30:109, 1989.

Kabakus N, Aydinoglu H, Yekeler H, Arslan IN: Fatal mumps nephritis and myocarditis. J Trop Pediatr 45:358, 1999. 430A.

Ni J, Bowles NE, Kim YH, et al: Viral infection of the myocardium in endocardial fibroelastosis: Molecular evidence for the role of mumps virus as an etiologic agent. Circulation 95:133, 1997. 431.

Hildes JA, Schaberg A, Alcock AUW: Cardiovascular collapse in acute poliomyelitis. Circulation 12:986, 1955. 432.

Thomas JA, Raroque S, Scott WA, et al: Successful treatment of severe dysrhythmias in infants with respiratory syncytial virus infections: Two cases and a literature review. Crit Care Med 25:880, 1997. 433.

Olesch CA, Bullock AM: Bradyarrhythmia and supraventricular tachycardia in a neonate with RSV. J Paediatr Child Health 34:199, 1998. 434.

435.

Frustaci A, Abdulla AK, Caldarulo M, et al: Fatal measles myocarditis. Cardiologia 35: 347, 1990.

436.

Degen JA: Visceral pathology in measles. Am J Med Sci 194:104, 1937.

Tsintsof A, Delprado WJ, Keogh AM: Varicella zoster myocarditis progressing to cardiomyopathy and cardiac transplantation. Br Heart J 70:93, 1993. 437.

438.

Matthews AW, Griffiths ID: Post-vaccinial pericarditis and myocarditis. Br Heart J 36:1043, 1974.

Rickettsial Myocarditis 439.

Chevalier P, Moncada E, Kirkorian G, et al: Q fever-induced EMF. Am Heart J 125:1818, 1993.

Raoult D, Tissot-Dupont H, Foucault C, et al: Q fever 1985-1998. Clinical and epidemiologic features of 1,383 infections. Medicine 79:109, 2000. 439A.

Marin-Garcia J, Barrett FF: Myocardial function in Rocky Mountain spotted fever: Echocardiographic assessment. Am J Cardiol 51:341, 1983. 440.

Yotsukura M, Aoki N, Fukuzumi N, et al: Review of a case of tsutsugamushi disease showing myocarditis and confirmation of rickettsia by endomyocardial biopsy. Jpn Circ J 55:149, 1991. 441.

Bacterial Myocarditis

Jubber AS, Gunawardana DR, Lulu AR: Acute pulmonary edema in Brucella myocarditis and interstitial pneumonitis. Chest 97:1008, 1990. 442.

Stevens DL, Troyer BE, Merrick DT, et al: Lethal effects and cardiovascular effects of purified alphaand theta-toxins from Clostridium perfringens. J Infect Dis 157:272, 1988. 443.

Kadirova R, Kartoglu HU, Strebel PM: Clinical characteristics and management of 676 hospitalized diphtheria cases, Kyrgyz Republic, 1995. J Infect Dis 181(Suppl 1):S110, 2000. 443A.

Havaldar PV, Patil VD, Siddibhavi BM, et al: Fulminant diptheretic myocarditis. Indian Heart J 41:265, 1989. 444.

Armengol S, Domingo C, Mesalles E: Myocarditis: A rare complication during Legionella infection. Int J Cardiol 37:418, 1992. 445.

Sandler MA, Pincus PS, Weltman MD, et al: Meningococcaemia complicated by myocarditis: A report of 2 cases. S Afr Med J 75:391, 1989. 446.

Agarwala BN, Ruschhaupt DG: Complete heart block from Mycoplasma pneumoniae infection. Pediatr Cardiol 12:233, 1991. 447.

448.

Odeh M, Oliven A: Chlamydial infections of the heart. Eur J Clin Microbiol Infect Dis 11:885, 1992.

Neuwirth C, Francois C, Laurent N, et al: Myocarditis due to Salmonella virchow and sudden infant death. Lancet 354:1004, 1999. 449.

Wander GS, Khurana SB, Puri S: Salmonella myopericarditis presenting with acute pulmonary oedema. Indian Heart J 44:55, 1992. 450.

Maher D, Ostrowski J: Highly virulent Streptococcus pyogenes rheumatic pancarditis and fatal septicaemia with septic shock. J Infect 26:195, 1993. 451.

O'Neill PG, Rokey R, Greenberg S, et al: Resolution of ventricular tachycardia and endocardial tuberculoma following antituberculosis therapy. Chest 100:1467, 1991. 452.

Chan AC, Dickens P: Tuberculous myocarditis presenting as sudden cardiac death. Forensic Sci Int 57:45, 1992. 453.

Whipple Disease Silvestry FE, Kim B, Pollack BJ, et al: Cardiac Whipple disease: Identification of Whipple bacillus by electron microscopy of a patient before death. Ann Intern Med 126:214, 1997. 454.

Elkins C, Shuman TA, Pirolo JS: Cardiac Whipple's disease without digestive symptoms. Ann Thorac Surg 67:250, 1999. 455.

Spirochetal Infections Singh SS, Vijayachari P, Sinha A, et al: Clinico-epidemiological study of hospitalized cases of severe leptospirosis. Indian J Med Res 109:94, 1999. 456.

457.

Rajiv C, Manjuran RJ, Sudhayakumar N, et al: Cardiovascular involvement in leptospirosis. Indian

Heart J 48:691, 1996. Sangha O, Phillips CB, Fleischmann KE, et al: Lack of cardiac manifestations among patients with previously treated Lyme disease. Ann Intern Med 128:346, 1998. 458.

Haywood GA, O'Connell S, Gray HH: Lyme carditis: A United Kingdom perspective. Br Heart J 70:15, 1993. 459.

Asch ES, Bujak DI, Weiss M, et al: Lyme disease: An infectious and postinfectious syndrome. J Rheumatol 21:454, 1994. 460.

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461.

Ledford DK: Immunologic aspects of vasculitis and cardiovascular disease. JAMA 278:1962, 1997.

Rees DH, Keeling PJ, McKenna WJ, et al: No evidence to implicate Borrelia burgdorferi in the pathogenesis of dilated cardiomyopathy in the United Kingdom. Br Heart J 71:459, 1994. 462.

Stanek G, Klein J, Bittner R, et al: Isolation of Borrelia burgdorferi from the myocardium of a patient with long-standing cardiomyopathy. N Engl J Med 322:249, 1990. 463.

Rahn DW, Malawista SE: Lyme disease: Recommendations for diagnosis and treatment. Ann Intern Med 14:472, 1991. 464.

465.

Mekasha A: Louse-borne relapsing fever in children. J Trop Med Hyg 95:206, 1992.

Chino M, Minami T, Nishikawa K: Ruptured ventricular aneurysm in secondary syphilis. Lancet 342:935, 1993. 466.

Fungal Infections of the Heart 467.

Bashour TT, Gord C, Baladi N, et al: Intracardiac actinomyocosis. Am Heart J 133:467, 1997.

Berarducci L, Ford K, Olenick S, et al: Invasive intracardiac aspergillosis with widespread embolization. J Am Soc Echocardiogr 6:539, 1993. 468.

Massin EK, Zeluff BJ, Carrol CL, et al: Cardiac transplantation and aspergillosis. Circulation 90:1552, 1994. 469.

Lafont A, Wolff M, Marche C, et al: Overwhelming myocarditis due to Cryptococcus neoformans in an AIDS patient. Lancet 2:1145, 1987. 470.

Kirchner SG, Hernanz-Schulman M, Stein SM, et al: Imaging of pediatric mediastinal histoplasmosis. Radiographics 11:365, 1991. 471.

Jackman JD Jr, Simonsen RL: The clinical manifestations of cardiac mucormycosis. Chest 101:1733, 1992. 472.

Protozoal Myocarditis 473.

Hagar JM, Rahimtoola SH: Chagas' heart disease. Curr Probl Cardiol 20:825, 1995.

Rossi MA, Bestetti RB: The challenge of chagasic cardiomyopathy: The pathologic roles of autonomic abnormalities, autoimmune mechanisms and microvascular changes, and therapeutic implications. Cardiology 86:1, 1995. 474.

Parada H, Carrasco HA, Anez N, et al: Cardiac involvement is a constant finding in acute Chagas' disease: A clinical, parasitological and histopathological study. Int J Cardiol 60:49, 1997. 475.

Reis MM, Higuchi M, de la Benvenuti LA, et al: An in situ quantitative immunohistochemical study of cytokines and IL-2R+ in chronic human chagasic myocarditis: Correlation with the presence of myocardial Trypanosoma cruzi antigens. Clin Immunol Immunopathol 83:165, 1997. 476.

Rossi MA: Comparison of Chagas' heart disease to arrhythmogenic right ventricular cardiomyopathy. Am Heart J 129:626, 1995. 477.

Anez N, Carrasco H, Parada H, et al: Myocardial parasite persistence in chronic chagasic patients. Am J Trop Med Hyg 60:726, 1999. 478.

Bellotti G, Bocchi EA, de Moraes AV, et al: In vivo detection of Trypanosoma cruzi antigens in hearts of patients with chronic Chagas' heart disease. Am Heart J 131:301, 1996. 479.

Bestetti RB, Muccillo G: Clinical course of Chagas' heart disease: A comparison with dilated cardiomyopathy. Int J Cardiol 60:187, 1997. 480.

Higuchi MD, Ries MM, Aiello VD, et al: Association of an increase in CD8+ T cells with the presence of Trypanosoma cruzi antigens in chronic, human, chagasic myocarditis. Am J Trop Med Hyg 56:485, 1997. 481.

Higuchi ML, Fukasawa S, De Brito T, et al: Different microcirculatory and interstitial matrix patterns in idiopathic dilated cardiomyopathy and Chagas' disease: A three dimensional confocal microscopy study. Heart 82:279, 1999. 482.

Bestetti RB, Dalbo CM, Arruda CA, et al: Predictors of sudden cardiac death for patients with Chagas' disease: A hospital-derived cohort study. Cardiology 87:481, 1996. 483.

Carrasco HA, Alarcon M, Olmos L, et al: Biochemical characterization of myocardial damage in chronic Chagas' disease. Clin Cardiol 20:865, 1997. 484.

Bestetti RB, Dalbo CM, Freitas QC, et al: Noninvasive predictors of mortality for patients with Chagas' heart disease: A multivariate stepwise logistic regression study. Cardiology 84:261, 1994. 485.

Giniger AG, Retyk EO, Laino RA, et al: Ventricular tachycardia in Chagas' disease. Am J Cardiol 70:459, 1992. 486.

de Paola AA, Gomes JA, Terzian AB, et al: Ventricular tachycardia during exercise testing as a predictor of sudden death in patients with chronic chagasic cardiomyopathy and ventricular arrhythmias. Br Heart J 74:293, 1995. 487.

488.

Carrasco HA, Parada H, Guerrero L, et al: Prognostic implications of clinical, electrocardiographic

and hemodynamic findings in chronic Chagas' disease. Int J Cardiol 43:27, 1994. de Paola AA, Gomes JA, Miyamoto MH, et al: Transcoronary chemical ablation of ventricular tachycardia in chronic chagasic myocarditis. J Am Coll Cardiol 20:480, 1992. 489.

Braga JC, Labrunie A, Villaca F, et al: Thromboembolism in chronic Chagas' heart disease. Rev Paul Med 113:862, 1995. 490.

Marin-Neto JA, Marzullo P, Marcassa C, et al: Myocardial perfusion abnormalities in chronic Chagas' disease as detected by thallium-201 scintigraphy. Am J Cardiol 69:780, 1992. 491.

Kalil Filho R, de Albuquerque CP: Magnetic resonance imaging in Chagas' heart disease. Rev Paul Med 113:880, 1995. 492.

Ferreira AW, de Avila SD: Laboratory diagnosis of Chagas' heart disease. Rev Paul Med 113:767, 1995. 493.

de Paola AA, Gondin AA, Hara V, et al: Medical treatment of cardiac arrhythmias in Chagas' heart disease. Rev Paul Med 113:858, 1995. 494.

Muratore C, Rabinovich R, Iglesias R, et al: Implantable cardioverter defibrillators in patients with Chagas' disease: Are they different from patients with coronary disease? Pacing Clin Electrophysiol 20:194, 1997. 495.

Apt W, Aguilera X, Arribada A, et al. Treatment of chronic Chagas' disease with itraconazole and allopurinol. Am J Trop Med Hyg 59:133, 1998. 496.

Bocchi EA, Bellotti G, Uip D, et al: Long-term follow-up after heart transplantation in Chagas' disease. Transplant Proc 25:1329, 1993. 497.

Bocchi EA, Bellotti G, Mocelin AO, et al: Heart transplantation for chronic Chagas' heart disease. Ann Thorac Surg 61:1727, 1996. 498.

Tsala Mbala P, Blackett K, Mbonifor CL, et al: Functional and immunologic involvement in human African trypanosomiasis caused by Trypanosoma gambiense. Bull Soc Pathol Exot Filiales 81:490, 1988. 499.

Hofman P, Drici MD, Gibelin P, et al: Prevalence of Toxoplasma myocarditis in patients with the acquired immunodeficiency syndrome. Br Heart J 70:376, 1993. 500.

Duffield JS, Jacob AJ, Miller HC: Recurrent, life-threatening atrioventricular dissociation associated with Toxoplasma myocarditis. Heart 76:453, 1996. 501.

Montoya JG, Jordan R, Lingamneni S, et al: Toxoplasmic myocarditis and polymyositis in patients with acute acquired toxoplasmosis diagnosed during life. Clin Infect Dis 24:676, 1997. 502.

Franzen D, Curtius JM, Heitz W, et al: Cardiac involvement during and after malaria. Clin Invest 70:670, 1992. 503.

Sharma SN, Mohapatra AK, Machave YV: Chronic falciparum cardiomyopathy. J Assoc Physicians India 35:251, 1987. 504.

Metazoal Myocardial Disease

Salih OK, Celik SK, Topcuoglu MS, et al: Surgical treatment of hydatid cysts of the heart: A report of 3 cases and a review of the literature. Can J Surg 41:321, 1998. 505.

Benomar A, Yahyaoui M, Birouk N, et al: Middle cerebral artery occlusion due to hydatid cysts of myocardial and intraventricular cavity cardiac origin: Two cases. Stroke 25:886, 1994. 506.

Miralles A, Bracamonte L, Pavie A, et al: Cardiac echinococcosis: Surgical treatment and results. J Thorac Cardiovasc Surg 107:184, 1994. 507.

Franchi C, Di Vico B, Teggi A: Long-term evaluation of patients with hydatidosis treated with benzimidazole carbamates. Clin Infect Dis 29:304, 1999. 508.

Dao AH, Virmani R: Visceral larva migrans involving the myocardium: Report of two cases and review of literature. Pediatr Pathol 6:449, 1986. 509.

Lazarevic AM, Neskovic AN, Goronja M, et al: Low incidence of cardiac abnormalities in treated trichinosis: A prospective study of 62 patients from a single-source outbreak. Am J Med 107:18, 1999. 510.

Compton SJ, Celum CL, Lee C, et al: Trichinosis with ventilatory failure and persistent myocarditis. Clin Infect Dis 16:500, 1993. 511.

TOXIC, CHEMICAL, IMMUNE, AND PHYSICAL DAMAGE TO THE HEART Eisenberg MJ, Mendelson J, Evans GT Jr, et al: Left ventricular function immediately after intravenous cocaine: A quantitative two-dimensional echocardiographic study. J Am Coll Cardiol 22:1581, 1993. 512.

Clarkson CW, Chang C, Stolfi A, et al: Electrophysiological effects of high cocaine concentrations on intact canine heart: Evidence for modulation by both heart rate and autonomic nervous system. Circulation 87:950, 1993. 513.

Kimura S, Bassett AL, Xi H, et al: Early afterdepolarizations and triggered activity induced by cocaine: A possible mechanism of cocaine arrhythmogenesis. Circulation 85:2227, 1992. 514.

Moliterno DJ, Lange RA, Gerard RD, et al: Influence of intranasal cocaine on plasma constituents associated with endogenous thrombosis and thrombolysis. Am J Med 96:492, 1994. 515.

516.

Jennings LK, White MM, Sauer CM, et al: Cocaine-induced platelet defects. Stroke 24:1352, 1993.

517.

Lange RA, Willard JE: The cardiovascular effects of cocaine. Heart Dis Stroke 2:136, 1993.

Gitter MJ, Goldsmith SR, Dunbar DN, et al: Cocaine and chest pain: Clinical features and outcome of patients hospitalized to rule out myocardial infarction. Ann Intern Med 115:277, 1991. 518.

Mittleman MA, Mintzer D, Maclure M, et al: Triggering of myocardial infarction by cocaine. Circulation 99:2737, 1999. 519.

Chakko S, Fernandez A, Mellman TA, et al: Cardiac manifestations of cocaine abuse: A cross-sectional study of asymptomatic men with a history of long-term abuse of "crack" cocaine. J Am Coll Cardiol 20:1168, 1992. 520.

Kloner RA, Hale S: Unraveling the complex effects of cocaine on the heart. Circulation 87:1046, 1993. 521.

Angulo MP, Navajas A, Galdeano JM, et al: Reversible cardiomyopathy secondary to alpha-interferon in an infant. Pediatr Cardiol 20:293; 1999. 522.

Pitts WR, Lange RA, Cigarroa JE, Hillis DA: Cocaine-induced myocardial ischemia and infarction: Pathophysiology, recognition, and management. Prog Cardiovasc Dis 40:65, 1997. 523.

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Hollander JE, Brooks DE, Valentine SM: Assessment of cocaine use in patients with chest pain syndromes. Arch Intern Med 158:62, 1998. 524.

Greenlund KJ, Kiefe CI, Gidding SS, et al: Differences in cardiovascular risk factors in black and white young adults: Comparisons among five communities of the CARDIA and the Bogalusa heart studies. Ann Epidemiol 8:22, 1998. 525.

McLaurin M, Apple FS, Henry TD, Sharkey SW: Cardiac troponin I and T concentrations in patients with cocaine-associated chest pain. Ann Clin Biochem 33:183, 1996. 526.

Kontos MC, Schmidt KL, Nicholson CS, et al: Myocardial perfusion imaging with technetium-99m sestamibi in patients with cocaine-associated chest pain. Ann Emerg Med 33:639, 1999. 527.

Braunwald E, Antman EM, Beasley JW, et al: ACC/AHA Guidelines for the management of patients with unstable angina. J Am Coll Cardiol. In press. 528.

Feenstra J, Grobbee DE, Remme WJ, et al: Drug-induced heart failure. J Am Coll Cardiol 33:1152, 1999. 529.

Goel M, Flaherty L, Lavine S, et al: Reversible cardiomyopathy after high-dose interleukin-2 therapy. J Immunother 11:225, 1992. 530.

Le Blaye I, Donatini B, Hall M, et al: Acute overdosage with thioridazine: A review of the available clinical exposure. Vet Hum Toxicol 35:147, 1993. 531.

Schmidt W, Lang K: Life-threatening dysrhythmias in severe thioridazine poisoning treated with physostigmine and transient atrial pacing. Crit. Care Med. 25:1925, 1997. 532.

533.

Combs, AB, Acosta, D: Toxic mechanisms of the heart: a review. Toxicol Pathol 18:583, 1990.

Ho PC, Dweik R, Cohen MC: Rapidly reversible cardiomyopathy associated with chronic ipecac ingestion. Clin Cardiol 21:780, 1998. 534.

535.

Silberstein SD: Methysergide. Cephalalgia 18:421, 1998.

Iglesias Cubero G, Rodriguez Reguero JJ, Rojo Ortega JM: Restrictive cardiomyopathy caused by chloroquine. Br Heart J 69:451, 1993. 536.

Sundar S, Sinha PR, Agrawal NK, et al: A cluster of cases of severe cardiotoxicity among kala-azar patients treated with a high-osmolarity lot of sodium antimony gluconate. Am J Trop Med Hyg 59:139, 1998. 537.

Ortega-Carnicer J, Alcazar R, De la Torre M, et al: Pentavalent antimonial-induced torsades de pointes. J Electrocardiol 30:143, 1997. 538.

539.

Groleau G: Lithium toxicity. Emerg Med Clin North Am 12:511, 1994.

Terao T, Abe H, Abe K: Irreversible sinus node dysfunction induced by resumption of lithium therapy. Acta Psychiatr Scand 93:407, 1996. 540.

Gerhardt RT: Acute halon (bromochlorodifluoromethane) toxicity by accidental and recreational inhalation. Am J Emerg Med 14:675, 1996. 541.

Brady WJ Jr, Stremski E, Eljaiek L, et al: Freon inhalational abuse presenting with ventricular fibrillation. Am J Emerg Med 12:533, 1994. 542.

Elian D, Harpaz D, Sucher E, et al: Reversible catecholamine-induced cardiomyopathy presenting as acute pulmonary edema in a patient with pheochromocytoma. Cardiology 83:118, 1993. 543.

Sardesai SH, Mourant AJ, Sivathandon Y, et al: Phaeochromocytoma and catecholamine induced cardiomyopathy presenting as heart failure. Br Heart J 63:234, 1990. 544.

Jiang JP, Downing SE: Catecholamine cardiomyopathy: Review and analysis of pathogenetic mechanisms. Yale J Biol Med 63:581, 1990. 545.

Raper R, Fisher M, Bihari D: Profound, reversible, myocardial depression in acute asthma treated with high-dose catecholamines. Crit Care Med 20:710, 1992. 546.

Kopp SJ, Barron JT, Tow JP: Cardiovascular actions of lead and relationship to hypertension: A review. Environ Health Perspect 78:91, 1988. 547.

Farber JP, Schwartz PJ, Vanoli E, et al: Carbon monoxide and lethal arrhythmias. Res Rep Health Eff Inst 36:1, 1990. 548.

Dahms TE, Younis LT, Wiens RD, et al: Effects of carbon monoxide exposure in patients with documented cardiac arrhythmias. J Am Coll Cardiol 21:442, 1993. 549.

McMeekin JD, Finegan BA: Reversible myocardial dysfunction following carbon monoxide poisoning. Can J Cardiol 3:118, 1987. 550.

Marius-Nunez AL: Myocardial infarction with normal coronary arteries after acute exposure to carbon monoxide. Chest 97:491, 1990. 551.

Kudoh C, Tanaka S, Marusaki S, et al: Hypocalcemic cardiomyopathy in a patient with idiopathic hypoparathyroidism. Intern Med 31:561, 1992. 552.

Feldman AM, Fivush B, Zahka KG, et al: Congestive cardiomyopathy in patients on continuous ambulatory peritoneal dialysis. Am Kidney Dis 11:76, 1988. 553.

554.

Kurnik BR, Marshall J, Katz SM: Hypomagnesemia-induced cardiomyopathy. Magnesium 7:49, 1988.

Riggs JE, Klingberg WG, Flink EB, et al: Cardioskeletal mitochondrial myopathy associated with chronic magnesium deficiency. Neurology 42:128, 1992. 555.

556.

Paulson DJ: Carnitine deficiency-induced cardiomyopathy. Mol Cell Biochem 180:33, 1998.

Ergur AT, Tanzer F, Cetinkaya O: Serum-free carnitine levels in children with heart failure. J Trop Pediatr 45:168, 1999. 557.

558.

Huttunen JK: Selenium and cardiovascular diseases--an update. Biomed Environ Sci 10:220, 1997.

Levy JB, Jones HW, Gordon AC: Selenium deficiency, reversible cardiomyopathy and short-term intravenous feeding. Postgrad Med J 70:235, 1994. 559.

Kumar EB, Soomro RS, al Hamdani A, et al: Scorpion venom cardiomyopathy. Am Heart J 123:725, 1992. 560.

561.

Gueron M, Ilia R, Sofer S: Scorpion venom cardiomyopathy. Am Heart J 125:1816, 1993.

Ferreira DB, Costa RS, De Oliveira JA, et al: An infarct-like myocardial lesion experimentally induced in Wistar rats with africanized bee venom. J Pathol 177:95, 1995. 562.

Wagdi P, Mehan VK, Burgi H, et al: Acute myocardial infarction after wasp stings in a patient with normal coronary arteries. Am Heart J 128:820, 1994. 563.

Lalloo DG, Trevett AJ, Nwokolo N, et al: Electrocardiographic abnormalities in patients bitten by taipans (Oxyuranus scutellatus canni) and other elapid snakes in Papua New Guinea. Trans R Soc Trop Med Hyg 91:53, 1997. 564.

Kurnik D, Haviv Y, Kochva E: A snake bite by the burrowing asp, Atractaspis engaddensis. Toxicon 37:223, 1999. 565.

Hall JC, Harruff R: Fatal cardiac arrhythmia in a patient with interstitial myocarditis related to chronic arsenic poisoning. South Med J 82:1557, 1989. 566.

Hypersensitivity Getz MA, Subramanian R, Logemann T, et al: Acute necrotizing eosinophilic myocarditis as a manifestation of severe hypersensitivity myocarditis: Antemortem diagnosis and successful treatment. Ann Intern Med 115:201, 1991. 567.

Burke AP, Saenger J, Mullick F, et al: Hypersensitivity myocarditis. Arch Pathol Lab Med 115:764, 1991. 568.

Webster J, Koch HF: Aspects of tolerability of centrally acting antihypertensive drugs. J Cardiovasc Pharmacol 27 (Suppl 3):S49, 1996. 569.

Giant Cell Myocarditis Garty BZ, Offer I, Livni E, et al: Erythema multiforme and hypersensitivity myocarditis caused by ampicillin. Ann Pharmacother 28:730, 1994. 570.

Cooper LT Jr, Berry GJ, Shabetai R: Idiopathic giant-cell myocarditis--natural history and treatment. N Engl J Med 336:1860, 1997. 571.

Hyogo M, Kamitani T, Oguni A, et al: Acute necrotizing eosinophilic myocarditis with giant cell infiltration after remission of idiopathic thrombocytopenic purpura. Intern Med 36:894, 1997. 572.

Levy NT, Olson LJ, Weyand C, et al: Histologic and cytokine response to immunosuppression in giant-cell myocarditis. Ann Intern Med 128:648, 1998. 573.

Meyer T, Grumbach IM, Kreuzer H, Morguet AJ: Giant cell myocarditis due to coxsackie B2 virus infection. Cardiology 88:296, 1997. 574.

Litovsky SH, Burke AP, Virmani R: Giant cell myocarditis: An entity distinct from sarcoidosis characterized by multiphasic myocyte destruction by cytotoxic T cells and histiocytic giant cells. Mod Pathol 9:1126, 1996. 575.

Kilgallen CM, Jackson E, Bankoff M, et al: A case of giant cell myocarditis and malignant thymoma: A postmortem diagnosis by needle biopsy. Clin Cardiol 21:48, 1998. 576.

Khoury Z, Keren A, Benhorin J, et al: Aborted sudden death in a young patient with isolated granulomatous myocarditis. Eur Heart J 15:397, 1994. 577.

Desjardins V, Pelletier G, Leung TK, et al: Successful treatment of severe heart failure caused by idiopathic giant cell myocarditis. Can J Cardiol 8:788, 1992. 578.

Nieminen MS, Salminen US, Taskinen E, et al: Treatment of serious heart failure by transplantation in giant cell myocarditis diagnosed by endomyocardial biopsy. J Heart Lung Transplant 13:543, 1994. 579.

Frustaci A, Chimenti C, Pieroni M, Gentiloni N: Giant cell myocarditis responding to immunosuppressive therapy. Chest 117:905, 2000. 579A.

Laruelle C, Vanhaecke J, van de Werf F, et al: Cardiac transplantation in giant cell myocarditis: A case report. Acta Cardiol 49:279, 1994. 580.

Physical Agents Loyer EM, Delpassand ES: Radiation-induced heart disease: Imaging features. Semin Roentgenol 28:321, 1993. 581.

Veeragandham RS, Goldin MD: Surgical management of radiation-induced heart disease. Ann Thorac Surg 65:1014, 1998. 582.

Gyenes G, Fornander T, Carlens P, et al: Detection of radiation-induced myocardial damage by technetium-99m sestamibi scintigraphy. Eur J Nucl Med 24:286, 1997. 583.

Orzan F, Brusca A, Gaita F, et al: Associated cardiac lesions in patients with radiation-induced complete heart block. Int J Cardiol 39:151, 1993. 584.

Dematte JE, O'Mara K, Buescher J, et al: Near-fatal heat stroke during the 1995 heat wave in Chicago. Ann Intern Med 129:173, 1998. 585.

586.

Danzl DF, Pozos RS: Accidental hypothermia. N Engl J Med 331:1756, 1994.

Walpoth BH, Walpoth-Aslan BN, Mattle HP, et al: Outcome of survivors of accidental deep hypothermia and circulatory arrest treated with extracorporeal blood warming. N Engl J Med 337:1500, 1997. 587.

588.

Lazar HL: The treatment of hypothermia. N Engl J Med 337:1545, 1997.




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Chapter 49 - Primary Tumors of the Heart WILSON S. COLUCCI FREDERICK J. SCHOEN

With an incidence of 0.002 to 0.3 percent in autopsy series,[1] [2] [3] [4] [5] [6] [7] primary tumors of the heart* are far less common than metastatic tumors to the heart.[8] Benign primary cardiac tumors occur more frequently than malignant ones. The most common cardiac tumor is the myxoma. In a large single-institution series of primary cardiac tumors, comprising 124 cases diagnosed at surgery and autopsy over 40 years (at the University of Minnesota), 42 percent were cardiac myxomas and 16 percent were malignant tumors (sarcomas) (Fig. 49-1) . [9] The proportion of myxomas in comparison with other tumors was increased (to 77 percent) when consideration was limited to surgically excised lesions.[9] [10] Before the advent of modern cardiopulmonary bypass surgical techniques, the correct antemortem diagnosis of an intracardiac tumor was largely academic, because effective therapy was not possible. However, now that many cardiac tumors are curable by operation, it is critically important to establish this diagnosis whenever possible. During the past decade, major advances in noninvasive cardiovascular diagnostic techniques--especially echocardiography (see Chap. 7) , computed tomography (CT), and magnetic resonance imaging (MRI) (see Chap. 10) --have greatly facilitated this task, and it is now possible safely and readily to screen patients suspected of having a cardiac tumor, in many cases arriving at a definitive

diagnosis preoperatively. Nevertheless, a high index of suspicion remains the most important element in diagnosing a cardiac tumor. CLINICAL PRESENTATION SYSTEMIC FINDINGS.

The cardiac tumor myxoma causes various nonspecific clinical signs and symptoms that often masquerade as many other more common cardiovascular and systemic diseases (Tables 49-1 and 49-2) . Cardiac myxoma can produce a broad array of systemic (i.e., noncardiac) findings including fever, cachexia, malaise, arthralgias, Raynaud's phenomenon, rash, clubbing, and episodic bizarre behavior,[11] [12] as well as systemic and pulmonary emboli. [12A] Various laboratory findings have been reported, including hypergammaglobulinemia, elevated erythrocyte sedimentation rate, thrombocytosis, thrombocytopenia, polycythemia, leukocytosis, and anemia. Systemic signs and symptoms frequently resolve when the tumor is removed. Role of Interleukin-6.

The association of constitutional symptoms with cardiac myxoma is likely to be due to the tumor's constitutive synthesis and secretion of interleukin-6 (IL-6), [13] [14] [15] [16] [17] [18] [19] [20] [20A] an inflammatory cytokine thought to be a major inducer of the acute phase response, which is associated with fever, leukocytosis, and activation of the complement and clotting cascades.[14] In vitro, IL-6 induces the synthesis of C-reactive protein, serum amyloid A, alpha2 -macroglobulin, and fibrinogen by human hepatocytes.[14] High levels of myxoma production of IL-6 may be accompanied by elevated serum concentration in patients who have cardiac myxoma and symptoms characteristic of autoimmune diseases.[18] In some cases, serum IL-6 levels become undetectable and the immunological features resolve on removal of the tumor.[19] Increased titers of antibodies to myocardium [20] and neutrophils[21] have also been found in patients with myxoma and were shown to decline after removal of the tumor. A case of multiple myeloma has been attributed to continuous immunological stimulation by a left atrial myxoma.[22] Because the cardiac findings are nonspecific and may be subtle or absent, it is not unusual for these systemic findings to lead to a diagnosis of collagen-vascular disease, infection, or noncardiac malignant disease.[23] [24] [25] Rarely, myxomas may be superinfected by bacteria or fungi.[26] [27] [28] EMBOLIC PHENOMENA.

Embolization of tumor fragments or of thrombi from the surface of a tumor is a frequent and often dramatic clinical occurrence.[29] [30] [31] [32] [33] Although myxomas are the source of most tumor emboli because of the combination of their friable consistency and intracavitary location (Fig. 49-2) , other types of cardiac tumors occasionally may embolize. The distribution of tumor emboli depends on the location of the tumor and the presence or absence of intracardiac shunts. Left-sided tumors embolize to the systemic

circulation, resulting in infarction and hemorrhage of viscera, including the heart,[29] as well as peripheral limb ischemia and vascular aneurysms. The diagnosis of an intracardiac tumor may be made after histological examination of systemic embolic material,[34] [35] and therefore it is of critical importance to make every effort to recover and examine embolic material. In some cases, particularly when petechiae are present, biopsy of skin or muscle[33] can demonstrate intravascular tumor emboli. Multiple systemic emboli may mimic systemic vasculitis[33] or infective endocarditis, especially when associated with other manifestations of a systemic illness such as fever, *Tumors arising elsewhere in the body and metastasizing to the pericardium and heart are discussed in Chap. 50 (Pericardial Disease) and Chap. 69 (Hematologic-Oncologic Disorders and Heart Disease).

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Figure 49-1 Relative incidence of cardiac tumors. A, Incidences of both surgical and autopsy cases are considered. B, Relative incidences of only surgical series are considered. When only surgical series are considered, the proportion of myxomas increases. (Adapted from Molina JE, Edwards JE, Ward HB: Primary cardiac tumors: Experience at the University of Minnesota. Thorac Cardiovasc Surg 38:183, 1990.)

weight loss, arthralgias, elevated erythrocyte sedimentation rate, and elevated serum gamma globulins. The finding at angiography of numerous vascular aneurysms secondary to tumor emboli in the cerebral, renal, femoral, and coronary arteries is not infrequent[36] and may lead to the mistaken diagnosis of polyarteritis nodosa.[23] The neurological consequences of embolization include transient ischemic attacks, seizures, syncope, and cerebral, cerebellar, brain stem, spinal cord, or retinal infarction. [37] The neurological event may occasionally be the first or only clinical manifestation of a cardiac tumor. An embolic stroke in a young person without evidence of cerebrovascular disease, particularly in the presence of sinus rhythm, should raise the suspicion of intracardiac myxoma, as well as infective endocarditis and prolapse of the mitral valve. TABLE 49-1 -- SYMPTOMS AND SIGNS OF CARDIAC MYXOMA SYMPTOMS INCIDENCE (%) Dyspnea on exertion

>75

Paroxysmal dyspnea

~25

Fever

~50

Weight loss

~25

Severe dizziness/syncope

~20

Sudden death

~15

Hemoptysis

~15

SIGNS

INCIDENCE (%)

Mitral diastolic murmur

~75

Mitral systolic murmur

~50

Pulmonary hypertension

~70

Right heart failure

~70

Pulmonary emboli

~25

Anemia

>33

Elevated ESR

>33

Third heart sound (tumor plop)

>33

Atrial fibrillation

~15

Elevated globulins

~10

Clubbing

~5

Raynaud's phenomenon

3 mm Hg at rest, both of which increase with exercise


Simultaneous wedge and left ventricular pressure recording Left ventriculogram

Large systolic pressure wave in wedge tracing. Regurgitation of contrast from left ventricular angiogram into the left atrium

Left ventricular diastolic dysfunction Restrictive cardiomyopathy

Left ventricular pressure Right ventricular pressure

LVEDP >15 mm Hg LVEDP response to intravenous fluid challenge: normalization of LVEDP with marked reduction in pulmonary artery pressure with intravenous nitroprusside

LVEDP=left ventricular end-diastolic pressure. Modified from Reeves JT, Groves BM: Approach to the patient with pulmonary hypertension. In Weir EK, Reeves JT: Pulmonary Hypertension. Mt Kisco, NY, Futura, 1984, p 20. *Ventilation=perfusion lung scans precede catheterization.

the contrast load. Pulmonary wedge angiography using a segmental angiographic technique with hand injection of small amounts of angiographic contrast through the terminal lumen of a balloon flotation catheter while the balloon is inflated is not a substitute for pulmonary angiography. COMPUTED TOMOGRAPHY OF THE CHEST.

Chest radiographs, as well as chest CT scans, have been used to determine the presence and severity of pulmonary hypertension based on the diameter of the main pulmonary arteries.[129] [132] This information may be useful when performing chest CT to investigate the lung parenchyma in patients with pulmonary hypertension who are undergoing diagnostic evaluation. In addition, high-resolution chest CT scans have been used successfully in diagnosing chronic thromboembolic pulmonary hypertension.[132] In addition to visualization of thrombi in the pulmonary vasculature with contrast enhancement, a mosaic pattern of variable attenuation compatible with irregular pulmonary perfusion can be determined in the unenhanced CT scan. Marked variation in the size of segmental vessels is also a specific feature of chronic thromboembolic disease. In some institutions, high-resolution CT scanning has replaced lung scintigraphy as a test to make this diagnosis. EXERCISE TESTING.

The use of a symptom-limited exercise test can be very helpful in the evaluation of patients with pulmonary hypertension. Besides allowing objective assessment of the severity of symptoms, exercise testing has been shown to also be predictive of survival. Two types of exercise testing have recently become popularized. The Naughton protocol uses a treadmill with increases in work of 1-MET increments at 2-minute stages to allow patients with very limited exercise tolerance to perform. In the 6-minute walk

test, patients are instructed to walk down a 100-ft corridor and cover as much ground as possible within the 6 minutes. The total distance walked is determined by a tester. The application of exercise testing has been particularly helpful in evaluating the efficacy of drug therapy.[133] CARDIAC CATHETERIZATION.

The diagnosis of PPH cannot be confirmed without cardiac catheterization (Table 53-2) . Besides allowing the exclusion of other causes, it also establishes the severity of disease and allows an assessment of prognosis. By definition, patients with PPH should have a low or normal pulmonary capillary wedge pressure. Although it has often been stated that one may be unable to obtain an accurate wedge pressure in these patients, such is rarely the case in experienced hands.[76] However, when an increased wedge pressure is obtained, it must be correlated with left ventricular end-diastolic pressure and not attributed to a "falsely elevated" reading.[134] It has been shown that left ventricular diastolic compliance becomes significantly impaired in PPH and parallels the severity of the disease; thus, pulmonary capillary wedge pressure tends to rise slightly in the late stages of PPH, although it rarely exceeds 16 mm Hg. Measurements of all right-sided pressures are properly made at expiration to avoid incorporating negative intrathoracic pressures. It can be extremely difficult to pass a catheter into the pulmonary artery in patients with pulmonary hypertension because of the tricuspid regurgitation, dilated right atrium and ventricle, and low cardiac output. Flow-directed thermodilution balloon catheters, which are the proper devices to use, also lack stiffness and can be difficult to place. A specific flow-directed thermodilution balloon catheter has been developed for patients with pulmonary hypertension (American Edwards Laboratories, Irvine, CA); it has an extra port for the placement of a 0.32-inch guidewire to provide better stiffness to the catheter. The risk associated with cardiac catheterization in patients with PPH is extremely low in experienced hands, but deaths have been reported.[76] DIAGNOSIS (Table 53-3) It is essential that diagnostic efforts be pursued vigorously in patients with severe pulmonary hypertension to ensure that no patient with secondary pulmonary hypertension is erroneously classified as having PPH. Patients with PPH may tolerate diagnostic procedures poorly. These individuals can experience sudden cardiovascular collapse and even death during or shortly after the induction of general anesthesia for surgical procedures and during cardiac catheterization and angiography. The differential diagnosis of PPH includes a number of well-defined causes of secondary pulmonary hypertension (Table 53-4) . Exclusion of mitral stenosis, congenital cardiac defects (including cor triatriatum, pulmonary thromboembolism, and pulmonary venous obstruction by means of catheterization and angiography is imperative. "Silent" mitral stenosis, i.e., without the characteristic diastolic murmur, can be excluded by means of echocardiographic visualization of the motion of the mitral valve and the absence

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TABLE 53-3 -- DIAGNOSTIC STUDIES USEFUL FOR ELUCIDATING CAUSES OF PULMONARY HYPERTENSION POTENTIAL CAUSE OF PULMONARY DIAGNOSTIC STUDIES HYPERTENSION Pulmonary thromboembolic disease

Ventilation/perfusion scans, computed tomography of chest, pulmonary angiography

Pulmonary venous thrombosis or obstruction

Chest x-ray, angiography, computed tomography, magnetic resonance imaging

Congenital intracardiac shunts

Transesophageal echocardiography with contrast

Increased left atrial pressure secondary to mitral or aortic valve disease, left ventricular dysfunction, or systemic hypertension

Pulmonary artery wedge pressure or left atrial pressure (via patent foramen ovale) (>15 mm Hg and LVEDP)

Pulmonary airway disease (e.g., chronic bronchitis and emphysema)

Respiratory function tests (FVC/FEV, chest x-ray)

Hypoxic pulmonary hypertension associated with Sleep apnea studies and respiratory (1) impaired ventilation, either central (CNS) or function tests peripheral (chest wall problems or upper airway obstruction) and (2) residence at high altitude Interstitial lung disease, pneumoconioses, and fibrosis (e.g., silicosis, rheumatoid disease, and sarcoidosis)

Chest x-ray, spirometry and carbon monoxide diffusion, high-resolution chest computed tomography

Collagen-vascular disease (e.g., SLE, polyarteritis nodosa, scleroderma)

Serological and immunogenetic studies; skin, muscle, or other tissue biopsy; esophageal motility studies

Parasitic disease (schistosomiasis or filariasis)

Rectal biopsy, complement fixation, skin tests, blood smears

Cirrhosis with portal hypertension

Liver function tests, ultrasonography, computed tomography

Peripheral pulmonary artery stenosis (including Takayasu disease and fibrosing mediastinitis)

Selective pulmonary angiography or pressure gradient at catheterization

Sickle cell disease

Erythrocyte morphology, hemoglobin electrophoresis

CNS=central nervous system; FEV1 =forced expiratory volume in 1 second; FVC=forced vital capacity; SLE=systemic lupus erythematosus. Modified from Weir EK: Diagnosis and management of primary pulmonary hypertension. In Weir EK, Reeves JT: Pulmonary Hypertension. Mt Kisco, NY, Futura, 1984, p 141. of a transvalvular pressure gradient (see Chap. 46) . Congenital cardiac defects with Eisenmengers syndrome can usually be ruled out if significant left-to-right or right-to-left shunts are absent, although occasional patients with equal pulmonary and systemic vascular resistance may have no detectable shunt at rest. Transesophageal echocardiography can reliably detect congenital cardiac defects and distinguish an atrial septal defect from a patent foramen ovale.[135] Cor triatriatum (see Chaps. 43 and 44) is recognized by appropriate hemodynamic studies and angiographic visualization of the left atrial membrane. This entity has a characteristic left atrial echocardiogram with normal mitral valve motion. Cardiac catheterization reveals a hemodynamic pattern similar in some ways to mitral stenosis, i.e., a diastolic pressure gradient between the left ventricle and the pulmonary capillary bed. Pulmonary embolism (see Chap. 52) can be excluded by pulmonary angiography, and sickle cell disease with in situ pulmonary vascular thrombosis (see Chap. 69) can be evaluated by hemoglobin electrophoresis. The presence of severe pulmonary parenchymal disease can be recognized by the characteristic physical findings, chest radiograph, pulmonary function tests, and high-resolution chest CT. Collagen-vascular disease is suggested by the involvement of other organ systems or the presence of abnormal immunological phenomena such as antinuclear antibodies and LE cells (see Chap. 67) . TABLE 53-4 -- DIAGNOSTIC CLASSIFICATION OF PULMONARY HYPERTENSION Pulmonary arterial hypertension Interstitial lung disease Primary

Sleep-disordered breathing

Sporadic

Alveolar hypoventilation disorders

Familial

Chronic exposure to high altitude

Secondary Collagen-vascular disease Congenital systemic-to-pulmonary shunts Portal hypertension

Neonatal lung disease Alveolar-capillary dysplasia Other Pulmonary hypertension from chronic thrombotic and/or embolic disease

HIV infection Drugs/toxins

Thromboembolic obstruction of proximal pulmonary arteries

Anorexigens

Obstruction of distal pulmonary arteries

Other

Obstruction of distal pulmonary arteries

Persistent pulmonary hypertension of the newborn Other Pulmonary venous hypertension

Pulmonary embolism (thrombus, tumor, ova and/or parasites, foreign material) In situ thrombosis Sickle cell disease

Left-sided atrial or ventricular heart disease

Pulmonary hypertension caused by disorders directly affecting the pulmonary vasculature

Left-sided valvular heart disease Extrinsic compression of central pulmonary veins

Inflammatory

Fibrosing mediastinitis

Schistosomiasis

Adenopathy/tumors

Sarcoidosis

Pulmonary venoocclusive disease

Other

Other Pulmonary hypertension associated with disorders of the respiratory system and/or hypoxemia

Pulmonary capillary hemangiomatosis

Chronic obstructive pulmonary disease From Rich S (ed): Primary Pulmonary Hypertension: Executive Summary from the World Symposium--Primary Pulmonary Hypertension 1998. Available from the World Health Organization via the Internet (http://www.who.int/ncd/cvd/pph.html).

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Figure 53-12 An algorithm for the management of primary pulmonary hypertension. NYHA = New York Heart Association. (From Rubin LJ: Primary pulmonary hypertension. N Engl J Med 336:111-117, 1997. Copyright © 1997 Massachusetts Medical Society. All rights reserved.)

TREATMENT (Fig. 53-12) LIFE STYLE CHANGES.

The diagnosis of PPH does not necessarily imply total disability for the patient. However, physical activity can be associated with elevated pulmonary artery pressure inasmuch as marked hemodynamic changes have been documented to occur early in the onset of increased physical activity.[136] For that reason, graded exercise activities, such as bike riding or swimming, in which patients can gradually increase their workload and easily limit the extent of their work, are thought to be safer than isometric activities. Isometric activities such as lifting weights or stair climbing can be associated with

syncopal events and should be limited or avoided. The subject of pregnancy should also be discussed with women of childbearing age. The physiological changes that occur in pregnancy can potentially activate the disease and result in death of the mother and/or the child. Besides the increased circulating blood volume and oxygen consumption that will increase right ventricular work, circulating procoagulant factors and the risk of pulmonary embolism from deep vein thrombosis and amniotic fluid are serious concerns. Syncope and cardiac arrest have also been reported to occur during active labor and delivery, and a syndrome of postpartum circulatory collapse has been described.[137] For these reasons, surgical sterilization should be given strong consideration by women with PPH or their husbands. DIGOXIN.

Animal studies performed on the utility of digoxin in right ventricular systolic overload show that prior administration helps prevent the reduction in contractility of the right ventricle. Recently, it has been shown that digoxin can exert a favorable hemodynamic effect when given acutely to patients with right ventricular failure from pulmonary hypertension.[138] An increase in resting cardiac output of approximately 10 percent was noted, which is similar to observations made in patients with left ventricular systolic failure. In addition, it was also observed that digoxin causes a significant reduction in circulating norepinephrine, which was markedly increased. Digitalis toxicity in patients with pulmonary hypertension and normal renal function is uncommon. Consequently, digoxin appears to be a potentially useful medication for patients who have right ventricular failure, either with isolated pulmonary hypertension or in combination with left ventricular systolic failure. DIURETIC THERAPY.

Diuretics appear to be of marked benefit in symptom relief of patients with PPH. Their traditional role has been limited to patients manifesting right ventricular failure and systemic venous congestion. However, patients with advanced PPH can have increased left ventricular filling pressures that contribute to the symptoms of dyspnea and orthopnea, which can be relieved with diuretics. Diuretics may also serve to reduce right ventricular wall stress in patients with concomitant tricuspid regurgitation and volume overload. The fear that diuretics will induce systemic hypotension is unfounded because the main factor limiting cardiac output is pulmonary vascular resistance and not pulmonary blood volume. Patients with severe venous congestion may require high doses of loop diuretics or the use of combined diuretics. In these instances, electrolytes need to be carefully watched to avoid hyponatremia and hypokalemia. SUPPLEMENTAL OXYGEN THERAPY.

Hypoxic pulmonary vasoconstriction can contribute to pulmonary vascular disease in patients with alveolar hypoxia from parenchymal lung disease. Supplemental low-flow oxygen alleviates arterial hypoxemia and attenuates the pulmonary hypertension in

these disorders; in contrast, most patients with PPH do not exhibit resting hypoxemia and derive little benefit from supplemental oxygen therapy. Patients who experience arterial oxygen desaturation with activity, however, may benefit from ambulatory supplemental oxygen because increased oxygen extraction develops in the face of fixed oxygen delivery. Patients with severe right-sided heart failure and resting hypoxemia resulting from markedly increased oxygen extraction at rest should be treated with continuous oxygen therapy to maintain their arterial oxygen saturation above 90 percent.[139] Patients with hypoxemia caused by a right-to-left shunt via a patent foramen ovale do not improve their level of oxygenation to an appreciable degree with supplemental oxygen.

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VASODILATOR TREATMENT.

Because of early reports showing a reduction in pulmonary artery pressure following the acute administration of vasodilators, it has been presumed that vasodilators are the mainstay of treatment in patients with PPH. This presumption, however, is not supported by the published literature over the past two decades. Vasodilators appear to be effective in a subset of patients with PPH, but many complexities regarding vasodilator administration make their use in these patients very difficult. The first principle in using vasodilators in patients with PPH is to establish accurate baseline hemodynamics. Because substantial hemodynamic variability has been reported to exist in the pulmonary vascular bed and will produce changes in cardiac output and pulmonary artery pressure from moment to moment, serial baseline recordings are required to evaluate the magnitude of change in hemodynamics that may be attributed to variability rather than to drug effect. [140] The practice of attributing "peak" effect of the drug to an administered agent introduces bias into the assessment. Thus, by choosing the highest level of pulmonary artery pressure as the baseline and the subsequent lowest one as drug effect, one may be misled to attribute a favorable influence from a medication when in fact no effect or even an adverse one is occurring. It must also be emphasized that hemodynamic assessment of the entire circulatory system is essential when determining the influence of drugs in these patients. Small changes in pulmonary artery pressure are probably due to variability and are not related to direct drug influence. Changes in pulmonary vascular resistance cannot be directly measured but are computed by the change in pulmonary pressure and cardiac output simultaneously. Because thermodilution cardiac output, the method that is most commonly used in these patients, can be associated with large errors in reproducibility, particular care should be taken in the methodology of thermodilution used in these patients. In addition, when an underlying right-to-left shunt exists or severe tricuspid regurgitation is a concern, the Fick determination of cardiac output is preferred. Changes in pulmonary capillary wedge pressure can have important influences on the determination of pulmonary vascular resistance. A rising capillary wedge pressure secondary to increased cardiac output may be the first sign of impending left ventricular

failure and an adverse effect of a drug, whereas the calculated pulmonary vascular resistance may become lower and suggest a beneficial effect. Right atrial pressure also reflects the filling characteristics of the right ventricle. A right atrial pressure increase in the face of rising cardiac output suggests right ventricular diastolic dysfunction. [141] The resting heart rate is a physiological parameter of marked importance in patients with congestive heart failure, and treatments that cause an increased heart rate are likely to yield deleterious long-term results. Finally, the systemic arterial oxygen content should be evaluated in patients with PPH. Effective vasodilator drugs can result in vasodilatation of blood vessels supplying poorly ventilated areas of the lung and worsen hypoxemia. This effect is particularly noticeable in patients with underlying chronic lung disease. For all these reasons it has been advocated that vasodilators be initiated only in the hospital setting with central catheter placement for direct hemodynamic recordings and never initiated in the outpatient setting.[139] [142] ACUTE TESTING WITH INTRAVENOUS VASODILATORS (Table 53-5)

Intravenous vasodilators may be of value in the short-term assessment of pulmonary vasodilator reserve in patients with PPH.[139] Historically, tolazoline received attention as an agent to acutely test the responsiveness of the pulmonary vascular bed in patients with pulmonary hypertension from several causes. However, it is poorly tolerated acutely because of its side effects and has largely been replaced by other agents. Acetylcholine was one of the first medications used to evaluate patients with PPH. It is rapidly inactivated by the lung, which explains why intravenous administration seems to produce selective pulmonary vasodilator effects. Although it has been reported to produce substantial acute reductions in pulmonary artery pressure in some patients, chronic therapy with this drug is not feasible. Isoproterenol is a potent beta-adrenergic agent that affects both the systemic and pulmonary vascular beds and increases cardiac output by chronotropic and inotropic mechanisms. It is considered a pulmonary vasodilator because it results in lowering of the calculated pulmonary vascular resistance. However, it rarely results in substantial lowering of pulmonary artery pressure in patients with pulmonary hypertension because of its more direct effect in increasing cardiac output. Phentolamine is a potent alpha-adrenergic blocker that has been shown to cause pulmonary vasodilatation in animals and humans. Its widespread use is limited by the profound systemic hypotension that occurs upon administration, and it is not generally used in the evaluation of PPH. Sodium nitroprusside is a potent vasodilator that acts on arterial and venous beds. Its short half-life is also an advantage because the effects rapidly dissipate when infusion of the drug is stopped. Like phentolamine, its use as a test of vasodilator reserve is limited by the marked lowering of systemic blood pressure that occurs. ADENOSINE.

This substance is an intermediate product in the metabolism of adenosine triphosphate that has potent vasodilator properties through its action on specific vascular receptors. In addition to pulmonary vasodilatation, it can also produce systemic and coronary vasodilatation. It is believed to stimulate the endothelial cell and vascular smooth muscle receptors of the A2 type, which induce vascular smooth muscle relaxation by increasing cyclic adenosine monophosphate.[143] In patients with PPH, adenosine has

been shown to be an extremely potent vasodilator and predictive of the subsequent effects of intravenous prostacyclin and oral calcium channel blockers.[144] [145] Adenosine has an extremely short half-life (less than 5 seconds), which provides a safety net by its rapid dissolution should any adverse side effects occur. It is administered intravenously in doses of 50 ng/kg/min and titrated upward every 2 minutes until uncomfortable symptoms develop (such as chest tightness or dyspnea). It should be noted that adenosine is given as an infusion and not as an TABLE 53-5 -- HEMODYNAMIC ASSESSMENT OF VASODILATORS IN PULMONARY HYPERTENSION PARAMETER DESIRED ACUTE COMMENTS MEASURED CHANGES Mean pulmonary artery pressure

>25% fall; ideally mean PAP below 30 mm Hg

Must not be any associated significant fall in systemic blood pressure

Pulmonary vascular resistance

>33% fall; ideally, PVR below 6 units

Should be associated with a fall in PA pressure and an increase in cardiac output. An increase in cardiac output alone may lead to future RV failure

Right atrial pressure

No change or fall

An increase in RA pressure signals impending RV failure

Pulmonary capillary wedge pressure

No change

An increase in wedge pressure suggests pulmonary venoocclusive disease or coexisting LV dysfunction

Systemic blood pressure

Minimal fall; mean arterial pressure should remain above 90 mm Hg

A significant hypotensive response makes chronic vasodilator therapy contraindicated

Cardiac output

Increase

The increase should be related to increased stroke volume and not solely due to increased heart rate

Heart rate

No significant change A chronic increased heart rate will result in RV failure. Watch for bradycardia if high doses of diltiazem are used

Systemic arterial oxygen saturation

Increase if reduced on room air, little change if normal

A fall in systemic arterial oxygen saturation suggests lung disease or right-to-left shunting and prohibits chronic use

Pulmonary artery (mixed venous)oxygen saturation

Increase

Should reflect the increase in cardiac output and improved tissue oxygenation

LV=left ventricular; RA=right atrial; RV=right ventricular.

Reprinted from Rubin LJ, Rich S: Medical management. In Rubin LJ, Rich S (eds): Primary Pulmonary Hypertension. New York, Marcel Dekker, 1997, pp 271-286 by courtesy of Marcel Dekker, Inc.

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intravenous bolus as is used to treat supraventricular tachyarrhythmias. PROSTACYCLIN.

This substance (epoprostenol sodium, or PGI2 ) is a metabolite of arachidonic acid that is synthesized and released from vascular endothelium and smooth muscle. Its vasodilatory effects are thought to be mediated by activation of specific membrane PGI2 receptors that are also coupled to the adenylate cyclase system. [28] Other effects include inhibition of platelet activation and aggregation, as well as leukocyte adhesion to the endothelium.[146] Prostacyclin has been used as an acute test of vasodilator reserve in patients with PPH. Like adenosine, its short half-life allows use of the drug to be discontinued if any acute adverse effects result. Also similar to adenosine, it is administered incrementally, at 2 ng/kg/min and increased every 15 to 30 minutes until systemic effects such as headache, flushing, or nausea occur, which limits the acute dose titration. Favorable acute effects from prostacyclin appear to be predictive of a favorable response to oral calcium channel blockers.[147] Adenosine and prostacyclin possess potent inotropic properties, in addition to their ability to vasodilate the pulmonary vascular bed. When using these drugs for the acute testing of patients, one needs to pay particular attention to changes in cardiac output that occur in association with the changes in pulmonary arterial pressure. An increase in cardiac output with no change in pulmonary arterial pressure will result in a reduction in calculated pulmonary vascular resistance and may be erroneously interpreted as a vasodilator response. Instead, one should look at the magnitude of change of each individual parameter to determine the effects that the drug is having on the pulmonary circulation, as well as the type of response that it elicits. NITRIC OXIDE.

This substance, whose activity is identical to that of endothelium-derived relaxing factor, is produced from L-arginine by NO synthase.[148] NO diffuses to vascular smooth muscle and mediates vasodilatation by stimulating soluble guanylate cyclase to produce cyclic GMP. Because it binds very rapidly to hemoglobin with high affinity and is thereby inactivated, inhalation of NO gas results in selective pulmonary vascular effects without influencing the systemic circulation. Inhalation of NO by patients with PPH has been shown to produce a reduction in pulmonary vascular resistance acutely, similar to that achieved with intravenous adenosine, and to also predict the effectiveness of calcium channel blockers.[149] [150] NO has also been shown to be effective in patients with pulmonary hypertension secondary to congenital heart disease and the adult respiratory

distress syndrome.[151] Although NO seems to have similar acute effects on pulmonary arterial pressure that are predictive of the chronic response to oral vasodilator agents, it differs importantly from adenosine and prostacyclin in that it has little effect on cardiac output. Chronic Treatment CALCIUM CHANNEL BLOCKERS.

Of the vasodilators tested in patients with PPH, calcium channel blockers appear to have the widest usage. Early studies using conventional doses failed to demonstrate a chronic sustained benefit. Moreover, calcium channel blockers have properties that could worsen the underlying pulmonary hypertension, including negative inotropic effects on right ventricular function (Fig. 53-13) and reflex sympathetic stimulation, which may increase the resting heart rate.[141] It has been reported that patients with PPH who are challenged with very high doses of calcium channel blockers may manifest a dramatic reduction in pulmonary artery pressure and pulmonary vascular resistance, which upon serial catheterization has been maintained for over 5 years.[122] Importantly, the patient's quality of life is restored with improved functional class, and survival (94 percent rate at 5 years) is improved when compared with nonresponders and historical control subjects (36 percent rate) (Fig. 53-14 A). This experience suggests that some patients with PPH have the ability to have their pulmonary hypertension reversed and their quality of life and survival enhanced. It is unknown whether the response to calcium channel blockers identifies two subsets of patients with PPH, different stages of PPH, or a combination of both. However, it is essential to point out that patients who do not exhibit a dramatic hemodynamic response to calcium channel blockers do not appear to benefit from their long-term administration. Unfortunately, it is becoming common practice for physicians to prescribe calcium channel blockers at conventional doses to all patients with pulmonary hypertension, often without hemodynamic guidance. This unfortunate practice may result in quicker deterioration in these patients and should be strongly discouraged. CHRONIC PROSTACYCLIN INFUSION THERAPY.

Continuous-infusion prostacyclin therapy has now been shown in prospective randomized trials to improve quality of life and symptoms related to PPH, exercise tolerance, hemodynamics, and survival.[133] [152] [153] [154] [155] (Fig. 53-14 B). The initial enthusiasm for prostacyclin was based on the demonstration of pulmonary vasodilator effects when administered to experimental animals with acute pulmonary vasoconstriction and when subsequently administered to patients with PPH. The long-term effects of prostacyclin in PPH include its vasodilator and antithrombotic effects, but its effects may also be importantly related to its ability to restore the integrity of the pulmonary vascular endothelium. A recent study revealed that significant reductions in pulmonary vascular resistance that go beyond acute vasodilation were the rule in the patients treated with intravenous prostacyclin for 1 year.[155] On average, patients had a reduction in pulmonary vascular resistance of greater than 50 percent which occurred even if no acute hemodynamic effects were noted (Fig. 53-15) .

Prostacyclin is generally administered through a central venous catheter that is surgically implanted and delivered by an ambulatory infusion system. The delivery system is complex and requires patients to learn the techniques of sterile drug preparation, operation of the pump, and care of the intravenous catheter. Most of the serious complications that have occurred with prostacyclin therapy have been attributable to the delivery system and include catheter-related infections and thrombosis and temporary interruption of the infusion because of pump malfunction. Anecdotal reports of rebound pulmonary hypertension occurring in patients in whom the infusion was interrupted suggest

Figure 53-13 Adverse effects of calcium channel blockers in pulmonary hypertension. The hemodynamic effects of verapamil and nifedipine in patients with pulmonary hypertension are shown. An increase in right atrial pressure in association with no significant change in cardiac index as produced by nifedipine suggests that right ventricular dysfunction is occurring. The increased right atrial pressure associated with a fall in cardiac index, as produced by verapamil, suggests that negative inotropic effects are producing overt right ventricular failure. (Adapted from Packer M, Medina N, Yushak M: Adverse hemodynamic and clinical effects of calcium channel blockade in pulmonary hypertension secondary to obliterative pulmonary vascular disease. Am Coll Cardiol 4:890, 1994.)

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Figure 53-14 A, Effect of high doses of calcium channel blockers on survival over 5 years in patients with primary pulmonary hypertension (PPH). Patients who responded to the high-dose regimen (open circles) had a 95 percent 5-year survival rate, as opposed to the nonresponders (solid line), who had a 36 percent 5-year survival rate. Rates were similar in patients studied in the National Institutes of Health (NIH) Registry on PPH (triangles), as well as patients from the University of Illinois only (solid circles). B, Effect of intravenous prostacyclin (PGI2 ) on survival in patients with PPH. The survival of patients given a chronic infusion of prostacyclin and monitored for 5.5 years is compared with that of functional Class III and IV patients from the NIH Registry (historical controls). C, Effects of anticoagulation on survival in patients with PPH who did not respond to calcium channel blockers. Patients who received warfarin (open circles) had a marked survival advantage over those who received no warfarin. (A and C from Rich S, Kaufmann E, Levy PS: The effects of high doses of calcium channel blockers on survival of primary pulmonary hypertension. N Engl J Med 327:76, 1992. Copyright © 1992 Massachusetts Medical Society. All rights reserved. B from Barst RJ, Rubin LJ, McGoon MD et al: Survival of primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med 121:409, 1994.)

that great care must be taken to ensure that the infusion is never stopped. Side effects related to prostacyclin therapy include flushing, headache, nausea, diarrhea, and a unique type of jaw discomfort that occurs with eating. In most patients, these symptoms are minimal and well tolerated. Chronic foot pain and a poorly defined gastropathy with prolonged use develop in some patients. Tachyphylaxis to the drug develops at low doses and therefore may require a periodic dose increase to maintain its efficacy. To date, chronic prostacyclin has been given to patients with PPH for over

10 years with continued favorable effectiveness. In some patients (Class IV) who are critically ill, it serves as a bridge to lung transplantation by stabilizing the patient to a more favorable preoperative state. Patients who are less critically ill may do so well with prostacyclin therapy that they may delay the need to consider transplantation, perhaps indefinitely. A high-cardiac output state has been reported in a large series of patients with PPH receiving chronic prostacyclin therapy and is consistent with the drug having positive inotropic effects.[156] Whether the effect is a direct one on the myocardium or indirect via neurohormonal activation has not been determined. Although most patients with PPH have reduced cardiac output on initial examination, the development of a chronic high-output state could have long-term detrimental effects on underlying cardiac function. The follow-up assessment of patients receiving intravenous prostacyclin is quite variable from medical center to medical center, but it does appear important to determine the cardiac output response to therapy periodically to optimize dosing.[157]

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Figure 53-15 Long-term reduction in pulmonary vascular resistance (PVR) with chronic therapy with epoprostenol (prostacyclin) for primary pulmonary hypertension (PPH) in relation to the short-term reduction after the administration of adenosine. Although patients with the greatest short-term reduction in PVR had the greatest long-term reduction, patients who had little or no reduction acutely still had a significant reduction in PVR with long-term therapy. This finding suggests that mechanisms other than acute vasodilatation are responsible for the long-term benefit of intravenous prostacyclin therapy in PPH and supports the notion that reversal of pulmonary vascular remodeling is occurring. (From McLaughlin VV, Genthner DE, Panella MM, et al: Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med 338:273-277, 1998. Copyright © 1998 Massachusetts Medical Society. All rights reserved.) ANTICOAGULANTS.

Oral anticoagulant therapy is widely recommended for patients with PPH, although its clinical efficacy as a therapy is difficult to prove. A retrospective review of patients with PPH monitored over a 15-year period at the Mayo Clinic suggested that patients who received warfarin had improved survival over those who did not.[57] The influence of warfarin therapy has been investigated in patients with PPH who failed to respond to high doses of calcium channel blockers.[119] Significant improvement in survival was observed in patients who received anticoagulation, with a 1-year survival rate of 91 percent and 3-year survival rate of 47 percent as compared with 1- and 3-year rates of 62 and 31 percent, respectively, in patients who did not receive anticoagulants (Fig. 53-14 C). The current recommendation is to use warfarin in relatively low doses, as has been recommended for prophylaxis of venous thromboembolism, with the international normalized ratio maintained at 2.0 to 2.5 times control.[156] Given its inhibitory effects on smooth muscle proliferation, heparin might be a suitable anticoagulant in PPH, although its use is more difficult. With the recent advent of low-molecular-weight heparins requiring once-a-day administration without the need for adjusting the dose to its

antithrombotic effect, treatment with these agents is becoming a more viable alternative. They may be particularly useful in patients who are believed to be at increased risk for pulmonary thromboembolism. ATRIAL SEPTOSTOMY

The rationale for the creation of an atrial septostomy in PPH is based on experimental and clinical observations suggesting that an intraatrial defect allowing right-to-left shunting in the setting of severe pulmonary hypertension might be of benefit. Although over 60 patients have undergone this procedure worldwide, it should still be considered investigational.[159] [160] [161] [162] Nonetheless, atrial septostomy may represent a real alternative for selected patients with severe PPH. Indications for the procedure include recurrent syncope and/or right ventricular failure despite maximum medical therapy, as a bridge to transplantation if deterioration occurs in the face of maximum medical therapy, or when no other option exists.[162] Because the disease process in PPH appears to be unaffected by the procedure, the long-term effects of atrial septostomy must be considered palliative. The procedure-related mortality with atrial septostomy in patients with PPH is high, and thus it should be attempted only in institutions with an established track record in the treatment of advanced pulmonary hypertension and experience in performing atrial septostomy with low morbidity.[161] It should not be performed in a patient with impending death and severe right ventricular failure or a patient receiving maximum cardiorespiratory support. Predictors of procedure-related failure or death have been identified and include a mean right atrial pressure of greater than 20 mm Hg, a pulmonary vascular resistance index of greater than 55 units m2 or a predicted 1-year survival rate of less than 40 percent. The mechanisms responsible for the beneficial effects of atrial septostomy remain unclear. Possibilities include increased oxygen delivery at rest and/or with exercise, reduced right ventricular end-diastolic pressure or wall stress, improvement in right ventricular function by the Frank Starling mechanism, or relief of ischemia. HEART-LUNG AND LUNG TRANSPLANTATION. (see also Chap. 20) .

Heart-lung transplantation has been performed successfully in patients with PPH since 1981.[163] Because these patients have pulmonary vascular disease and severe right ventricular dysfunction, it was originally believed that heart-lung transplantation was the only transplantation option. Widespread application of heart-lung transplantation, however, has been limited by the number of centers with expertise to perform the procedure, the scarcity of suitable donor organs, and the very long waiting times required for TABLE 53-6 -- GENERAL GUIDELINES FOR SELECTION OF LUNG TRANSPLANT RECIPIENTS Indications

Advanced obstructive, fibrotic, or pulmonary vascular disease with a high risk of death within 2 to 3 yr Lack of success or availability of alternative therapies Severe functional limitation but preserved ability to walk Age 55 yr or less for candidates for heart-lung transplantation, age 60 yr or less for candidates for bilateral lung transplantation, and age 65 yr or less for candidates for single-lung transplantation Absolute Contraindications Severe extrapulmonary organ dysfunction, including renal insufficiency with a creatinine clearance below 50 ml/min, hepatic dysfunction with coagulopathy or portal hypertension, and left ventricular dysfunction or severe coronary artery disease (consider heart-lung transplantation) Acute, critical illness Active cancer or recent history of cancer with substantial likelihood of recurrence (except for basal cell and squamous cell carcinoma of the skin) Active extrapulmonary infection (including infection with HIV, hepatitis B, hepatitis C) Severe psychiatric illness, noncompliance with therapy, and drug or alcohol dependence Active or recent (preceding 3 to 6 mo) cigarette smoking Severe malnutrition (130% of ideal body weight) Inability to walk, with poor rehabilitation potential Relative Contraindications Chronic medical conditions that are poorly controlled or associated with target organ damage Daily requirement for more than 20 mg of prednisone (or equivalent) Mechanical ventilation (excluding noninvasive ventilation) Extensive pleural thickening from prior thoracic surgery or infection Active collagen-vascular disease Preoperative colonization of the airways with pan-resistant bacteria (in patients with cystic fibrosis) From Arcasoy SM, Kotloff RB: Lung transplantation. N Engl J Med 340:1081-1091, 1999. Copyright © 1999 Massachusetts Medical Society. All rights reserved.

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patients with end-stage right-sided heart failure. More recently, bilateral or double-lung transplantation and single-lung transplantation have been performed successfully in patients with PPH.[164] Hemodynamic studies have shown an immediate reduction in pulmonary artery pressure and pulmonary vascular resistance associated with improvement in right ventricular function.[165] The ages of recipients of heart-lung and lung transplantation for pulmonary hypertension have ranged from 2 months to 61 years.[166] Operative mortality ranges

between 16 and 29 percent and is somewhat higher for recipients of a single-lung transplant. The 1-year survival rate is between 70 and 75 percent, the 2-year survival rate is between 55 and 60 percent, and the 5-year survival rate is between 40 and 45 percent. Transplantation should be reserved for patients with pulmonary hypertension who have progressed in spite of optimal medical management.[167] (Table 53-6) . Patients should be referred for evaluation for transplantation at the appropriate time. [168] The course of the disease and the waiting time must be taken into account, as well as other factors such as the anticipated waiting time before transplantation in the region and the expected survival after transplantation. It is generally accepted that patients should be considered for transplantation when they are New York Heart Association Functional Class III or IV in spite of medical therapy or when treatment with prostacyclin is failing or causing intolerable side effects. The major long-term complications in patients who survive the operation are the high incidence of bronchiolitis obliterans in the transplanted lungs, acute organ rejection, and opportunistic infection.[169] Although several studies have documented significant improvement in quality of life after heart-lung and lung transplantation for pulmonary hypertension, cost-effectiveness has not yet been addressed. In many patients, prostacyclin may prove to be an ideal bridge to keep patients alive and stable until organs become available.[170]




Secondary Pulmonary Hypertension Although PPH is relatively rare, with an estimated incidence of 1 to 2 per million in the population, severe pulmonary arterial hypertension associated with other conditions is more common[171] [172] [173] [174] [175] [176] [177] (Table 53-7) . The most common etiology is associated with collagen-vascular disease states, primarily scleroderma, including the CREST syndrome (calcinosis cutis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia), and mixed connective tissue disease.[172] Pulmonary arterial hypertension is also relatively common in patients with congenital heart defects, especially those with ventricular septal defects or a patent ductus arteriosus.[174] Other major etiologies include cirrhosis with portal hypertension and HIV infection.[97] [177] In some instances, increased resistance to pulmonary blood flow downstream leads to what has been referred to as "passive" pulmonary hypertension because in many cases, elevation in pulmonary artery pressure but no significant elevation in pulmonary vascular resistance is observed. Reactive pulmonary hypertension often coexists in these states, with pulmonary artery pressure and pulmonary vascular resistance elevated to levels higher than can be accounted for purely by increased downstream resistance to blood flow. In some instances, relieving the downstream obstruction results in normalization of pulmonary artery pressure and pulmonary vascular resistance, whereas in other instances it may not. Failure of normalization has been believed to be related to chronicity of the reactive pulmonary hypertension leading to irreversible vascular changes, although this hypothesis has never been proved. When reactive pulmonary hypertension occurs, it often results in right ventricular failure, which can predominate in the patient's clinical symptomatology and lead to marked deterioration in functional class and death. PULMONARY HYPERTENSION ASSOCIATED WITH COLLAGEN-VASCULAR DISEASES (see alsoChap. 67)

Scleroderma, either from progressive systemic sclerosis or the CREST syndrome, is the most common etiology of pulmonary hypertension in collagen-vascular disease states.[171] [172] Scleroderma is associated with pulmonary hypertension in as many as one-third of patients, and CREST syndrome in as many as 50 percent. [172] [178] The high incidence suggests that periodic screening with echocardiography in these patients may be a reasonable practice. Although pulmonary hypertension may occur as a result of entrapment and obstruction of the pulmonary microvasculature by interstitial inflammation or fibrosis, patients initially seen with severe pulmonary hypertension usually do not have evidence of interstitial lung disease and have a pulmonary vasculature with histological features that resemble those of PPH.[179] Patients with systemic lupus erythematosus may also have pulmonary hypertension, although less common than in scleroderma. On occasion, pulmonary hypertension may precede the clinical diagnosis of lupus by several years. Mixed connective tissue disease is a less common form of collagen-vascular disease, but pulmonary hypertension may occur in as many as two-thirds of these patients. Pulmonary hypertension has also been described in patients with polymyositis, dermatomyositis, and rheumatoid arthritis. Because collagen-vascular diseases may have an insidious onset and slowly progressive course, early recognition of the symptoms of pulmonary hypertension may be difficult. Although easy fatigability may be a feature of the collagen-vascular disease, it may also be an initial symptom of pulmonary hypertension. Dyspnea is still the most common initial symptom and should not be attributed to advancing age. Syncope, presyncope, or peripheral edema represents advanced pulmonary hypertension and right-sided heart failure. Physical findings of an elevated jugular venous pressure and an increased pulmonic component of the second heart sound along with a right ventricular fourth heart sound are typical features of pulmonary hypertension and warrant an evaluation for pulmonary hypertension. A murmur of tricuspid regurgitation generally reflects more advanced disease. Arterial hypoxemia is characteristic and should also prompt an evaluation of possible pulmonary hypertension in these patients. The prognosis of patients with collagen-vascular disease in whom pulmonary hypertension develops is very poor.[179] Conventional therapy with digitalis, diuretics, and supplemental oxygen is used, and TABLE 53-7 -- ADVANCED PULMONARY HYPERTENSION BY DISEASE CATEGORY DISEASE PREVALENCE PERCENTAGE OF ESTIMATED NUMBER PATIENTS WITH PH IN NORTH AMERICA AND EUROPE Systemic sclerosis

190/million

33

37,620

Congenital heart defects (ASD/VSD/PDA)

300/million

15-20

31,500

Cirrhosis

1600/million

0.6

5760

HIV related

2500/million

0.5

7500

Primary PH

7/million

100

4200

ASD=atrial septal defect; PDA=patent ductus arteriosus; PH=pulmonary hypertension; VSD=ventricular septal defect.

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Figure 53-16 Mean pulmonary artery pressure (top) and pulmonary vascular resistance (bottom) before and after prostacyclin therapy in patients with secondary pulmonary hypertension. White bars indicate patients with congenital heart disease, striped bars indicate patients with collagen-vascular disease, and black bars indicate patients with portopulmonary hypertension. * p16 mm Hg) and an enlarged main pulmonary artery on the PA projection are indicative of pulmonary artery hypertension in patients with COPD.

or right ventricular dysfunction in patients with chronic obstructive pulmonary disease (COPD), because clinical signs are often obscured by hyperinflation of the chest. The jugular venous pressure may also be difficult to assess in patients with COPD because of large swings in intrathoracic pressure. A systolic left parasternal heave indicates right ventricular hypertrophy, whereas the murmur of tricuspid regurgitation suggests right ventricular dilatation, but these are not always present and may be modified by hyperinflation. Accentuation of the pulmonic component of the second heart sound indicating pulmonary hypertension is a specific but insensitive finding in patients with COPD. Peripheral edema can be due to other causes (such as hypoalbuminemia) and

does not always occur in patients with pulmonary hypertension. A progressive decrease in exercise tolerance in the absence of worsening pulmonary function should suggest a cardiovascular cause and prompt a thorough evaluation. CHEST RADIOGRAPH

(Fig. 54-2) . The presence of pulmonary arterial hypertension in patients with COPD has been shown to be related to the width of the right descending pulmonary artery. A right descending pulmonary artery ranging from greater than 16 mm Hg in its widest dimension[41] to greater than 20 mm Hg has been reported to identify patients with pulmonary arterial hypertension.[42] In addition, a high value for the cardiothoracic ratio was 95 percent sensitive and 100 percent specific for the presence of pulmonary hypertension in patients with COPD.[42] Although measurements on plain chest radiography may be useful as an initial screening test for the presence of pulmonary arterial hypertension, they cannot be used to predict the level of pulmonary arterial pressure in individual patients. Dilatation of the right ventricle gives the heart a globular appearance, but right ventricular hypertrophy or dilatation is not easily discernible on a plain chest radiograph. Encroachment of the retrosternal air space on the TABLE 54-2 -- FREQUENTLY USED ECG CRITERIA FOR RIGHT VENTRICULAR HYPERTROPHY Right-axis deviation>110° R/S ratio in V1 >1 R wave in V1 7 mm S wave in V1 10.5 mm R/S ratio in V5 or V6 1 Onset of intrinsicoid deflection in V1 = 0.035-0.055 second rSR1 in V1 with R1 10 mm Adapted from Chou T-C: Right ventricular hypertrophy. In: Electrocardiography in Clinical Practice. Philadelphia, WB Saunders 1991, pp 53-68. lateral film may be a helpful sign to confirm that the enlarged silhouette is a result of right ventricular dilatation. ELECTROCARDIOGRAPHY.

The detection of right ventricular hypertrophy by the electrocardiogram (ECG) is highly specific but has a low sensitivity (see Chap. 5 ). Frequently used criteria for the diagnosis of right ventricular hypertrophy are outlined in Table 54-2 . However, these ECG abnormalities are usually less pronounced in COPD than other forms of pulmonary hypertension because of the relatively modest degree of pulmonary hypertension that occurs and because of the effects of hyperinflation (Fig. 54-3) . Butler and coworkers have introduced three criteria for right ventricular hypertrophy: (1) P wave amplitude 0.01) and pulmonary vascular resistance (r = 0.65, p > 0.01).[54] Interestingly, the right ventricular free-wall volume as an estimate of wall mass correlates with the PaCO2 but not with the PaO2 .[54] MRI can be used to diagnose right ventricular hypertrophy in patients with COPD and to study the effect of therapeutic interventions. It can also be used to quantify regional right ventricular function to determine the impact of chronic pulmonary hypertension on right ventricular performance.[55] PULMONARY HYPERTENSION ASSOCIATED WITH RESPIRATORY DISORDERS Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease is the fourth leading cause of death in the United States, affecting over 14 million people.[56] The incidence, morbidity, and mortality from COPD is rising and varies widely among countries. In fact, the mortality attributed to COPD in the United States rose by 32 percent during the past decade.[56] This may be related to differences in exposure to risk factors as well as to large variations in individual susceptibility. COPD is a heterogeneous group of diseases that share a common feature: the airways are narrowed, which causes the inability to exhale completely. Although there are numerous disorders that fall under the heading of COPD, the two largest components are emphysema and chronic bronchitis. The American Thoracic Society defines COPD as a disorder characterized by abnormal tests of expiratory flow that do not change markedly either spontaneously over short periods of time or after administration of a bronchodilator.[57] Although clear-cut distinctions can often be made, there is considerable overlap as to the dominant abnormality in the individual patient in whom features of both may be manifest. Chronic bronchitis is a condition associated with excessive tracheal bronchial mucous production sufficient to cause cough with expectoration for at least 3 months of the year for more than 2 consecutive years. Emphysema is defined as the permanent, abnormal distention of the air spaces distal to the terminal bronchial with destruction of the alveolar septa. In lungs from patients with COPD studied at postmortem, the major site of air flow obstruction has been shown to be in the small airways. Cigarette smoking is the most commonly identified correlate with COPD and accounts for 80 to 90 percent of the

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risk of developing COPD.[58] It has been estimated that 15 percent of one-pack-per-day smokers and 25 percent of two-pack-per-day smokers will eventually develop COPD during their lifetime.[58] [59] Why the proportion is so small is not known, but underlying host factors may play a role. Other potential environmental causes include air pollution, occupational exposures, and infection. Individuals who are homozygous for alpha1 -antitrypsin deficiency develop severe emphysema in the third and fourth decades of life. Dusty occupational environments are well-established risks but probably not major factors in North America. PATHOPHYSIOLOGY OF PULMONARY HYPERTENSION.

Most commonly, pulmonary hypertension in COPD is due to multiple factors, which include pulmonary vasoconstriction caused by alveolar hypoxia, acidemia, and hypercarbia; the mechanical effects of the high lung volume on pulmonary vessels; the loss of small vessels in the vascular bed in regions of the emphysema and lung destruction; and the increased cardiac output and blood viscosity from polycythemia secondary to hypoxia. Of these causes, hypoxia is undoubtedly the most important and is associated with pathological changes that occur characteristically in the peripheral pulmonary arterial bed.[60] The small pulmonary arteries develop accumulations of vascular smooth muscle cells in their intima that are laid down longitudinally along the length of the vessels. Intimal thickening appears to be an early event that occurs in association with progressive air flow limitation.[61] Medial hypertrophy in the muscular pulmonary arteries, and less commonly fibrinoid necrosis in these vessels, has also been reported in patients with COPD with chronic pulmonary arterial hypertension. Thus, structural change, rather than hypoxic vasoconstriction, is required for the development of sustained pulmonary hypertension in patients with COPD.[62] Changes in airway resistance may augment pulmonary vascular resistance in patients with COPD by affecting the alveolar pressure. The normal linear relationship between pressure and flow in the pulmonary circulation changes when alveolar pressure is increased. The effect of airway resistance on pulmonary artery pressure may be particularly important when ventilation increases (such as in acute exacerbation of COPD). In patients with COPD, even the small increases in flow that occur during mild exercise may increase pulmonary artery pressure significantly. Alveolar hypoxia is a potent arterial constrictor in the pulmonary circulation, which reduces perfusion with respect to ventilation in an attempt to restore PaO2 . In patients with COPD there is a positive correlation between the PaCO2 and the pulmonary artery pressure. Polycythemia, which may develop in response to chronic hypoxemia, increases the blood viscosity, which may also contribute to the severity of pulmonary arterial hypertension. Pulmonary arterial thrombosis may also occur in patients with COPD and may be a result of peripheral airway inflammation. HEMODYNAMIC CHANGES.

The elevation in pulmonary artery pressure tends to be rather mild in patients with COPD. Naeije studied 74 patients with severe, but clinically stable COPD. All presented with episodes of acute and chronic respiratory failure in the past, and almost half presented with peripheral edema.[63] They all had severe air flow limitations (FEV1 25.7 ± 1 percent of predicted) and hypoxemia (PaO2 mean 43 mm Hg, range 23 to 67 mm Hg), and the majority were also hypercapnic (PaCO2 mean 51 mm Hg, range 33 to 68 mm Hg). However, the pulmonary artery pressure was only modestly raised to a mean of 35 mm Hg in this group. Although the pulmonary artery pressure may be normal or only slightly elevated when measured at rest in patients with COPD, it may increase to abnormal levels during exercise.[64] The progression of pulmonary hypertension seems to be related to hypoxemia. In 93 patients with COPD observed for 5 years, hemodynamic worsening, defined as an increase in mean pulmonary artery pressure by more than 5 mm Hg, was observed in 29 percent of patients.[65] In these patients there was a marked worsening of hypoxemia that was not observed in the others. In patients with mild COPD, right ventricular end-diastolic pressure and right ventricular stroke work, which were normal at rest, increased during exercise due to an increase in work against a higher pulmonary artery pressure.[66] Severe pulmonary arterial hypertension is uncommon in the presence of COPD. In a review of 500 patients referred with cor pulmonale, only 6 were found to have severe elevation in mean pulmonary artery pressure (>50 mm Hg), which was not related to the severity of their underlying lung disease.[67] This observation suggests that a different biological mechanism results in changes in the pulmonary vascular bed in susceptible patients and that pulmonary hypertension occurs in the presence of lung disease rather than as a result of the lung disease. This has important implications with respect to treatment. Patients who present with severe pulmonary hypertension should be evaluated for another disease process that is responsible for the high pulmonary arterial pressures before attributing it to the COPD. PROGNOSIS AND PREDICTORS OF SURVIVAL.

Although pulmonary arterial hypertension progresses slowly in patients with COPD, its presence confers a poor prognosis. Weitzenblum and coworkers showed a 72 percent 4-year survival rate in those with normal pulmonary artery pressure compared with a 49 percent survival rate in those with an elevated pulmonary artery pressure (mean > 20 mm Hg).[68] Burrows and colleagues studied 50 patients with chronic airway obstruction over 7 years and showed that the pulmonary vascular resistance was the hemodynamic parameter that correlated best with mortality. [69] In this study, none of the patients whose pulmonary vascular resistance exceeded 7 Wood Units survived for more than 3 years. France and colleagues, in a study of 115 patients with COPD, found that a number of variables correlated significantly with mortality, including PaO2 , PaCO2 , FEV1, and the presence of peripheral edema.[70] Others have reported that patients with COPD who develop peripheral edema have a 5-year survival rate of only 27 to 33 percent. [71]

A 10-year follow-up study conducted on a cohort of 870 patients with severe COPD concluded that (1) patients with COPD have a high mortality rate from acute respiratory failure, cor pulmonale, and lung cancer; (2) patients' age at the time of diagnosis influences the death hazard; (3) patients who need long-term oxygen treatment have a higher death hazard than those who do not; (4) the higher the FEV1 or PaO2 at the time of diagnosis, the lower the death hazard; (5) patients who need and use long-term oxygen treatment have a lower death hazard compared with those who need it but do not use it properly; and (6) patients with a partial reversible airway obstruction who regularly attend the clinic for planned checkups have a lower death hazard compared with those who have the same characteristics but do not show adherence to the care program.[72] In another study, among a cohort of 270 patients with COPD, the median survival was 3.1 years. Death was predicted by the following variables: age, ECG signs of right ventricular hypertrophy, chronic renal failure, ECG signs of myocardial infarction or ischemia, and FEV1 less than 590 ml.[73] Among 166 patients treated with long-term oxygen therapy, the overall survival rates were 78.3 percent and 67.1 percent at 2 and 3 years, respectively. A multivariate analysis showed an independent predictive power for right ventricular systolic pressure, age, and FEV1 .[74] Once endotracheal intubation is necessary, the prognosis is usually poor and the survival after 1 year is usually lower than 40 percent.[75] Pulmonary embolism is a common cause of death, with the frequency estimated to be approximately 11 percent.[76]

1941

Among patients with COPD in the intensive care unit, pulmonary embolism was the most frequent cause of death at 40.6 percent. Treatment

Management goals in COPD are to ameliorate air flow obstruction and improve symptoms, to avoid secondary complications, to maintain functional capacity, and to improve the quality of life. Recent advances in smoking cessation strategies and surgical techniques (lung volume reduction surgery and lung transplantation) and renewed interest in noninvasive positive-pressure ventilation have expanded treatment options to meet the patient's needs. In addition to the specific therapies discussed here, all patients should receive a yearly influenza vaccination and the 23-valent pneumococcal vaccination at least once in their lifetime. For patients who do not receive influenza vaccine and are at risk for influenza type A infection, amantadine, 200 mg/d, or rimantadine, 100 mg twice per day, should be prescribed until the risk of infection has subsided. SMOKING CESSATION.

The importance of smoking cessation cannot be overemphasized. The annual rate of decline of FEV1 in smokers is approximately 80 ml per year, in contrast to 25 to 30 ml

per year in nonsmokers. The Lung Health Study reported that patients who stopped smoking had a small improvement in FEV1 (57 ml) after 1 year. [77] Thereafter, the rate of decline in lung function is similar to age-matched nonsmokers. The short-term success rates with smoking cessation are variable (18-77 percent), but success is more likely if the patient abstains from smoking within the first 2 weeks of entry into a program. The use of nicotine replacement therapy should always include a structured behavioral modification program to increase the likelihood of success. Pharmacological methods to reduce addictive behavior have not been found to be effective in controlled clinical trials.[78] Recently, the novel antidepressant bupropion (Zyban), which enhances noradrenergic activity, was reported to have a successful smoking cessation rate of 44 percent, compared with 19 percent in the placebo group.[79] PULMONARY REHABILITATION.

Patients with advanced COPD often lead a sedentary lifestyle because of breathlessness during mild to moderate exercise. The lack of exercise leads to deconditioning and worsening dyspnea, even with low levels of activity. The overall goal of a pulmonary rehabilitation program is to maintain the individual's maximal level of independence and functioning in the community. Pulmonary rehabilitation can improve exercise endurance and decrease the sense of breathlessness. Several studies have demonstrated that pulmonary rehabilitation can improve exercise capacity, subjective symptoms, and quality of life. Because of hyperinflation, deconditioning, and malnutrition, patients with advanced air flow obstruction have weakened ventilatory muscles. Moreover, because of the increased work of breathing, the inspiratory muscles are prone to fatigue. Fortunately, the respiratory muscles can be trained to improve their strength and endurance. Strength training can be achieved by high-intensity, low-frequency stimuli such as inspiring against a closed glottis or shutter valve. Endurance training may also improve inspiratory muscle strength. OXYGEN.

Hypoxemia is a common finding in patients with advanced COPD and is easily corrected with low-flow supplemental O2 . In key clinical trials sponsored by the National Institutes of Health (NIH, Nocturnal Oxygen Therapy Trial [NOTT] Group, 1980) and the British Medical Research Council (1981) long-term oxygen therapy clearly improved the survival of hypoxemic patients with COPD (Fig. 54-4) .[80] [81] The British study compared the effect of treatment with oxygen for approximately 15 hours per day with the effects of no oxygen therapy, whereas the NIH

Figure 54-4 Survival curves in the MRC (British) and NIH (US) long-term oxygen therapy trials in patients with severe hypoxemia and cor pulmonale. (From Flenley DC, Muir AL: Cardiovascular effects of oxygen therapy for pulmonary arterial hypertension. Clin Chest Med 4:297, 1983.)

study compared nocturnal oxygen therapy (about 12 hours per day) to "continuous" oxygen therapy (at least 19 hours per day). In each study, the mean baseline PaO2 when the patients were breathing ambient air was 51 mm Hg; the mean FEV1 was 0.7 to 0.8 liter. Oxygen therapy was beneficial in both studies (see Fig. 54-4 ). In the British study, 19 of 42 (45 percent) oxygen-treated patients died within 5 years, whereas 30 of 45 (67 percent) untreated patients died. In the NIH study, the mortality rate after a year was 20.6 percent in the group receiving nocturnal oxygen and 11.9 percent in the group receiving continuous oxygen therapy; and after 2 years, mortality was 40.8 percent and 22.4 percent, respectively. The relative risk of death for nocturnal oxygen therapy compared with continuous oxygen was 1.94. Oxygen therapy is therefore effective, and continuous therapy is more effective than nocturnal therapy only. HEMODYNAMIC EFFECTS OF OXYGEN.

How oxygen therapy improves survival is unknown. Two major hypotheses have been proposed: (1) oxygen relieves pulmonary vasoconstriction, decreasing pulmonary vascular resistance and thus enabling the right ventricle to increase stroke volume, and (2) oxygen therapy improves arterial oxygen content, providing enhanced oxygen delivery to the heart, brain, and other vital organs. These two hypotheses are not mutually exclusive, and each one has supporting evidence. Oxygen therapy clearly alleviates the progressive pulmonary hypertension of untreated COPD. Patients who exhibit a significant decrease in pulmonary artery pressure (>5 mm Hg) after acute oxygen therapy (28 percent oxygen for 1 day) have better survival than patients who do not respond acutely when both groups of patients are subsequently treated with long-term continuous oxygen therapy.[82] Enhanced right ventricular performance during short-term oxygen therapy may also be the direct result of improved tissue (e.g., myocardial) oxygenation rather than decreased pulmonary vascular resistance.[83] RECOMMENDATIONS.

Criteria for chronic home O2 therapy are shown in Table 54-3 . Long-term oxygen therapy is warranted if the resting PaO2 remains less than 55 mm Hg after a 3-week stabilization period on maximal medical therapy (e.g., bronchodilators, antimicrobial agents, diuretics). Patients with a PaO2 above 55 mm Hg should be considered for oxygen therapy if they are polycythemic or have clinical evidence (e.g., ECG, physical examination) of pulmonary hypertension.[84] Hypoxemia should be documented after the stabilization period to avoid the cost of long-term

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TABLE 54-3 -- INDICATIONS FOR HOME OXYGEN

Absolute PaO 2 55 mm Hg or SaO 2 88% PaO 2 55-59 mm Hg or SaO 2 = 89% in the presence of any of the following Dependent edema suggesting congestive heart failure P pulmonale on theECG (P wave 56% Specific Situations During exercise PaO 2 50% have CHD: ASD and VSD

Aneuploidy +13

Patau

~80% have CHD; 75% of CHD is complex: PDA, VSD, ASD, PS, AS, dextrocardia, CoA

+18

Edwards

~90% have CHD: most CHD is complex: VSD, PDA, ASD, bicuspid PV and AV, CoA

+21

Down

~40% have CHD: ECD, TOF: MVP in ~20%; AR

+8 mosaicism

~25% have CHD, most of little clinical consequence: VSD, PDA, CoA, PS

+9 mosaicism

~70% have CHD, usually complex: VSD, PDA, PLSVC

45,X

Turner

47,XXX 47,XXY

47,XYY

~10% have clinically important CHD: 50% of these have CoA; mild CoA is likely much more common; also AS, ARD, VSD, ASD, dextrocardia CHD not increased

Klinefelter

CHD possibly slightly increased; ? mild conduction changes; venous thromboembolic disease CHD not increased; ? mild conduction changes

Deletions 4p-

Wolf-Hirschhorn ~50% have CHD, usually complex: VSD, ASD, PDA, PS

5p-

Cri du chat

~20% have CHD, usually single: VSD, PDA, ASD, PS

7q-

~20% have CHD, various, often complex

13q-

CHD common, often severe, but depend on region deleted

18p-

CHD uncommon

18q-

~25% have CHD, usually single, of little consequence: VSD, PDA, ASD, PS

ring 18

~20% have CHD: CoA, PA hypoplasia, HLH, PLSVC

Duplications 4p trisomy

~10% have CHD, usually single: no defect predominates

9p trisomy

50% have CHD: PDA with or without ASD, VSD, PPS, IAA

Trimethadione ~50% have CHD: complex combinations most frequent (involving VSD, ASD, PDA, AS, PS), VSD, TOF Valproic acid

>50% have CHD: left- and right-sided flow lesions: CoA, HLH, ASD, VSD, pulmonary atresia

Vitamin D

Supravalvular aortic stenosis is the cardinal manifestation; PPS

Warfarin

~10% have CHD: PDA, PS; rarely, intracranial hemorrhage.

CHD=congenital heart defect(s); VSD=ventricular septal defect; TOF=tetralogy of Fallot; ASD=atrial septal defect; ECD=endocardial cushion defect; PS=valvular pulmonic stenosis; TGA=transposition of great arteries; IAA=interrupted aortic arch; PPS=peripheral pulmonic stenosis; PDA=patent ductus arteriosus; AS=aortic stenosis; CoA=coarctation of aorta; HLH=hypoplastic left heart. *Among patients with the full clinical spectrum associated with each teratogen; cardiovascular defects listed in decreasing order of prevalence.

1994

Ventricular septal defects and patent ductus arteriosus each occur in about 10 percent. Congenital anomalies of coronary arteries are occasionally and unexpectedly found during evaluation of more obvious defects. The electrocardiogram often shows left anterior hemiblock and a deep precordial S wave, a pattern not common in pulmonic stenosis of other causes. Lymphatic dysplasia, especially of the lower limbs, is common but causes clinical difficulties in less than 20 percent.[146] Although evidence of lymphedema often disappears during childhood, chylothorax and a protein-losing enteropathy represent the severe end of the spectrum.[150] Noonan syndrome shares features with other cardiofacial syndromes, and in sporadic cases (which account for 50 percent of Noonan syndrome) diagnosis can be difficult. All are autosomal dominant, so genetic counseling is somewhat easier. Affected males have reduced reproductive capabilities because of testicular abnormalities. Susceptibility to malignant hyperthermia can be detected by family history, elevated skeletal muscle creatine kinase levels, or muscle biopsy. Despite the relatively high frequency of Noonan syndrome, estimated to be as great as 1 per 1000, neither its cause nor its pathogenesis is clear. One gene has been mapped to 12q24.2-q 24.31,

but interlocus genetic heterogeneity is likely.[151] [152] Intriguing issues that may shed light on these uncertainties are the overlap in phenotype with type I neurofibromatosis[153] [154] (the gene for which is on chromosome 17), and the frequent coexistence of Noonan syndrome and deficiency of coagulation factor XI.[155] Teratogenic Effects

A teratogen is any agent that adversely affects embryonic or fetal development, such as infectious vectors, radiation, drugs, and other chemicals (see Table 56-10) . [156] Teratogenic effects on the cardiovascular system are considered in this chapter for several reasons: First, the phenotypes are often reminiscent of those due to chromosomal aberrations and single-gene mutations. Second, clinical geneticists and dysmorphologists are involved in diagnosing, managing, and investigating both teratogenic and genetic syndromes. Finally, how the organism responds to an encounter with a potential teratogen is largely determined by its genome. The entire field of ecogenetics and part of pharmacogenetics are concerned with these issues. The abilities to resist disruption of normal human embryogenesis and development involve systems quite distinct from physiological homeostasis and related only in part with developmental homeostasis. Genetic susceptibilities to teratogens can be illustrated by diverse mechanisms: reduced or inaccurate repair of radiation-induced DNA damage; enhanced receptiveness to viral entry or replication; immune deficiencies that prevent inactivation of infectious vectors or maintenance of immunity; slow inactivation of a compound that exerts a direct deleterious effect; or rapid conversion of an inoffensive drug to a teratogenic metabolite. These types of hereditary variation may be determined by single genes, with susceptibility inherited as a mendelian trait, or by many genes, each of small effect. Either situation can account for the well-known fact that only a fraction of pregnancies exposed to a given agent are affected adversely. Variation in dose and timing of exposure also confound interpretation of epidemiological and family data. It is not surprising, then, that the actual appearance of the abnormal phenotype is not amenable to traditional pedigree analysis. Rather, examination of the biochemical susceptibilities have proved, and will continue to prove, more enlightening. Some teratogens, such as warfarin, have a clear action that explains how the pleiotropic manifestations emerge. The action of other teratogens, such as alcohol, is obscure. Finally, in some teratogenic syndromes, such as that in offspring of women with diabetes mellitus, the actual offensive agent is unclear, and numerous pathogenetic mechanisms seems to pertain.[157] [158] Regardless of cause and pathogenetic mechanism, the phenotypes of many teratogens often share manifestations, especially prenatal growth retardation, abnormalities of the craniofacies, and mental retardation.[159] The following syndromes have prominent consequences on the cardiovascular system. FETAL ALCOHOL SYNDROME.

Ethanol is the most common teratogen to which the human embryo and fetus are exposed. The period of greatest vulnerability is the first trimester, and the risks are clearly related to the amount of alcohol consumed; the risk of the fetal alcohol syndrome's occurring in an offspring of a chronic alcoholic woman is 30 to 50 percent.

The features are highly variable and include growth retardation, mild to moderate mental retardation, hyperactivity, short palpebral fissures, a smooth philtrum with a thin upper lip, and small distal phalanges.[160] [161] Congenital heart defects occur in more than one-half of children with the full spectrum of the phenotype; ventricular septal defects are most common and often insignificant, but atrial septal defects, tetralogy of Fallot, and aortic coarctation can occur. FETAL HYDANTOIN SYNDROME.

Virtually all antiseizure medications can affect the fetus. Hydantoin was the first to be identified as a teratogen. The risk to the fetus depends in part on the genotype of the fetus; defects in arene oxidase predispose to the full syndrome.[162] [163] The features include prenatal and postnatal growth retardation, mild mental retardation, a broad face with a short nose, short distal phalanges with small nails, and hip dislocation. Cardiovascular defects, which are an inconstant part of the syndrome, include septal defects, right- and left-sided flow defects, and a single umbilical artery. RETINOIC ACID EMBRYOPATHY.

Isotretinoin was not recognized as a teratogen until after it was licensed for the treatment of acne. The vulnerable period extends from the first week through the fourth month of gestation. Isotretinoin increases the risks of miscarriage and stillbirth. The phenotype includes anomalies of the craniofacies and gross neuroanatomical disruption. Cardiovascular defects are common and emphasize various conotruncal malformations.[164] Live-born infants often succumb to the cardiac and brain anomalies. Although the mechanism of action is not certain, vitamin A derivatives such as retinoic acid function as morphogens during embryogenesis, serving as signals for cell migration. The fact that the cardiovascular defects are primarily those of rotation and folding suggests disruption of a normal developmental homeostatic system. WARFARIN EMBRYOPATHY.

Coumarin-related vitamin K antagonists are usually prescribed for various cardiovascular problems to women of childbearing age and can cause diverse cardiovascular and other organ damage to the fetus. Coumarin interferes with embryogenesis directly when administered during gestational weeks 6 through 9. The most pronounced effects are on cartilage because of inhibition of enzymes of extracellular matrix metabolism. Congenital cardiac defects are perhaps increased in frequency but fit no specific pathogenetic mechanism.[165] The second pattern of coumarin effects involves exposure during the second and third trimesters and includes spontaneous abortion, stillbirth, and various central nervous system defects. The last are not due simply to intracranial hemorrhage as was once assumed.[165] What predisposes to the adverse fetal effects of coumarin remains to be discovered. First, more than 75 percent of women who take coumarin derivatives throughout pregnancy have normal offspring; reassuring most women while identifying those at risk for adverse effects has obvious advantages. Second, placing all pregnant women on a

regimen of heparin is not an acceptable solution, because heparin can cause stillbirth or premature fetal loss in about 20 percent of exposures, is not as effective as coumarin in some indications for anticoagulation, and is more trouble to administer and regulate. MATERNAL PHENYLKETONURIA.

The inborn error of metabolism phenylketonuria (PKU), produces severe mental retardation unless the phenylalanine content of the diet is markedly reduced soon after birth.[166] Deficiency of phenylalanine hydroxylase in the fetus produces no harm because fetal blood levels of phenylalanine are regulated by the heterozygous mother's enzyme. Because neonatal screening for this disease is now routine in all states, virtually all patients receive treatment and grow to adulthood with average intelligence. Many patients discontinue the rigorous dietary therapy during adolescence when the elevated phenylalanine levels have far less deleterious effects. The embryopathy occurs when a woman with homozygous deficiency for phenylalanine hydroxylase becomes pregnant and her fetus is exposed to high levels of the amino acid, which overwhelm its ability to metabolize. The result is highly predictable if the mother does not restart dietary restriction of phenylalanine for the entire gestation: moderate to severe mental retardation, prenatal and postnatal growth retardation, microcephaly, and various cardiovascular defects in 15 to 20 percent.[167] This condition can largely be prevented by effective counseling of female patients with PKU. FETAL RUBELLA EFFECTS

(see Chapter 29) . About 50 percent of fetuses become infected with the rubella virus when the mother is infected during the first trimester. An infected fetus not only suffers varied and severe interference with development and organogenesis but acquires a chronic viral illness that can persist for years. The most common features of the embryopathy are mental deficiency, deafness, cataract, and cardiovascular defects. PDA is common, as are septal defects. Peripheral pulmonary stenosis and fibromuscular proliferation of medium and small arteries often improve postnatally.

1995

CARDIOMYOPATHIES (See also Chap. 48) Each of the three clinical categories of primary cardiomyopathy--hypertrophic, dilated, and restrictive--can be caused by mutations in single genes as judged by mendelian inheritance of a consistent phenotype in numerous families. Many other mendelian and mitochondrial disorders also cause cardiomyopathies as a secondary consequence of their basic metabolic disturbance. Hypertrophic Cardiomyopathy

In the more than four decades since the recognition of hypertrophic cardiomyopathy as

a clinical entity, many aspects of its natural history, pathology, and management have been substantially clarified.[168] [169] The phenotype is most clearly defined anatomically and histologically and consists of myocardial hypertrophy without secondary cause; cellular and myofiber disarray; myocardial fibrosis; and mediointimal proliferation of small coronary arteries. None of these features is pathognomonic; for example, myofiber disorganization is present in the normal human heart during embryogenesis and in congenital heart defects that place strain on the right-sided circulation. About half of probands with idiopathic hypertrophic cardiomyopathy of any segment of the left ventricle have affected first-degree relatives, and in those families the phenotype is inherited as an autosomal dominant, familial hypertrophic cardiomyopathy (FHC). There is wide variability of expression within a family, in part because of age dependence of the trait.[168] Later generations of relatives in adolescence and childhood may not have developed echocardiographic evidence of hypertrophy. Hence, pedigree screening by phenotype for clinical, counseling, or investigative purposes should not be considered complete until the following criteria are satisfied: Two-dimensional echocardiography is used to ensure that segmental hypertrophy is detected; a person at risk has normal echocardiographic findings and no evidence of electrocardiographic abnormality or important dysrhythmia after about age 20; and a person of any age has left ventricular hypertrophy without any other explanation, such as hypertension or aortic stenosis. FHC is a disease of the sarcomere, with primary defects of thick and thin filaments now defined. Mutations of at least six and perhaps more loci cause FHC (see Table 56-2) . The first gene identified was the cardiac beta-myosin heavy chain gene (MYH7). Depending on the population studied, about 50 percent of all FHC mutations occur in MYH7, and many mutations have been described.[169] [170] Patients with neither parent affected may also have MYH7 mutations, suggesting that the genetic alteration occured in the egg or sperm of a parent. [171] The likelihood of germline mosaicism is strongly suggested by two sibs with FHC and the same mutation in MHY7, even though neither parent shows the mutation in leukocyte DNA[171A] Mutations that alter charge of the beta-myosin heavy chain generally carry a worse prognosis in terms of age of detection, electrocardiographic abnormalities, and sudden death.[172] [173] [174] Thus, defining the specific gene involved, followed by the specific mutation, has likely clinical importance.[175] However, because of the substantial technical challenges and expense of identifying the specific mutation in any given patient with FHC, genetic testing is not yet routine.[176] How the mutant protein interacts with other components of the sarcomere of both cardiac and skeletal muscle to produce the phenotype is another area of active research, as is the generation and characterization of animal models of FHC.[177] Although intergenic and intragenic heterogeneity account for much of the interfamilial variability in the FHC phenotype, considerable variation remains among relatives who share the same mutation. Both environmental and genetic factors have impacts. A possible example of the latter is the angiotensin I-converting enzyme (ACE) genotype, with different polymorphic variants of ACE associated with more or less hypertrophy. [178] The importance of presymptomatic and even prehypertrophy diagnosis through

mutation analysis in families will become more important as improved methods of therapy evolve.[178A] Dilated Cardiomyopathy

The prevalence of idiopathic dilated cardiomyopathy is about double that of the hypertrophic form, or about 2 to 8 per 100,000.[179] [180] [181] Although numerous occurrences of familial dilated cardiomyopathy (FDC) are reported, few investigations have been conducted of an unselected series of probands for clinical and subclinical evidence of cardiac disease.[182] Thus, it is unclear what fraction of patients with idiopathic dilated cardiomyopathy have a mendelian disease, how many have a new mutation for a mendelian disease, and how many have phenocopies of nongenetic causes. Estimates of a positive family history, which could suggest a mendelian condition or a shared environmental cause, range from 7 to 30 percent. [168] [169] [182] Because of the risk of severe dysrhythmia in dilated cardiomyopathy, early detection of individuals with the disorder can be life saving. Two-dimensional echocardiography is a sensitive method for detecting affected relatives with subclinical disease. Individuals who have equivocal left ventricular enlargement or dysfunction can have ambulatory electrocardiographic monitoring and, if the diagnosis is still uncertain, can have serial examinations. Certainly every patient with idiopathic dilated cardiomyopathy should have a detailed family history; about 20 percent reveal an affected relative. [182] If any close relative has a history consistent with cardiomyopathy, dysrhythmia, or sudden death at a relatively young age, counseling about the risk of a familial disease and the potential benefits of pedigree screening should be offered. The majority of instances of FDC fit autosomal dominant inheritance, but X-linked, autosomal recessive, and mitochondrial forms exist.[168] [183] [184] [185] Clinical variability characterizes virtually all pedigrees; variation in severity, clinical phenotype, and age of onset is typical. In late 1999, the causes of most of the autosomal dominant forms of FDC were unknown. Mutation of the cardiac actin gene (ACTC) causes one uncommon form of FDC.[186] In some families with autosomal dominant disease, a mild proximal skeletal myopathy of type I fibers coexists with cardiac involvement.[187] In one family, cardiomyopathy developed only in association with pregnancy.[188] Although peripartum cardiomyopathy is a well-recognized, usually sporadic disorder, its occurrence in five women in two generations suggests a hereditary predisposition. Histological examination of myocardium generally shows nonspecific hypertrophy and fibrosis. By electron microscopy, however, mitochondria are distinctly abnormal, a finding not seen in congestive heart failure due to other causes.[189] Although various mutations of the mitochondrial chromosome can cause dilated cardiomyopathy, including of childhood onset, the inheritance pattern in most cases does not suggest maternal transmission.[185]

1996

Some pedigrees show convincing evidence of X linkage of dilated cardiomyopathy. At least three loci have been identified. In Barth syndrome, cardiac involvement is associated with skeletal myopathy, proportionate short stature, and neutropenia. The cause is mutation of the (TAZ) gene at Xq28.[189] [190] Mutations of this gene can also cause isolated FDC and noncompaction of the left ventricle.[168] [191] Many males with Duchenne and some with Becker muscular dystrophy develop myocardial dysfunction (see Chap. 71) .[192] In the Becker form, right ventricular involvement may be unassociated with left ventricular dysfunction.[193] Deletion of exon 49 of the dystrophin gene predisposes to cardiomyopathy. This pleiotropic feature in a disease that presents as a skeletal myopathy prompted evaluation of the dystrophin locus in pedigrees with apparently isolated cardiomyopathy. Mutations in the 5 end of the dystrophin gene have been found to account for some instances of X-linked dilated cardiomyopathy.[194] [195] Why some dystrophin mutations are selectively expressed in cardiac muscle (and other in brain) is unclear. Emery-Dreifuss muscular dystrophy (see Chap. 71) is distinguishable clinically from the Duchenne and Becker forms by absence of pseudohypertrophy of skeletal muscle, early involvement of the arms with elbow contractures, and early onset of cardiac conduction abnormalities and atrial dysrhythmia.[192] [196] Autosomal dominant and X-linked recessive forms occur. In the latter, female heterozygotes are also commonly affected, albeit more mildly than males.[197] The disease was mapped to the distal region of Xq28, and a previously unknown gene, called emerin, was found to be mutated.[198] Hearts show replacement of myocardium, especially in the atria, with fat and fibrosis. Even though the conduction system is not primarily affected histologically, sudden death is common in both hemizygous men and heterozygous women; thus, carrier detection can be life saving. The dominant form of Emery-Dreifuss muscular dystrophy is caused by mutations in the lamin A/C gene.[199] Both emerin and lamin A/C are expressed in the nuclear membrane of skeletal and heart muscle. An autosomal recessive form of limb-girdle muscular dystrophy with dilated cardiomyopathy has been found to be due to mutations in the gene encoding beta sarcoglycan.[200] In a number of families with severe, adult-onset autosomal dominant skeletal myopathy, cardiac conduction defects, and cardiomyopathy have been due to mutations in the gene encoding the intermediate filament protein, desmin.[200A] Restrictive Cardiomyopathy

The pathogenesis of the majority of cases of restrictive cardiomyopathy involves infiltration or replacement of the myocardium or both. The causes are varied and can be nongenetic or genetic; the latter are mostly metabolic diseases with secondary effects on the heart and are summarized in Table 56-9; some are reviewed subsequently. One

form of restrictive cardiomyopathy that has primary genetic forms among many other causes is endocardial fibroelastosis. Other mutations produce restriction through pericardial constriction. Isolated pedigrees of primary myocardial fibrosis without secondary cause and leading to restrictive hemodynamics are not classifiable.[201] [202] ENDOCARDIAL FIBROELASTOSIS

(see Chap. 48) . This abnormality is characterized by thickening of the endocardium, which leads to decreased compliance and impaired diastolic function. Primary forms, discussed here, are unassociated with other cardiac anomalies (see Table 56-9) . In infants there is often an indolent course of failure to thrive, tachypnea, and tachycardia, until a precipitant such as an upper respiratory infection leads to rapid cardiac decompensation. Treatment of children with primary endocardial fibroelastosis is ineffective; cardiac transplantation now offers some hope. Autopsy shows enlargement of the left ventricle and perhaps other chambers, no abnormality of lung vessels, and collapse of the left lower lobe. Histopathological study reveals extensive deposition of extracellular matrix, primarily collagen and elastic fibers, in the endocardium. X-linked recessive inheritance is the most firmly established of the single-gene causes. Some pedigrees show mainly small, contracted cardiac chambers, whereas others have chamber dilatation; both are compatible with the functional pathophysiology described by the term "restrictive." Males are affected earlier and more severely by both forms, and death in infancy is not unusual.[203] The condition must be distinguished from X-linked dilated cardiomyopathy and Barth syndrome (see also earlier on this page).[189] Morphological abnormalities of mitochondria occur on ultrastructural studies of heart and leukocytes. Insufficient longitudinal experience is recorded to know whether females heterozygous for this mutation develop a dilated or restrictive cardiomyopathy later in life. Several pedigrees suggestive of autosomal recessive inheritance of primary endocardial fibroelastosis were reported before the routine availability of laboratory methods to diagnose metabolic derangements, especially defects in fatty acid catabolism.[204] The occurrence of hydrocephalus, endocardial fibroelastosis, and neonatal cataracts may be due to a single gene mutation but could represent sequelae of a viral infection. [205] Endocardial fibroelastosis can be a prominent finding at autopsy in patients with autosomal dominant dilated cardiomyopathy[206] , whether the endocardial changes are primary, representing yet another mendelian form of this disorder, or whether they are secondary is unclear. Restrictive cardiomyopathy often occurs with both hemodynamic evidence of impaired diastolic filling and wall thickening; any of the conditions causing pseudohypertrophy of the myocardium can eventually exhibit restrictive pathophysiology. Hemochromatosis and the amyloidoses, both hereditary and acquired forms, are especially likely to present in this manner. Connective tissue replaces myocytes or infiltrates the interstitium in a number of conditions. Fibrosis of the myocardium may cause pseudohypertrophy, but the clinical consequences are more those of restriction. Restrictive pathophysiology often accompanies fibrosis of the myocardium, at least in the early stages. Replacement of myocytes or infiltration of the interstitium by collagen

and proteoglycan occurs in various conditions, such as muscular dystrophies and disorders that predispose to ischemia due to coronary artery occlusion, such as diabetes mellitus, hemoglobinopathies associated with sickling, Fabry disease, and the mucopolysaccharidoses. Severe fibrosis may produce considerable thickening of the myocardium, or pseudohypertrophy. Finally, a number of hereditary conditions are associated with endocardial fibroelastosis (Table 56-11) . CONSTRICTIVE PERICARDITIS

(see also Chap. 50) . Two rare autosomal recessive disorders include fibrous thickening of the pericardium as a manifestation. In both, signs and symptoms of constrictive pericarditis develop insidiously, and treatment by pericardiotomy is life saving. One condition was first described in Finland and given the name MULIBREY nanism, a combination of a mnemonic for muscle, liver, brain, and eye and an archaic word for dwarfism (nanism). Growth failure from an early age is common, and growth does not improve once pericardial constriction is abated. Subsequently, more than a dozen patients, generally with consanguineous parents, have been reported from around the world.[207] The disease locus has been mapped to 17q.[208] The arthropathy-camptodactyly syndrome previously had been reported because of the skeletal and rheumatological manifestations before pericardial effusion and fibrous thickening of the pericardium were recognized as manifestations.[209] The disease locus was mapped in consanguineous kindreds by homozygosity by descent to 1q25-q31, and mutations occur in the gene, CACP, that encodes a secreted proteoglycan.[210] [211]

1997

TABLE 56-11 -- DISORDERS ASSOCIATED WITH RESTRICTIVE CARDIOMYOPATHY OMIM NO.* Primary Endocardial Fibroelastosis Familial endocardial fibroelastosis

226000, 305300

Faciocardiorenal syndrome

227280

Secondary Endocardial Fibroelastosis As a Relatively Common Manifestation Maternal lupus erythematosus Pseudoxanthoma elasticum

177850, 264800

Systemic carnitine deficiency

212140

Trisomy 18 As a Relatively Infrequent Manifestation

Cornelia de Lange syndrome

122470

Rubinstein-Taybi syndrome

268600

Secondary Infiltrative Cardiomyopathy Familial amyloidoses I and III

176300

Fabry disease

301500

Gaucher disease type I

230800

Glycogen storage disorder II

232300

Glycogen storage disorder III

232400

Hemochromatosis

235200

Mucopolysaccharidosis IH

252800

Mucopolysaccharidosis II

309900

*Data from Online Mendelian Inheritance in Man (www.ncbi.nlm.nih.gov/omim).

Cardiomyopathies Secondary to Other Causes INBORN ERRORS OF METABOLISM.

These can affect the left ventricle by various mechanisms (Table 56-12) and produce diverse anatomical, histological, and functional disturbances. The most common anatomical result is an apparent hypertrophic cardiomyopathy, which is actually pseudohypertrophic because the thickened walls are not due to myocardial cell hypertrophy but to cellular or interstitial infiltration by metabolites. Abnormalities of both systolic and diastolic function result, outflow obstruction may occur, and in some cases the hemodynamic characteristics resemble a restrictive cardiomyopathy. The offending metabolite may be an incompletely degraded macromolecule such as glycogen (glycogen storage disorder II [Pompe disease] and glycogen storage disorder III), proteoglycan and glycosaminoglycan (mucopolysaccharidoses I, III, IV, VI, and VII), sphingolipid (Fabry disease, Tay-Sachs disease, Farber disease, Refsum disease, and Gaucher disease), glycoprotein (fucosidosis and mannosidosis), and amyloid (familial amyloidoses I and III) or a small molecule such as iron in hemochromatosis. Some of these disorders are discussed later. True myocardial hypertrophy occurs as a part of mendelian syndromes, such as Noonan syndrome, von Recklinghausen neurofibromatosis,[212] and leopard syndrome,[213] [214] and monogenic errors of metabolism, notably those producing hyperthyroidism and pheochromocytoma. Any of the mendelian disorders that cause hypertension may, over time, produce true myocardial hypertrophy. Dilated cardiomyopathy often results from inborn errors of energy production, especially fatty acid metabolism. Various disorders associated with carnitine deficiency, mitochondrial and peroxisomal dysfunction, and muscle dysfunction can present with

symptoms of congestive heart failure or dysrhythmia. PRIMARY DISORDERS OF RHYTHM AND CONDUCTION Virtually every dysrhythmia and conduction abnormality has been reported to occur in relatives.[215] [216] For example, familial disturbance of conduction occurs, without evident cause, at the sinus node,[217] [218] atrioventricular node,[219] [220] and bundle branches.[221] [222] However, understanding the genetics of cardiac electrophysiology has been hampered by several characteristics of this extensive literature: Most families have been small, so that mode of inheritance, or even whether the inheritance is mendelian, is uncertain; many of the families show a mixture of different defects, partly because the disease is progressive[223] [224] ; and some specific conduction defects are associated with hereditary myocardial diseases, such as familial cardiomyopathy,[168] [225] atrial cardiomyopathy,[226] and familial amyloidosis.[227] As noted earlier, there seems to be genetic control of normal electrical conduction, so it would not be surprising to find mutations in single genes that produced clinically important disturbance. Several important causes of complete heart block, although not mendelian, nonetheless involve genetic factors. The association between rheumatic diseases and heart block was clearly established when the offspring of mothers with acquired disorders of connective tissue, especially lupus erythematosus, were found to have complete heart block.[228] [229] [230] Many examples of "autosomal recessive" congenital heart block represent this familial but nonmendelian etiology. The risk is not related to severity of the maternal disease but is highest in children of women with antibodies to ribonucleoprotein (anti-Ro[SS-A])[231] and at least one allele for HLA-DR3.[232] Thus, it may be the maternal genotype that determines susceptibility to inflammation of the fetal heart at vulnerable periods, such as gestational weeks 3 to 4, when the atrioventricular node is forming. Also, genetic susceptibility to inflammation of the atrioventricular node of patients themselves is suggested by the relatively high association of HLA-B27 in adults requiring permanent pacemakers[233] ; not all of these patients have overt evidence of HLA-B27-associated rheumatic diseases. Familial dysrhythmia is also not uncommon.[215] Nodal rhythm,[234] ventricular irritability, [235] and tachydysrhythmia associated with accessory atrioventricular pathways[236] [237] have been reported in families. Familial atrial fibrillation has been genetically mapped to 10q22-q24.[238] In one family, three generations were affected by a syndrome of ventricular extrasystoles and tachydysrhythmias with recurrent syncope, hypoplasia of the distal toes, and hypoplasia of the mandible (Robin sequence).[239] ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA.

Hereditary cardiomyopathies are another cause of familial dysrhythmia, and a notable example is arrhythmogenic right ventricular dysplasia (ARVD), an autosomal dominant condition with variable expression[240] [241] (see also Chap. 25) . Although ARVD is uncommon, the familial form shows clusters of high incidence (0.4 percent) in some regions of Italy and is an underappreciated cause of life-threatening dysrhythmia. [242] The right ventricle is involved primarily in most cases, with thinning and replacement of myocardium by fat and fibrosis.[243] [243A] Dysrhythmia, usually ventricular but occasionally

supraventricular, may precede signs of right ventricular dysfunction. About one-third of cases are familial, generally in an autosomal dominant pattern. At least six loci can cause ARVD (see Table 56-2) .[244] [244A] Whether the pathogenesis is homogeneous or not and whether true dysplasia, degeneration (due to a metabolic defect or muscular dystrophy), or inflammation has the leading role are unclear. LONG QT SYNDROME

(see Chap. 26) . Familial syncope and sudden death have long been associated with ventricular dysrhythmia, but a distinct syndrome was not recognized until Ward [245] and Romano,[246] working independently three decades ago, reported the characteristic prolonged QT interval. Subsequent investigations of numerous families have clearly established that the defect in repolarization is inherited as an autosomal dominant. Although a long QTc is consistently present, other abnormalities of conduction also occur, although they may not be evident on the resting electrocardiogram. [247] Long QT syndrome is generally unassociated with systemic abnormalities, but three patients with a negative family history for long QT had syndactyly of multiple fingers and toes.[248]

1998

TABLE 56-12 -- MENDELIAN ERRORS OF METABOLISM WITH MANIFESTATIONS DISORDER EPONYM OR OMIM PATHOGENESIS CARDIOVASCULAR COMMON NO.* INVOLVEMENT NAME Aminoacidopathies Alkaptonuria

Ochronosis

203500 Deposition of AS; atherosclerosis homogentisic acid in connective tissue

Cystinosis, nephropathic type

219800 Lysosomal storage

Hypertension from renal failure, vascular wall thickening

Homocystinuria

236200 Unknown

Early CAD; venous thrombosis; pulmonary embolism

259900 Vascular and tissue accumulation of oxalate

Conduction defect; vascular occlusions; Raynaud's phenomenon

Oxalosis I

Hyperoxaluria

Defects in Fatty Acid Metabolism

Carnitine transport defect

Primary carnitine 212140 Lipid myopathy; deficiency defective energy generation

DCM: ECF

MCAD deficiency

201450 Lipid myopathy; defective energy generation

DCM

LCAD deficiency

201460 Lipid myopathy; defective energy generation

DCM

Glycogen Storage Disorders GSD I

Pompe


Pseudohypertrophic CM; short PR interval; ECF

GSD II

Adult acid maltase deficiency


Primarily skeletal muscle; respiratory insufficiency; cor pulmonale

GSD III

Forbes; debrancher deficiency

232400 Intracellular glycogen accumulation fibrosis

Pseudohypertrophic CM

Phosphorylase kinase deficiency

GSD of the heart

DCM

Glycoproteinoses Fucosidosis, severe


Myocardial thickening

Fucosidosis, mild


Angiokeratoma

Mannosidosis


Myocardial thickening; valvular thickening; conduction disturbance

Aspartylglycosaminuria


Valvular thickening

Mucolipidoses ML II

I-cell


Same as MPS IH

ML III

Pseudo-Hurler polydystrophy


Valvular thickening and dysfunction, esp. AS, AR

Mucopolysaccharidoses (MPS) MPS IH

Hurler


Early CAD; PH and OAD CP; valvular dysfunction, esp. MR, AR; pseudohypertrophic CM

MPS IS

Scheie


Valvular dysfunction, esp. AS

MPS IH/S

Hurler-Scheie


Same as MPS IH

MPS II

Hunter


Same as MPS IH; less severe in mild MPS II variant

MPS III A

Sanfilippo A


Valvular thickening and occasional dysfunction

MPS III B

Sanfilippo B



MPS III C

Sanfilippo C



MPS III D

Sanfilippo D

Lysosomal storage


MPS IV A

Morquio A


Valvular dysfunction, esp. AR

MPS IV B

Morquio B


Milder than MPS IV A

MPS VI

Maroteaux-Lamy 253200 Lysosomal storage

Same as MPS IH

MPS VII

Sly

Valvular thickening

Sphingolipidoses


alpha-Galactosidase A Fabry deficiency

301500 Cellular accumulation of trihexosyl ceramide, esp. endothelium

Early CAD, valvular thickening and dysfunction; pseudohypertrophic CM; short PR interval; arteriolar occlusion; angiokeratoma

Ceramidase deficiency Farber

228000 Histiocytic infiltration

Nodular thickening of valves

Glucocerebrosidase deficiency

230800 Cellular PH accumulation of CP; interstitial glucocerebroside infiltration of myocytes by Gaucher cells; constrictive pericarditis

Gaucher, adult form

Miscellaneous Disorders Acid lipase deficiency

Wolman

278000

Atherosclerosis Cholesterol; foam cell infiltration

Acid lipase deficiency

Cholesterol ester storage disease

278000

Atherosclerosis; PH Cholesterol; foam cell infiltration

Geleophysic dysplasia


Valvular dysfunction

Hereditary angioedema

106100 Complement and Angioedema kinin activation

CAD=coronary artery disease; DCM=dilated cardiomyopathy; ECF=endocardial fibroelastosis; CM=ca regurgitation; PH=pulmonary hypertension; OAD=obstructive airway disease; CP=cor pulmonale; MR *Data from Online Mendelian Inheritance in Man (www.ncbi.nlm.nih.gov/omim). Gene symbol; for chromosomal locus see Table 56-2 . Naturally occurring mutants; does not include transgenic and knockout rodent models.

1999

2000

Long QT syndrome is genetically heterogeneous, and mutations of at least 5 loci can produce similar disorders (see Table 56-2) . Each gene identified encodes a protein involved with a cation channel.[249] Most mutations in individuals with an autosomal dominant form of long QT occur in potassium channel, rather than sodium channel gene.[250] Long QT syndrome should be suspected as a cause of sudden death, especially in young people without other evident cardiovascular risk factors, and especially when the death is associated with exercise or fright.[251] A positive family history of sudden death would obviously heighten the suspicion of long QT, but in many families penetrance is reduced.[252] Use of genotype to determine unequivocally who is heterozygous for the mutation has permitted assessment of both penetrance and the reliability of electrocardiographic criteria for diagnosis.[253] Not unexpectedly, the criterion of a corrected QT interval greater than 0.44 second is good, but it is less than 90 percent sensitive and specific. Treatment with beta-adrenergic blockade or an automatic implanted defibrillator is effective. Individuals heterozygous for the mutant gene should be identified through a detailed family history, clinical assessment, and, if necessary, DNA testing, and counseled appropriately. In some instances, the nature of the mutation has prognostic implications and can be used to guide the aggressiveness of therapy.[254] [255] However, given the extensive intergenic and intragenic heterogeneity, molecular testing, especially of a person with no family history, is not warranted, given the current technology.[176] The association of familial syncope, sudden death, and congenital deafness was codified by Jervell and Lange-Nielsen in 1957,[256] although as with most eponymous syndromes, reports of affected individuals occurred previously. As would be expected for a rare autosomal recessive condition, the parents of affected children are more likely than average to be consanguineous. The frequency of a long QT c among deaf children is about 1 per 100, so routine electrocardiographic screening of anyone with congenital deafness is warranted. Fright and rage clearly precipitate syncope and sudden death. Patients with this disorder are homozygous or compound heterozygotes for mutations of several of the same cation-channel genes that cause dominant long QT syndrome.[257] DISORDERS OF CONNECTIVE TISSUE The two broad classes of disorders of connective tissue are those due to mutations in single genes that determine or somehow affect components of the extracellular matrix and those due to extrinsic factors affecting the extracellular matrix, such as rheumatoid arthritis and systemic lupus erythematosus. The former category includes many disorders that affect the cardiovascular system. Susceptibility to so-called acquired disorders of connective tissue is, in part, determined by genes, and this specific aspect is reviewed. Mendelian Disorders of the Extracellular Matrix

Close to 200 distinct phenotypes now compose this category, which was first defined less than four decades ago with fewer than 10 disorders.[258] Several reviews and textbooks describe the phenotypes, genetics, and causes of many of the conditions (Table 56-13) .[14] [259] [260] [261] [262] Marfan Syndrome

This autosomal dominant disorder is relatively frequent ( 1 per 10,000), occurs in all races and ethnic groups, and is often not diagnosed during life.[262] In light of the classical TABLE 56-13 -- CARDIOVASCULAR MANIFESTATIONS OF HERITABLE DISORDERS OF CONNECTIVE TISSUE DISORDER OMIM CARDIOVASCULAR MANIFESTATIONS * NO. Cutis laxa

219100

PS, PPS, CP

123700

MVP

Ehlers-Danlos I

130000

MVP

II

130010

MVP

III

130020

MVP

IV

130050

Arterial rupture, MVP

VI

225400

MVP

VIII

130080

MVP

X

225310

MVP, aortic root dilatation

Osteogenesis imperfecta I

166200

MVP, mild aortic root dilatation

II

166210

CP, arterial calcification

III

259420

MVP

IV

166220

Aortic root dilatation

Marfan syndrome

154700

MVP, aortic root dilatation, aortic dissection

MASS phenotype

157700

MVP, mild aortic root dilatation

Pseudoxanthoma elasticum

177850

Arteriolar sclerosis, claudication, myocardial infarction, endocardial fibroelastosis

PS=valvular pulmonic stenosis; PPS=peripheral pulmonic stenosis; CP=cor pulmonale; MVP=mitral valve prolapse. *Data from Online Mendelian Inheritance in Man (www.ncbi.nlm.nih.gov/omim).

phenotype, failure to diagnose Marfan syndrome may seem surprising; however, marked clinical variability, age dependence of all of the manifestations, and a high ( 30 percent) rate of new mutation all conspire to make detection of mildly affected, young, sporadic patients challenging.[262A] Even with the discovery of the genetic and biochemical bases of the condition, the diagnosis of Marfan syndrome outside of families with the classical phenotype remains entirely clinical. Current criteria (Table 56-14) depend on the manifestations in the cardinal organ systems--the eye, the skeleton, the heart, and the aorta--and other systems, as well as the family history[141] [176] (Fig. 56-7) . The presence of manifestations more specific for Marfan syndrome, such as aortic dilatation, aortic dissection in a nonhypertensive young person, ectopia lentis, and dural ectasia, clearly is more important diagnostically than features common in other connective tissue disorders and in the general population, such as scoliosis, joint hypermobility, myopia, and MVP. The most common cardiovascular features are MVP and dilatation of the sinuses of Valsalva.[263] [264] Associated clinical problems of mitral regurgitation, aortic regurgitation, and aortic dissection account, if untreated, for most of the early mortality that results in an average age of death in the fourth and fifth decades of life.[265] Children tend to be more severely affected by mitral valve disease,[266] [267] whereas aortic problems are progressive and more likely in adolescence and beyond. MITRAL VALVE INVOLVEMENT.

MVP (see also Chap. 46) is age dependent and more common in women with Marfan syndrome. The incidence reaches 60 to 80 percent when patients are studied by two-dimensional echocardiography,[142] and the valve leaflets generally have an elongated and redundant appearance. Progression of severity, as judged by appearance or worsening of mitral regurgitation by clinical and echocardiographic criteria, occurs in at least one-quarter of patients,[268] a much higher rate than in MVP found in the general population.[133] The mitral annulus dilates

2001

TABLE 56-14 -- DIAGNOSTIC CRITERIA FOR MARFAN SYNDROME PHENOTYPIC MANIFESTATIONS* Skeleton Joint hypermobility, tall stature, pectus excavatum, reduced thoracic kyphosis, scoliosis, arachnodactyly, dolichostenomelia, pectus carinatum, erosion of the lumbosacral vertebrae from dural ectasia Eye

Myopia, retinal detachment, elongated globe, ectopia lentis Cardiovascular Mitral valve prolapse, endocarditis, dysrhythmia, dilated mitral annulus, mitral regurgitation, tricuspid valve prolapse, aortic regurgitation, aortic dissection , dilatation of the aortic root Pulmonary Apical blebs, spontaneous pneumothorax Skin and Integument Inguinal hernias, incisional hernias, striae atrophicae Central Nervous System Attention deficit disorder, hyperactivity, verbal-performance discrepancy, dural ectasia , anterior pelvic meningocele If the family history is positive for a close relative clearly affected by Marfan syndrome, to make the diagnosis in the patient, a major criterion should be present as well as findings in one other system. If the family history is negative or unknown, to make the diagnosis, the patient should have one major criterion and manifestations in two other systems. *Manifestations are listed within each organ system in increasing specificity for Marfan syndrome, although none is completely specific; those indicated by are the most specific and constitute major criteria.[ 141]

and contributes to the regurgitation, as do stretching and occasional rupture of chordae. About 10 percent of patients with marked prolapse have calcification of the mitral annulus. Standard treatment for chronic mitral regurgitation is indicated, but coexistent aortic root dilatation usually requires that increasing inotropy be avoided. When mitral regurgitation becomes severe enough to warrant surgical intervention, two considerations must be added to the balance: (1) Repair of the mitral apparatus is often successful and durable in Marfan syndrome.[269] [270] Repair is less easily accomplished when the cusps are extremely redundant, there is marked chordal damage, or the annulus is heavily calcified. (2) The aorta may be enlarged enough to permit concomitant repair. In Marfan syndrome, as in virtually all of the heritable disorders of connective tissue, there is an increased susceptibility to dehiscence of prosthetic mitral valves, regardless of the care taken in placing them. AORTIC ROOT INVOLVEMENT (See also Chap. 40) .

The sinuses of Valsalva are often dilated at birth, and the rate of progression varies widely among patients in general and also among relatives (Fig. 56-8) . Thus, predicting

long-term risks of developing aortic regurgitation (which clearly is positively associated with aortic root diameter[271] ), suffering aortic dissection (which is less clearly associated with diameter), or requiring aortic surgery is fraught with uncertainty. Transthoracic echocardiography is sufficient for detecting and monitoring changes in diameter, because in the absence of dissection, dilatation is limited to the proximal ascending aorta, and the rate of change is slow, measured in millimeters per year. Rare exceptions of principal dilatation of the thoracic aorta can be monitored with transesophageal echocardiography or magnetic resonance imaging. Patients with dilatation less than 1.5 times the mean diameter predicted for their body size[272] can be observed annually; as the diameter increases, more frequent evaluation is necessary. Aortic regurgitation often appears in adults at a diameter of 50 mm but may be absent at diameters of more than 60 mm.[271] [272] The risk of dissection increases with the size of the aorta and fortunately occurs infrequently below a diameter of 55 mm in the adult. Many physicians have adopted the criterion of a 50 to 55 mm maximal aortic root dimension for performing elective surgery in adult patients with Marfan syndrome, regardless of the severity of the aortic regurgitation,[270] although patients with a family history of aortic dissection should have surgery at the lower end of this range. The perioperative results of both elective and emergency repair of the aortic

Figure 56-7 External phenotype of a patient with Marfan syndrome, showing long extremities and digits, tall stature, and pectus carinatum.

2002

Figure 56-8 Dilatation of the aortic root in Marfan syndrome. A, Lateral angiogram of the ascending aorta showing dilatation of the sinuses of Valsalva and proximal ascending aorta and relatively normal caliber of the ascending aorta. B, Lateral magnetic resonance imaging of the same patient.

root have been excellent and a marked improvement from the pre-composite graft era that ended in the mid 1970s. Long-term results of operation are limited by the problems of endocarditis and anticoagulation, common to all prosthetic valves, but in the absence of chronic aortic dissection appear favorable for patients with Marfan syndrome.[270] [273] [274] [275]

Several approaches to repairing the dilated or dissected aortic root while preserving the native aortic valve have been developed.[276] Both short- and now long-term follow-up of patients with Marfan syndrome who have undergone this repair have been quite favorable.[270] [276A] The operation must be performed before the root is widely dilated and the valve commisures and cusps markedly stretched. This approach is increasingly being taken in all patients when the maximal root dimension reaches 50 mm, and it is an especially suitable procedure for women of childbearing age who want to consider pregnancy, as well as for all others in whom anticoagulation is contraindicated.

THORACIC ABNORMALITIES.

Severe pectus excavatum may complicate cardiovascular surgery by hampering exposure of the heart by median sternotomy. For elective cardiovascular surgery, repair of the sternal deformity some months in advance permits sufficient healing of the costochondral junctions that a stable and functionally and cosmetically improved thoracic cage will facilitate further surgery and postoperative recovery. [277] Simultaneous repair of cardiac and sternal defects, although possible, is a long procedure, and intraoperative bleeding from bone can be considerable because of the anticoagulation associated with cardiopulmonary bypass. AORTIC DISSECTION

(see also Chap. 40) . This complication usually begins just above the coronary ostia (type A in the Stanford scheme) and extends the entire length of the aorta (type I in DeBakey scheme). About 10 percent of dissections begin distal to the left subclavian (type B or III), but rarely is dissection limited to the abdominal aorta. Angiography, magnetic resonance imaging, and transesophageal echocardiography all have a role in the diagnosis of acute dissection in Marfan syndrome, with the capabilities and experience of the medical center and the stability of the patient important determinants of the approach. Because many acute dissections of the ascending aorta in Marfan syndrome have a stuttering course that culminates in death due to rupture or hemopericardium, rapid transfer to a facility prepared to perform immediate repair is essential. Not all acute dissections in Marfan syndrome involve severe, tearing chest pain that radiates to the back; indeed, some extensive dissections have been occult. This experience reinforces the need for a high index of suspicion by physicians whenever a tall, nearsighted young person with a thoracic cage deformity arrives at an emergency department with vague complaints of lightheadedness, chest or abdominal discomfort, or a murmur of aortic regurgitation. Similarly, patients known to have Marfan syndrome and their close relatives need to be educated about the signs and symptoms of aortic dissection. In general, the management of acute and chronic dissection in Marfan syndrome follows standard practice, with several departures. First, all dissections of the ascending aorta should be repaired promptly, preferably with a composite graft. Second, regular evaluation with magnetic resonance imaging is important, as the diameter of any region of dissected aorta is likely to expand over time.[278] [279] Third, reduction of systolic blood pressure and administration of negative-inotropic doses of beta-adrenergic blockers should be even more strictly adhered to than in dissections without a connective tissue abnormality. In most instances, any region of the aorta should be repaired when complications of further dissection, branch vessel occlusion, or dilatation beyond about 50 mm occur. A staged approach to total replacement of the Marfan aorta is now both feasible and successful.[280] DYSRHYTHMIAS.

Some patients develop serious ventricular or supraventricular dysrhythmia. The latter often accompanies chronic mitral regurgitation, but the former may be of high grade and difficult to suppress when only MVP is present. Some patients have the syndrome of autonomic dysfunction, atypical chest pain, and palpitations seen in some patients with MVP unassociated with a flagrant connective tissue abnormality. MANAGEMENT.

Routine cardiological management of Marfan syndrome is multifaceted: regular clinical and echocardiographic examinations; routine endocarditis prophylaxis for dental and other procedures; restriction of activity from heavy weightlifting, contact sports, and any exertion at maximal capacity; and long-term beta-adrenergic blockade form the basic approach, with individual variation often appropriate. Support for the role of beta blockade comes from several prospective studies that show a reduction in the rate of aortic dilatation and the risk of aortic dissection in patients treated with negatively inotropic doses of propranolol or atenolol.[281] [282] However, short-term administration of propranolol to patients with large sinus of

2003

Valsalva aneurysms, although reducing heart rate and peak systolic pressure, did not improve the impedance characteristics recorded in the ascending aorta. However, in the presence of studies that emphasize the importance of central pulse pressure to aortic dilation,[284] use of beta blockade seems warranted.[283] A woman with Marfan syndrome has two concerns about pregnancy (see also Chap. 65) . The first is the 50:50 risk that any child will inherit the condition; prenatal diagnosis can currently be attempted in selected situations. The second is the risk of dissection that the hemodynamic stresses of pregnancy place on the aorta. Several dozen case reports attest to the heightened incidence of dissection during the third trimester, parturition, and the first month post partum. [285] [286] However, in the majority of instances, serious aortic dilatation was present. Prospective evaluation of 21 women through 45 pregnancies confirmed our earlier recommendation that the cardiovascular risks are relatively low if the aortic diameter does not exceed 40 mm and cardiac function is not compromised[286] , a view shared by others.[287] ETIOLOGY.

Marfan syndrome is caused by mutations in the gene that encodes fibrillin-1 (FBN1), the major constituent of microfibrils, components of the extracellular matrix that are widely dispersed and perform numerous functions.[262] [288] [289] Microfibrils and tropoelastin form elastic fibers. Fragmentation and disorganization of elastic fibers in the aortic media have long been a histological marker (inappropriately

called cystic medial necrosis) of Marfan syndrome,[263] although similar microscopic pathology occurs in familial aortic aneurysms and aging aortas of the normal population. A defect in microfibrils explains all of the pleiotropic manifestations of Marfan syndrome.[262] [290] More than 100 distinct mutations in FBN1, the gene that encodes fibrillin-1, have been found in different families, and only a few have occurred, by chance, in unrelated patients.[290] [291] Because FBN1 is such a large gene ( 9000 nucleotides in the mRNA), finding a mutation is still not a simple matter.[176] [292] Once the mutation is identified, diagnosis in that family is straightforward. In families with several alive and cooperative affected members, linkage analysis can be used for presymptomatic and prenatal diagnosis. The use of molecular testing is confounded, however, by the discovery that autosomal dominant ectopia lentis, familial tall stature, MASS phenotype, and familial aortic aneurysm all are phenotypes found to be due to mutations in FBN1 and are exactly the conditions clinicians are interested in excluding in their patients of questionable diagnosis.[290] Mutations in FBN1 have distinct effects on microfibril formation: Some affect synthesis, others secretion, and others incorporation of fibrillin-1 monomers into the extracellular matrix.[293] [294] MITRAL VALVE PROLAPSE AND THE MASS PHENOTYPE.

This heterogeneous group of conditions, described earlier (see p. 1993 ) likely contains large numbers of patients and families who have a defect of the extracellular matrix underlying the phenotypes. Some but not all have mutations in FBN1.[262] [290] Ehlers-Danlos Syndrome

This group of heterogeneous conditions is linked by variable involvement of the skin and the joints, with hyperelasticity and fragility of the former occurring with hypermobility of the latter[261] [295] (Fig. 56-9) . Mitral valve prolapse is clearly increased in frequency in most of the clinical types,[296] but aortic root dilatation is an uncommon finding. The most serious cardiovascular problems occur in the vascular form of Ehlers-Danlos syndrome with spontaneous rupture of large- and medium-caliber arteries.[296A] Various defects of type III collagen are the cause of the phenotype in virtually all patients studied.[297] Analysis of collagen production by cultured skin fibroblasts should be

Figure 56-9 Legs of a patient with Ehlers-Danlos syndrome type IV who died of rupture of the subclavian artery. Note the mild joint hypermobility and the striking dermal abnormalities--elastosis perforans serpiginosa and thin, atrophic scars over areas of recurrent trauma.

used to confirm the diagnosis.[14] True aneurysms rarely form; rather, a rupture without dissection usually occurs as a catastrophic event. Most prone are the abdominal aorta

and its branches, the great vessels of the aortic arch, and the large arteries of the limbs. False aneurysms and fistulas[298] may be one result in those patients who do not die of the initial rupture. Vascular surgery is difficult, as the normal-appearing vessels around the rent fall to hold sutures. As a consequence, elective surgery to repair vascular anomalies, such as false aneurysms, that are causing no immediate problem is contraindicated in most cases. The vascular form of Ehlers-Danlos syndrome is often sporadic but, when familial, is usually autosomal dominant.[298A] Prenatal diagnosis is possible by examining collagen production in amniocytes. However, pregnancy is particularly hazardous to women with this condition because of vascular rupture, although some mutations may not be as dangerous.[297] [299] Pseudoxanthoma Elasticum (PXE)

This is a clinically variable and genetically heterogeneous disorder of unknown cause. Histopathological examination of affected tissues shows fragmentation and calcification of elastic fibers. The skin, the eyes, the gastrointestinal system, and the cardiovascular system are the organs most severely affected. [261] [300] The skin shows highly characteristic raised yellowish papules (pseudoxanthoma) overlying areas of flexural stress, such as the neck, cubital and popliteal fossae, and groin (Fig. 56-10) . Breaks in the elastic lamella, Bruch membrane of the choroid, produce the funduscopic finding of angloid streaks. Gastrointestinal hemorrhage is common and potentially fatal; mucosal arterioles bleed, and because the calcified elastic fibers prevent effective vessel retraction, hemostasis is difficult. Selective arterial embolization was life saving in one instance.[301] The heart is affected in a number of ways. Endocardial fibroelastosis is common, but because primarily the atria are involved, a restrictive cardiomyopathy is uncommon. One patient with marked endocardial fibroelastosis was helped by resection of calcified elastic bands within the left ventricle.[306] Mitral valve prolapse may be increased in frequency[302] [303] but is rarely a clinical problem. Coronary artery disease with myocardial ischemia and infarction is a common cause of early death.[304] [305] Elastic and muscular arteries, including the coronaries, develop a type of arteriosclerosis similar to Monckeberg; progressive luminal narrowing occurs and can produce complete occlusion. This is initially most evident at the radial and ulnar arteries, where absence of pulses

2004

Figure 56-10 Skin of a young man with pseudoxanthoma elasticum. The neck is a typical location to notice the raised, yellowish papules from which the name of the condition derives.

and a positive Allen test result are noted early in the course.[304] Because narrowing progresses slowly, collaterals form, and peripheral ischemia is a late complication. Because the arterial stenoses tend to be diffuse, bypassing them often involves extensive surgery. Because of a positive association between phenotypic severity and dietary calcium intake, patients can be advised to restrict consumption of dairy products

and to avoid calcium supplements.[307] Hypertension and all risk factors for atherosclerosis should be aggressively controlled. Through linkage analysis, both the recessive and dominant forms of PXE have been mapped to the same region of chromosome 16.[308] Genetic Susceptibility to Acquired Disorders of Connective Tissue

Genetic factors are clearly implicated in the susceptibility to many of the rheumatic disorders and to specific complications of specific conditions.[233] The cardiovascular manifestations of these disorders are particularly interesting in this regard. For example, study of HLA-DR antigen frequencies suggests that immune-response factors are involved in the pathogenesis of chronic rheumatic heart disease in blacks.[309] INBORN ERRORS OF METABOLISM THAT AFFECT THE CARDIOVASCULAR SYSTEM Hundreds of biochemical defects that affect human metabolism have direct or secondary impact on the cardiovascular system (see Table 56-12) . Several examples are reviewed, selected for their relevance to clinical practice or their instructive lessons about pathophysiology. Aminoacidopathies

Inborn errors of amino acid metabolism result in the accumulation of precursors and a deficit of end products, either or both of which can be detrimental. Alkaptonuria

An intermediate of tyrosine catabolism polymerizes to homogentisic acid, which readily accumulates in the extracellular matrix.[310] Over many years, connective tissue of cartilage, heart valves, and arteries becomes increasingly abnormal. Aortic stenosis and arteriosclerosis are the cardiological sequelae. Homocystinuria

This condition is caused by a deficiency of cystathionine beta-synthase; the pathogenesis of the pleiotropic manifestations is largely unknown.[13] [311] [312] Perhaps the amino acid sulfhydryl groups bind to collagen, fibrillin, and other macromolecules and interfere with cross-linking. The clinical features, once confused with Marfan syndrome, include tall stature, skeletal deformity, ectopia lentis, mental retardation, psychiatric disturbances, and a predilection for venous and arterial thromboses. Those patients with mutations that render the enzyme activity able to be increased by pharmacological doses of pyridoxine are less severely affected; early treatment can prevent most aspects of the phenotype.[313] [313A] Patients unresponsive to pyridoxine can be helped by a low-protein diet to reduce intake of methionine and by oral betaine, a co-factor

essential for remethylation of homocysteine. Myocardial infarction, pulmonary embolism, and stroke are the most common causes of death. The pathogenesis of the vascular complications was once thought to involve abnormal platelet function, but platelet survival in untreated patients is normal.[314] Growing evidence supports a susceptibility of heterozygotes, who have none of the external phenotype of the disease, to atherosclerosis.[315] [316] [317] Various actions of homocysteine on endothelial receptors, stimulation of smooth muscle growth, and production of extracellular matrix components are being explored for clinical relevance.[318] [319] Current therapeutic approaches are focused on maintaining physiological levels of the co-factors involved in metabolism of sulfurated amino acids--folate and vitamins B6 and B12 .[320] Disorders of Fatty Acid Metabolism

Although most organs can metabolize fatty acids when faced with hypoglycemia, only the heart depends on fatty acids as the primary source of energy generation. Thus, it is not surprising that virtually all genetic defects in fatty acid metabolism, including generalized defects in mitochondria and peroxisomes, are associated with myocardial dysfunction. Other substrates--glucose, lactate, and oxaloacetate--also generate energy in myocardial cells by entry into mitochondria and the tricarboxylic acid (Krebs) cycle. Thus, defects in conversion of pyruvate to acetyl coenzyme A and in any point along the tricarboxylic acid cycle and the respiratory chain have a major impact on myocardial energy generation. Quite likely, some sporadic and familial instances of idiopathic cardiomyopathy may represent undiagnosed or undefined metabolic disorders. CARNITINE DEFICIENCIES.

Carnitine is a required co-factor for entry of long-chain fatty acids into mitochondria and is both synthesized endogenously and available from dietary sources.[321] Deficiency of carnitine effectively blocks metabolism of long-chain fatty acids throughout the body and hepatic metabolism of ketones. Because of their relative dependence on fatty acids, muscle cells, including myocytes, suffer out of proportion to other tissue when carnitine levels are low for any reason. Cytoplasmic inclusions of lipid are characteristic findings in myocytes and hepatocytes. Several mendelian defects produce primary or secondary carnitine deficiency. An autosomal recessive defect in carnitine palmitoyltransferase I leads to increased plasma carnitine and a skeletal muscle myopathy with little effect on the heart.[321] So-called systemic carnitine deficiency can have various causes: primary deficiency of intake, synthesis, or function, and secondary deficiency, the majority now known to be a result of defects in fatty acid metabolism. The latter group of conditions usually does not respond to pharmacological doses of carnitine.[321] [323] Primary carnitine deficiency usually presents in infancy with hypoglycemia, coma, and congestive heart failure due to dilated cardiomyopathy. In the few cases reported, problems largely resolve with carnitine treatment; they can be prevented from recurring

by oral supplementation with L-carnitine. [323] [324] Primary systemic carnitine deficiency is due to a defect in carnitine transport, which leads to excessive urinary loss and which affects muscle but not liver. [322] Thus, muscle cells still may be relatively deficient in carnitine, despite supplementation, and long-term prognosis is uncertain. DEFECTS OF BETA-OXIDATION.

At least 20 steps are involved when a molecule of free fatty acid leaves the plasma, enters beta-oxidation in the mitochondrion, and generates electrons and acetyl-CoA[321] At each turn of the oxidation spiral, two carbons are removed from the fatty

2005

acid, and the enzymes involved in this step are specific for substrates of only certain chain length: long-chain, medium-chain, and short-chain acetyl-CoA dehydrogenases, or LCAD, MCAD, and SCAD. Thus far, patients with defects in nine of the steps have been characterized. Patients homozygous for these generally autosomal recessive disorders develop episodic hypoketotic hypoglycemia, usually associated with fasting or intercurrent illness. Deficiency of MCAD is the most common cause and occurs in about 1 of every 7000 newborns in the United States. Hypoglycemic crises can rapidly progress to coma and death, and 50 to 60 percent of affected infants die in the first 2 years of life.[325] Because infants between episodes or before a fatal crisis appear normal, MCAD deficiency accounts for a proportion of so-called sudden infant deaths.[326] Histopathological examination shows microvesicular accumulation of fat in cardiac and skeletal muscle. One mutation in MCAD (A985G) accounts for a large percentage of all alleles that predispose to this lethal disorder, and various approaches to newborn screening are being investigated. MITOCHONDRIAL MYOPATHIES.

All of the enzymes of fatty acid oxidation are encoded by genes located on nuclear chromosomes, but the components of the electron transport chain are encoded by both nuclear and mitochondrial genes. Several syndromes involving various types of myopathies have been shown to be due to mutations in the mitochondrial chromosome.[10] [11] The Kearns-Sayre syndrome includes pigmentary degeneration of the retina, ophthalmoplegia, and cardiomyopathy as its most prominent manifestations; all of the affected tissues rely nearly exclusively on oxidative phosphorylation for energy generation. The MELAS syndrome (myopathy, encephalopathy, lactic acidosis, and strokelike episodes) is due to mutations in mitochondrial transfer RNA genes.[328] [329] In addition to the features that define the acronym, hypertrophic cardiomyopathy and diffuse coronary angiopathy are common. Various other mtDNA mutations are associated with

hypertrophic or dilated cardiomyopathy.[185] [330] Variations in both the actual mutations and the fraction of abnormal mitochondria in the cells of the different organs (heteroplasmy) account for many of the clinical differences in phenotype, severity, and age of onset among patients with this disorder. Inheritance is maternal for patients with mitochondrial mutations; apparent autosomal recessive and dominant inheritance may indicate that mutations of nuclear genes can impair electron transport similarly to mitochondrial mutations. Some patients have been treated with moderate success over the short term with coenzyme Q[331] and with cardiac transplantation in one case.[332] Glycogenoses

Three of the glycogen storage disorders affect cardiac muscle. GLYCOGEN STORAGE DISEASE II.

This autosomal recessive condition is due to deficiency of the lysosomal enzyme alpha-1,4-glucosidase and results in the lysosomal accumulation of glycogen in most tissues. Several allelic variants occur.[333] The condition with infantile onset is called Pompe disease, and cardiac involvement is profound.[334] Infants with Pompe disease appear well initially but soon fail to thrive and develop hypotonia, tachypnea, and tachycardia; the disease progresses during the first year to irreversible congestive heart failure and death due to pneumonia or cardiopulmonary failure. Auscultation typically reveals no murmurs until late in the course when obstruction develops, and hypoglycemia does not appear because the nonlysosomal pathway of glycogen catabolism is intact. The diagnosis is suggested by massive cardiomegaly on examination and chest radiography and by characteristic echocardiographic abnormalities of a short PR interval and markedly increased QRS voltage.[335] Echocardiography shows tremendously thickened (pseudohypertrophic) ventricles, and Doppler interrogation or catheterization may reveal subaortic and subpulmonic pressure gradients characteristic of obstructive cardiomyopathy. Reduced diastolic function of a restrictive cardiomyopathy develops eventually, and endocardial fibroelastosis is common.[335] [336] With these findings, the diagnosis of Pompe disease is virtually certain, but it can be confirmed by analysis of alpha-1,4-glucosidase activity in cultured fibroblasts. Prenatal diagnosis is possible by enzymatic assay of amniocytes. Treatment is supportive, but cardiac transplantation could correct the cardiac problem; unfortunately, involvement of other organs, including the lungs, liver, and skeletal muscle, might eventually prove just as serious as the cardiomyopathy. Bone marrow transplantation might be a solution if performed early in the course. An animal model of alpha-1,4-glucosidase deficiency exists in cattle and develops cardiac pathology typical of human Pompe disease.[337] Cardiomyopathy may develop in the juvenile-onset form of alpha-1,4-glucosidase deficiency,[338] but it is not invariable because of allelic heterogeneity. In one sibship without cardiac involvement, three brothers had extensive hepatic, skeletal muscle, and arterial smooth muscle accumulation of glycogen, and each died of rupture of a basilar

artery aneurysm.[339] The adult-onset form usually presents with insidious onset of respiratory insufficiency, and clinically important cardiac disease is rare.[340] GLYCOGEN STORAGE DISEASE III.

The striking clinical variability in phenotype associated with deficiency of alpha-1,4-glucosidase is due in large part to the extensive array of mutations that occur at the GAA locus.[341] This autosomal recessive deficiency of amylo-1,6-glucosidase results in infantile- and juvenile-onset syndromes of muscle weakness, wasting, and hepatomegaly. Clinical cardiac disease is not common, although both cytoplasmic (nonlysosomal) and intermyofibril glycogen is routinely present in the heart and causes pseudohypertrophy and increased voltage on electrocardiography. The diagnosis has been established by enzymatic assay of an endomyocardial biopsy specimen.[342] [343] [344] GLYCOGEN STORAGE DISEASE IV.

This is caused by deficiency of alpha-1,4-glucan: alpha-1,4-glucan 6-glycosyl transferase. It usually causes a fatal disorder of early childhood characterized by hepatic failure; although extensive deposition of polysaccharide occurs in the heart, death intervenes before cardiac symptoms appear. In the most severe form, the fetus has hydrops and generalized muscle degeneration.[345] As with all of the glycogen storage diseases, extensive allelic heterogeneity results in milder forms of the classic disorders. Patients with diagnosis later in adolescence tend to have more severe cardiomyopathy.[346] [347] Liver transplantation has been life saving in some cases and has, somewhat surprisingly, resulted in a reduction of glycogen deposits in the heart and skeletal muscles.[348] [349] CARDIAC PHOSPHORYLASE KINASE DEFICIENCY.

Few cases of this enzyme deficiency have been reported: deposition of glycogen is confined to the heart, which may be massively thickened and enlarged, and leads to early death.[350] [351] GLYCOPROTEINOSES.

This group of disorders results in the lysosomal accumulation of various compounds that cannot be catabolized further because of the specific enzyme deficiency (see Table 56-12) . Some have prominent cardiac pathology, generally of pseudohypertrophy and valvular thickening, which present with congestive failure, valvular dysfunction, conduction defects, or dysrhythmia.[352] Hematological Disorders (See Chap. 69) HEMOCHROMATOSIS.

This autosomal recessive disorder of unknown cause results in iron deposition in many

tissues, including the myocardium. The manifestations include diabetes mellitus, skin hyperpigmentation, hypogonadism, hepatic failure with cirrhosis, hepatoma, and congestive heart failure; severity is less, and age of onset later in women because of the autophlebotomy provided by menstruation.[353] The cause of the most common form of hereditary hemochromatosis is a gene, HFE, that is closely linked to the major histocompatibility locus on chromosome 6. One specific mutation accounts for a large proportion of the mutant alleles among whites.[354] Fully 10 percent of the population is heterozygous for a hemochromatosis mutation, suggesting that at an incidence of 2 to 3 per 1000, this disease is underdiagnosed. This frequency has given rise to interest in population screening by molecular genetic techniques, but for now traditional clinical laboratory approaches are appropriate.[355] Diagnosis depends on finding increased serum iron, ferritin, and, especially, transferrin saturation in the absence of any obvious cause of excessive iron intake.[356] Cardiac involvement often appears first as dysrhythmia or congestive heart failure. Dysrhythmia, conduction abnormalities, and low QRS voltage are typical electrocardiographic findings; cardiomegaly is seen on chest radiography, and a dilated cardiomyopathy with reduced systolic

2006

function can be documented on echocardiography.[357] [358] Occasional patients have a restrictive pattern on cardiac catheterization. [359] Treatment by repeated phlebotomy is most effective if begun before organ damage is irreversible. If a patient with congestive heart failure has not yet developed serious compromise in other organs, cardiac transplantation may be contemplated, as may combined heart-liver replacement. HEMOGLOBINOPATHIES (See also Chap. 69) .

Sickle cell disease and other hemoglobinopathies associated with sickling can produce ischemia and infarction in numerous organs by occlusion of small vessels[360] ; however, the heart is relatively resistant.[361] Nonetheless, the combination of chronic hypoxemia and anemia produces a sustained high-output state that leads to congestive heart failure in many adults. The cardiovascular system can also be compromized by systemic hypertension due to renal infarction, pulmonary embolism and infarction (the chest pain of which often causes concern about myocardial ischemia), pulmonary hypertension,[362] stroke,[360] and hemosiderosis from chronic transfusions. In addition to a hyperdynamic congestive failure, iron overload is the principal risk to the myocardium in other causes of decreased erythrocyte production (thalassemias) and increased erythrocyte consumption (hemolytic anemias) requiring repeated transfusions. Treatment with daily injections of deferoxamine can, if begun early, prevent the development of severe cardiac and hepatic disease.[363] Development of an oral iron chelator would greatly improve compliance and efficacy. Various approaches to

management of sickle cell disease, including hydroxyurea, show promise.[364] Combined heart-liver transplantation has been used in a case of end-stage organ failure with homozygous beta-thalassemia.[365] Mucopolysaccharidoses and Disorders of Targeting Lysosomal Enzymes

Many of the specific disorders in these two groups share phenotypical manifestations and are caused by various defects in the ability of lysosomes to catabolize proteoglycan and glycosaminoglycan. Short stature, progressive coarsening of facial features, a skeletal dysplasia termed dysostosis multiplex, corneal clouding, and protean effects on the cardiovascular system are common[366] [367] [368] [369] [370] (Fig. 56-11) . Only MPS IS (Schele syndrome), the mild form of MPS IH (mild Hunter syndrome), MPS IV (Morquio syndrome), and MPS VI (Maroteaux-Lamy syndrome) have minimal or no mental impairment. CARDIOVASCULAR MANIFESTATIONS.

The cardiovascular complications (see Table 56-12) , which are all progressive and usually insidious, arise from engorgement of cells and tissues with macromolecular storage material.[371] First, the ventricular walls become pseudohypertrophic, and systolic function gradually deteriorates. The electrocardiogram shows reduced QRS voltages; rarely is any conduction disturbance present. Second, coronary arteries narrow because of intimal and medial thickening.[372] Myocardial infarction is common in MPS IH and the severe form of MPS II, although the patients are usually too retarded to complain of classical symptoms, and the diagnosis is made post mortem.[373] Third, valve leaflets thicken and cause progressive dysfunction that is oddly specific for individual disorders. For example, aortic stenosis is common in MPS IS, and mitral regurgitation is frequently found in MPS IH and MPS IV. Finally, narrowing of the upper and middle airways causes obstructive apnea, chronic hypoxemia and hypercarbia, pulmonary hypertension, and eventually cor pulmonale.[374] [375] MANAGEMENT.

Treatment of children with those conditions that caused mental retardation has in the past been supportive. Increasing experience with bone marrow transplantation in many of the conditions shows that in the survivors of the transplant, somatic accumulation of mucopolysaccharide can be reduced, with clinical improvement in cardiopulmonary function.[366] [376] [377] However, improvement of central nervous system function has been marginal or absent. Nonetheless, bone marrow transplantation may have a role, especially in MPS IV and MPS VI, in which cardiopulmonary compromise can greatly shorten otherwise productive lives. Attempts at cardiovascular surgery, indeed of any procedure requiring general anesthesia, are fraught with risks of difficult intubation, hyperextension of the neck with cervical cord damage (the odontoid process is often hypoplastic), and prolonged efforts to wean from mechanical ventilation.[374]

Figure 56-11 Hurler syndrome in a 4-year-old girl. Note short stature and coarse facial features. Sphingolipidoses FABRY DISEASE.

This X-linked condition deserves comment because the diagnosis is often not made until adulthood, when serious end-organ damage has occurred.[378] As a result of deficiency of alpha-galactosidase A, ceramide trihexoside and other glycosphingolipids accumulate in lysosomes of many cells and organs, especially endothelial cells, glomerular and tubular cells of the kidneys, and the heart. Microangiopathy causes the characteristic skin lesion, angiokeratoma, and may contribute, along with primary nerve involvement, to acroparesthesias and painful crises. Proteinuria and hypertension precede renal failure, which has often led to death in males and often leads by the fourth decade to the need for long-term dialysis or renal transplantation. A successful kidney allograft does not correct the systemic metabolic defect,[379] and the disease usually progresses in other organs.[380] Infusion of purified human alpha-galactosidase A shows promise of reducing tissue storage of glycosphingolipid.[380A] CARDIAC MANIFESTATIONS.

Structural and functional cardiac involvement is qualitatively similar to that in the mucopolysaccharidoses. Thickening of the myocardium is pseudohypertrophy due to deposition of glycosphingolipid in lysosomes; the diagnosis has been made by endocardial biopsy during the evaluation of unexplained ventricular hypertrophy or frank obstructive cardiomyopathy.[381] [382] [383] [384] Chronic hypertension can exaggerate left ventricular dysfunction, as can ischemia and infarction due to diffuse luminal narrowing of the coronary arteries. Echocardiography is useful for serial documentation of myocardial function.[385] Although valvular thickening and MVP are common, hemodynamically important mitral regurgitation is not.[386] The pulmonary vasculature becomes narrowed and right-sided pressures rise, but cor pulmonale is rarely a problem. The electrocardiogram often shows a shortened PR interval, increased left ventricular voltages, and dysrhythmia. Medium-sized arteries throughout the body develop luminal narrowing, with cerebrovascular disease the most common cause of death after renal failure. Heterozygous females generally show some clinical manifestations, especially in the eyes, and at much later ages than hemizygous males develop renal, cerebrovascular, and cardiac disease.[378] [385] [386] [387] Prenatal diagnosis is possible, and a detailed family history and genetic counseling are essential whenever the disease is found. Various mutations occur in the gene for alpha-galactosidase A and account for much of the clinical variability.[382] [384] [388] Familial Amyloidoses (See also Chap. 48)

Various disorders, defined initially by clinical phenotype and due to progressive accumulation of amyloid in organs and tissues, are beginning to be categorized by the

underlying biochemical and genetic defects.[389] The several conditions termed familial amyloidosis with polyneuropathy and originally classified as separate autosomal dominant disorders are now known to be due to different mutations in the

2007

same gene encoding transthyretin, a thyroxine- and retinol-binding protein also called prealbumin. Although polyneuropathy dominates the early course during young adulthood, renal failure and restrictive cardiomyopathy supervene later and cause death in most cases. The age of onset, severity, and predilection for kidney and cardiac involvement are determined by the type of mutation, with males affected earlier and more severely.[390] [391] [392] Liver transplatation can prevent progression of the disease and potentially reverse some tissue accumulation[393] ; when the myocardium is severely infiltrated, combined liver-heart transplant offers the only hope. NEUROMUSCULAR DISORDERS (See Chap. 71) CARDIAC TUMORS (See also Chap. 49) The three most common tumors that originate in the heart are myxomas, fibromas, and rhabdomyomas. All occur as part of hereditary syndromes and as sporadic events. The new occurrence of any of these tumors, especially in a child, may represent the first manifestation of a systemic condition, so a detailed general examination and family history are always indicated.[394] [395] [396] [397] For example, 51 to 86 percent of cardiac rhabdomyomas occur because of tuberous sclerosis.[398] [398A] Tumors due to hereditary disorders tend to be multiple and to recur after resection. An example is the NAME syndrome (for nevi, atrial myxoma, myxoid neurofibromata, and ephelides; the acronym ignores the numerous endocrine tumors) also called Carney complex, in which many myxoma can occur throughout the myocardium. [399] [400] [401] [402] [403] [404] INHERITED DISORDERS OF THE CIRCULATION Hereditary Hemorrhagic Telangiectasia

This autosomal dominant condition, often called Osler-Rendu-Weber disease, is more common than appreciated. Because of marked intrafamilial and interfamilial variability, the condition may remain undiagnosed in affected patients for years despite mild manifestations.[405] [406] [406A] Mucocutaneous telangiectases, 0.5 to 3 mm in diameter, occur on the tongue, lips, and fingertips most commonly. Small and moderate-sized arteriovenous fistulas occur in the nose, leading to recurrent epistaxis, in the gastrointestinal system, where they cause recurrent bleeding and occult anemia, and in the lungs, resulting in hypoxemia, hemoptysis, polycythemia, clubbing, paradoxical embolization through the right-to-left shunt, and a hyperdynamic circulation. Less

common sites of vascular malformations are the brain,[407] [408] liver, [409] and the kidneys.[410] Diffuse ectasia of the coronary arteries was noted in one patient. [411] and hemorrhagic pericarditis with tamponade in another.[412] Bleeding is facilitated, even in the presence of normal platelet function and clotting function, because of the lack of resistance channels in the telangiectatic lesions.[413] Patients with hereditary hemorrhagic telangiectasia (HHT) and their close relatives should be screened for pulmonary arteriovenous malformations through auscultation, arterial blood gas analysis, and chest radiography. A low PaO2 should prompt consideration of angiography and therapeutic balloon occlusion of the feeding arteries of any sizable malformation to prevent systemic embolization, especially to the brain.[414] In a few patients, epistaxis and gastrointestinal blood loss have been reduced by antifibrinolytic therapy with danazol or aminocaproic acid.[415] [416] [417] Controlled trials of various approaches to chronic management, taking into account clinical and genetic variables, are sorely needed. At least three genes are capable of causing HHT, and two have been mapped, to 9q33-q34 and to 3p22. The former locus encodes a transforming growth factor-beta-binding protein called endoglin, and various mutations segregate with HHT in different families.[418] The other locus encodes an activin receptor-like kinase 1 gene,[419] which is a member of the serine-threonine kinase receptor family, expressed in endothelial cells. This suggests that defects in this gene might affect development or repair of vessels. Yet a third locus is likely.[420] Thus, by mutation detection or linkage analysis, presymptomatic and prenatal diagnosis is available to a large number of patients with a potentially life-threatening disorder. Von Hippel-Lindau Syndrome

The features of this autosomal dominant condition involve malformations and abnormal growth of small blood vessels. Retinal angioma, hemangioblastoma of the cerebellum, and hemangioma of the spinal cord occur in association with renal cell carcinoma, pancreatic and epididymal cystadenomas, and pheochromocytoma.[421] [422] Secondary hypertension due to renal disease and pheochromocytoma, which is often bilateral, occurs and predisposes to subarachnoid hemorrhage. The cause is a tumor suppressor gene, VHL, at 3p26-p25. [423] Patients inherit a germline mutation (and there is great diversity among families in the actual mutations)[424] that is present in all cells. When a somatic mutation in the normal allele occurs in a susceptible cell, such as in the renal parenchyma or adrenal medulla, the cell becomes functionally homozygous for a lack of the gene product, and the cascade toward neoplasia is initiated.[425] How this gene product stimulates or permits angiomatous malformations is unclear. Disorders Primarily Affecting Arteries

Mendellan disorders are associated with a diverse array of arterial pathology, and some were described or catalogued earlier in this chapter. This section deals with two categories of disorders caused by a single mutant gene: pleiotropic syndromes better known for affecting organ systems other than the vasculature, and primary

abnormalities of arteries. ADULT POLYCYSTIC KIDNEY DISEASE (APKD).

This relatively common autosomal dominant disease affects 0.5 million people and accounts for 8 to 10 percent of all long-term hemodialysis in the United States. Development of renal cysts is age dependent, and presymptomatic detection of heterozygotes, even by ultrasonography, can be uncertain into adulthood.[426] [427] About one-half of patients are hypertensive, one-half have hepatic cysts, one-half eventually develop severe renal failure, and an unknown (but probably high) fraction have colonic diverticula. Elevated plasma renin levels contribute to hypertension long before renal failure occurs.[428] The cardiovascular manifestations include MVP in one-quarter, mild dilatation of the aortic root, occasional thoracic and abdominal aneurysms, and a predisposition to regurgitation of the aortic, mitral, and tricuspid valves.[429] [430] [431] The association of diverticula, organ cysts, and cardiovascular lesions reminiscent of but milder than Marfan syndrome suggests some involvement of the extracellular matrix. The most serious vascular problem is typical berry aneurysms of the cerebral circulation, which occur in about 10 percent of heterozygotes but may remain asymptomatic throughout life. Hypertension predisposes to subarachnoid hemorrhage. How to screen for and treat intracranial aneurysms in patients without neurological symptoms remains controversial. Cerebral angiography carries higher risks in patients with APKD because of dissection and heightened vascular reactivity.[432] Magnetic resonance imaging detects most saccular aneurysms down to 2 to 3 mm in diameter. Whether to attempt prophylactic repair when a small aneurysm is detected has not been investigated systematically. Without question, aggressive blood pressure control is indicated in any patient with APKD. At least three genes cause APKD. The greatest portion of cases are due to mutations in a gene called PBP at the PKD1 locus (16p13.3).[432A]

2008

In most of the rest of families, the disease maps to the PKD2 locus in the region 4q23-q23. Families affected by mutations in PKD2 tend to develop renal failure later and have a milder course.[433] In both PKD1 and PKD2, the multiorgan cysts develop when a somatic mutation occurs in the normal allele at the respective mutant locus, analogous to the two-hit model so familiar with tumorigenesis.[434] [435] A French Canadian family with disease typical of PKD1 is unlinked to either locus, indicating that a PKD3 gene exists.[436] ARTERIOHEPATIC DYSPLASIA.

An autosomal dominant disorder of marked variability, Alagille syndrome causes neonatal jaundice due to aplasia of intrahepatic bile ducts and congestive heart failure in the most severely affected infants but may be asymptomatic in heterozygous

relatives.[437] [438] The cardiovascular findings include peripheral pulmonic and systemic arterial stenoses in the majority, occasionally associated with septal defects or PDA. A diffuse vasculopathy is present in some patients.[439] Renal disease may produce hypertension. The locus was initially mapped by studying chromosomes and finding in some patients that part or all of band 20p12 was missing (an interstitial deletion). The Jagged1 gene, which mapped to this exact region, was then identified as the cause.[440] [441]

ARTERIAL ANEURYSM, ECTASIA, OR DISSECTION

(see also Chaps. 30 , 40 , and 41) . Pedigrees abound in which dilatation of the aortic root, aneurysm of the abdominal aorta, aortic dissection without dilatation, or a combination of these problems occurs in an autosomal dominant pattern without evidence of a recognized heritable disorder of connective tissue.[442] [443] [444] Because of the variable presentation and natural history of the aortic disease, presymptomatic detection of presumed heterozygotes is uncertain, as is reassurance of relatives at risk who are of childbearing age and would prefer not to pass this condition to offspring. The association of dissection of the ascending aorta with bicuspid aortic valve and aortic coarctation is well known, although the cause and pathogenesis remain unclear. In such cases, the aortic wall shows abnormalities of elastic fibers.[445] A person with a congenitally bicuspid aortic valve or aortic coarctation should be screened for dilatation of the aortic root, and first-degree relatives should be screened for both lesions. This recommendation is based, in part, on bicuspid aortic valve being a congenital heart defect of the left-sided flow category, with a relatively high recurrence risk. In two families with autosomal dominant transmission of arterial aneurysms and mild increased skin fragility and bruisability, different mutations in the gene encoding type III procollagen occurred.[446] [447] Thus, depending on the mutation, deficiency of type III collagen can cause the vascular form of Ehlers-Danlos syndrome (see p. 2003 ) or a form of the much subtler but just as deadly syndrome, familial arterial rupture. For these families in which the mutations have been defined, reliable presymptomatic and prenatal diagnoses are at hand. However, suggestions that mutations in type III collagen would account for the majority of aortic aneurysms, including abdominal aneurysms in the elderly, have proved unfounded.[448] A predisposition to cervical arterial dissection in young people was found to be associated with diffuse lentiginosis in several families, with a suggestion of autosomal recessive inheritance.[449] An association is also noted between cervical dissection and intracranial hemorrhage, which is increased when congenital casdiovascular defects are present, especially bicuspid aortic valve or aortic coarctation.[450] [451] Formal genetic analysis of 91 families ascertained through a proband with abdominal aortic aneurysm suggests that an autosomal recessive predisposition exists for late-onset aneurysms.[452] This study and others [453] provide a rationale for offering ultrasound screening to sibs of patients with abdominal aortic dilatation.

FAMILIAL ARTERIAL TORTUOSITY.

This is a rare, possibly autosomal recessive condition of unknown cause. Diffuse ectasia of all systemic arteries occurs with, paradoxically, peripheral pulmonic stenoses.[454] FAMILIAL INTRACRANIAL HEMORRHAGE.

In addition to APKD, three syndromes predispose to subarachnoid or cerebral hemorrhage. Berry aneurysms without pleiotropic manifestations in other organs are a rare but well-documented autosomal dominant trait.[455] How aggressively near relatives should be screened for intracranial aneurysms remains controversial because of the relatively low risk of hemorrhage compared with the morbidity and mortality of current surgical techniques for repairing defects.[456] [457] [457A] A defect in type III collagen was suggested by linkage analysis, but sequence analysis of the gene in 55 unrelated patients found no mutations.[458] The cerebral arterial type of familial amyloidosis (type VI) is an autosomal dominant condition due to a defect in the proteinase inhibitor cystatin O.[459] This disease is rare outside of Iceland and Holland. The walls of cerebral arteries are thickened by a material resembling amyloid, and the vessels become tortuous and fragile. Recurrent cerebral hemorrhage is common in the fifth and sixth decades of life. [460] Familial hemangiomas have been reported infrequently to occur as an autosomal dominant condition.[461] The brain and retina are the principal sites of vascular malformation, although in some pedigrees, cutaneous lesions occur. The intracranial hemangioma can be large and present with varied neurological symptoms, including hemorrhage. A more benign familial disorder of primarily isolated cutaneous hemangiomas also exists.[462] FAMILIAL ARTERIAL OCCLUSIVE DISEASES.[ 463]

Fibromuscular dysplasia of the renal and other arteries occurs in von Recklinghausen neurofibromatosis and, along with pheochromocytoma, can be a cause of hypertension.[464] [465] Severe deficiency of alpha1 -antiprotease is another cause of fibromuscular dysplasia.[466] The arterial lesion can occur by itself in families and produce stroke, myocardial infarction, intermittent claudication, and hypertension at young ages, as early as childhood.[467] Inheritance is most consistent with autosomal dominance.[468] Familial hypoplasia of the carotid arteries,[469] familial arteriopathy caused by concentric thickening of systemic and pulmonic arteries,[470] familial moyamoya disease (which has been mapped to 3p24.2-p26),[471] and generalized arterial calcification of infancy[472] all are rare, possibly mendelian, syndromes of unknown cause.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is due to mutations in the NOTCH3 gene.[472A] Characteristic inclusions occur in vascular smooth muscle cells, and the deep, perforating cerebral arterioles develop occlusions that produce insidious onset of symptoms and transient ischemic attacks. FAMILIAL HEMIPLEGIC MIGRAINE.

The migraine syndrome is commonly familial and occurs in many generations. A severe form, associated with recurrent hemiplegia, is inherited as an autosomal dominant trait and is due to mutations in a sodium channel gene.[473] [474] However, some families with hemiplegic migraine and others with simple migraine are unlinked to this locus.[475] [476] In the same region of 19p is a locus causing autosomal dominant cerebral arteriopathy with subcortical infarcts.[477] Whether the two conditions are related through allelism is unclear. FAMILIAL PULMONARY HYPERTENSION

(see also Chap. 53) . Primary pulmonary hypertension (PPH) is occasionally familiar.[478] [479] [480] Inheritance is most consistent with an autosomal dominant predisposition with sex influence favoring expression in females. A locus for PPH occurs in the region 2q31-q32 and the defect in some way leads to monoclonal proliferation of endothelial cells.[481] [482] [483] Molecular defects favoring recurrent microemboli to the pulmonary circulation afford another area to explore. Pulmonary hypertension can occur in neurofibromatosis due to pulmonary fibrosis. [484] Disorders Primarily Affecting Veins VARICOSE VEINS.

Although a familial susceptibility to varicosities of the lower extremities clearly exists and favors women in a ratio of 2:1, mendelian inheritance has not been confirmed. Marfan syndrome, various Ehlers-Danios syndromes, and an autosomal recessive condition featuring distichiasis (a double row of eyelashes)[485] predispose to varicose veins. ATRETIC VEINS.

Some patients with the Klippel-Trenaunay-Weber syndrome of cutaneous hemangioma and hemihypertrophy have atresia of the deep venous system. [486] The concomitant superficial varicosities should not be stripped, lest the remaining venous drainage of the lower extremity be removed. This is a confusing syndrome that overlaps with several others; mendelian inheritance is uncertain. Renal arterial aneurysm and hemangioma occurred in one patient.[487]

CAVERNOUS ANGIOMAS.

Cavernous angiomas represent at least 15 percent of vascular malformations of the central nervous system, and familial occurrence is common.[488] These are not arteriovenous malformations but primarily a tortuous collection of veins. Seizure is the most common presenting feature, followed by headache, stroke, and progressive neurological deficit. Magnetic resonance (T2 -weighted) imaging is the procedure of choice because it is sensitive, and arteriography is not likely to detect the venous malformation. In some families, hepatic angiomas are an important feature.[489] The cause of one form has been identified as a gene, KRIT1, of unclear function. [490] [491] [492] ARTERIOVENOUS MALFORMATIONS.

The most common mendelian cause of arteriovenous malformations (AVM) is the various forms of hereditary hemorrhagic telangiectasia. However, AVM, especially of the brain, are relatively common findings,[493] and other genetic susceptibilities may exist. Disorders Primarily Affecting Lymphatics

Several forms of hereditary lymphedema exist, with the best studied inherited as autosomal dominants. An early-onset form bears the eponym Nonne-Milroy lymphedema and can cause a protein-losing enteropathy and pleural effusion. Meige lymphedema does not appear until about the time of puberty and is most severe in the legs, although one family with late-onset edema had involvement of the arms

2009

and face.[494] Considerable intrafamilial variability in age of onset is noted, however, and whether two or more distinct conditions exist remains unclear. Mutations in one of the receptors for vascular endothelial growth factor, FLT4, have been found in some families.[495] [496] GENETIC FACTORS PREDISPOSING TO ATHEROSCLEROSIS (see also Chap. 31) Various genetic factors, in addition to the well-studied errors of lipid metabolism, clearly predispose to atherosclerosis. Few genes outside of those involved in lipid metabolism have such an overwhelming impact as to be identifiable from the family history. However, genes that predispose to hypertension and diabetes mellitus; control arterial diameter, reactivity, and branching angles; affect platelet adhesiveness, thrombosis, and fibrinolysis; and regulate endothelial and smooth muscle function all can be considered candidate genes for study in families predisposed to atherosclerosis.[497] [498] [499] Screening numerous genes for common mutations and polymorphisms that convey risk information will be increasing possible.[501] [502]

ABNORMAL REGULATION OF BLOOD PRESSURE (see also Chap. 28) Blood pressure is a quantifiable trait that shows continuous variation within the population. Although many genes and environmental factors undoubtedly affect a person's blood pressure, familial transmission of some arbitrarily defined disease "hypertension" follows neither mendelian nor multifactorial inheritance.[503] [504] [505] Various cybernetic systems operate to maintain the blood pressure within tolerable limits. When this physiological homeostasis goes awry or its limits are too lax, pathological and clinical consequences occur.[509] For example, sensitivity of the baroreflex was impaired in patients who had untreated essential hypertension and a positive family history of hypertension compared with hypertensive patients with no family history and to nonhypertensive controls.[506] The complexities of such systems are considerable, and two approaches have been taken in recent years to focus the analysis.[505] [507] [508] [509] One involves a candidate-gene approach in humans, based on loci known to be involved in physiological pathways, and the second involves naturally occurring and experimentally created strains of animals. STUDIES OF HUMANS.

All of the classical approaches to detecting genetic influences in diseases--twin studies, familial aggregation, adoption--confirm that genes have a role, but less than 5 percent of patients with hypertension have a defined genetic cause. Occasional families show striking mendelian segregation of hypertension without being associated with one of the identifiable syndromes listed in Table 56-13 . One example, in which early, severe hypertension is inherited as an autosomal dominant trait, is Liddle syndrome.[510] [511] Because of hypokalemia, aldosteronism was suspected, but both aldosterone and renin levels were low. Attention then focused on sodium resorption in the distal nephron and its regulation. Mutations discovered in the beta subunit of the epithelial sodium channel render the channel insensitive to the usual regulators. Another example of successful application of the candidate gene approach is investigation of glucocorticoid-remediable aldosteronism.[512] The phenotype was mapped to chromosome 8q21, a region already known to contain two candidate genes, aldosterone synthase and 11beta-hydroxylase. By honing in on these loci, mutations creating a chimeric gene by unequal recombination were found to be the cause.[513] As a result of the fusion, aldosterone synthase comes under regulation of adrenocorticotropic hormone. The actual frequency of such mutational events is considerably higher than suspected in the population, and the molecular means are now available to assess the epidemiology of what will likely be a common cause of early hypertension. Angiotensinogen, the gene for which is in the region 1q42-q43, is a logical candidate gene to investigate because of the central role of its product in blood pressure regulation. Several polymorphic variants involving single amino acid substitutions occur; at positions 174 and 235, either methionine (M) or threonine (T) can exist. The special effects of these polymorphisms on activity, if any, are unclear, but persons homozygous for the 235T allele have plasma angiotensinogen levels 20 percent higher than those

with the 235M alleles. Some but not all studies have found an association between the 174M and 235T alleles and hypertension.[514] [515] [516] The importance of these polymorphisms seems to depend on the ethnic background.[517] The ACE gene, at 17q23, contains a common insertion/deletion polymorphism, termed I and D, respectively, that permits both association and linkage studies. The three possible genotypes are DD, ID, and II, and the plasma level of ACE is highest, for unclear reasons, in persons who are DD and lowest in those who are II. The DD genotype has been associated with predisposition to coronary artery disease and to myocardial infarction, which may account for a relative decrease of hypertensive patients with the DD genotype at older ages.[518] [519] Pregnancy is a clear risk factor for hypertension. A susceptibility locus for preeclampsia has been identified.[520] [521] The opposite of hypertension, inappropriate control of pressure on the low side, also has numerous genetic bases (Table 56-15) . [504] [522] [523] STUDIES IN ANIMALS.

The stroke-prone spontaneously hypertensive (SHRSP) rat is an example of an animal model for a human disease that arose in nature. The phenotype of the rat is clearly polygenic and is thus particularly relevant to much of essential hypertension in humans. Using polymorphic markers spread throughout the rat genome, it has been possible to conduct linkage analyses of hundreds of markers with hypertension when SHRSP animals were crossed with a nonhypertensive strain. Two loci have been identified, and one lies close to where ACE maps.[524] This general approach, called quantitative trait mapping or linkage (QTL), is increasingly being applied to various phenotypes in animals and humans. Determining the actual gene involved in the animal model should then suggest that the homologous locus in the human is a candidate for participation in normal and abnormal regulation of the trait. A second approach in animals involves transgenic or knockout techniques to create and breed a new, specific genotype. In simplest terms, a given gene can be eliminated, can be mutated in a specific way, can be moved to a different strain (genetic background), or can be overexpressed (See also Chap. 55) . For example, eliminating function of the gene that encodes atrial natriuretic peptide in the mouse resulted in moderate elevation of blood pressure when sodium intake was low or somewhat high. Mice heterozygous for the mutation had normal blood pressure on these salt loads but became abnormally hypertensive when fed a high-salt diet.[525] [526] A number of mendelian conditions, most of which are rare, cause major deviations of blood pressure from an appropriate physiological range (see Table 56-15) . These disorders are likely to be underdiagnosed.

2010

TABLE 56-15 -- MENDELIAN DISORDERS ASSOCIATED WITH ABNORMAL BLOOD PRESSURE DISORDER OMIM NO.* PATHOGENESIS Primarily elevated blood pressure Adrenal hyperplasia IV

202010,

11-beta-hydroxylase deficiency 11-deoxycorticosterone

Adrenal hyperplasia V

202110,

17-alpha-hydroxylase deficiency 11-deoxycorticosterone

Aldosteronism

103900, Aldosterone

Alport syndrome

104200,

Renal failure

105200,

Nephropathy

208000,

Arteriosclerosis

301050, Amyloidosis, familial visceral (amyloidosis VIII) Arterial calcification of infancy

Arterial fibromuscular dysplasia 135580,

Renal artery stenosis renin

Arteriohepatic dysplasia

118450,

Renal dysplasia; renal arterial stenosis

Bartter syndrome

241200,

Secondary to hyperaldosteronism

Fabry disease

301500,

Renal failure; renal arterial stenosis; arteriolar stenosis peripheral resistance

Liddle syndrome

177200,

Defective epithelial sodium channel k+ aldosterone, renin, angiotensin

Multiple endocrine neoplasia I

131100,

Adrenocortical adenoma Cushing syndrome

Multiple endocrine neoplasia II

171400,

Pheochromocytoma catecholamines

Nail-patella syndrome

161200,

Nephropathy

Neurofibromatosis type I

162200,

Pheochromocytoma catecholamines; and renal arterial fibromuscular dysplasia

Paraganglioma

168000, Catecholamines Pheochromocytoma catecholamines

Pheochromocytoma, familial

171300, Catecholamines

Polycystic kidney disease, adult 173900, 173910 Renin; renal failure Porphyria, acute intermittent

176000,

?, but only during acute attacks

Pseudohypoaldosteronism, type 264350,

Aldosterone receptor deficiency

Pseudohypoaldosteronism, type 145260,

Defective renal secretion of potassium

I II Pseudoxanthoma elasticum

177850,264800, Arteriosclerosis

Riley-Day syndrome

223900,

Dysautonomia

von Hippel-Lindau syndrome

193300,

Pheochromocytoma catecholamines

Wilms tumor

194070, 194071, 194090,

?

Primarily low blood pressure Dopamine beta-hydroxylase deficiency Fabry disease

223360, Synthesis of epinephrine 301500, Peripheral vascular tone

Hyperbradykininism

143850, Bradykinin

Pelizaeus-Merzbacher, late-onset

169500,

?

Peripheral motor neuropathy and dysautonomia

252320,

?

Pheochromocytoma, familial

171300, Catecholamines (epinephrine)

Shy-Drager syndrome

146500,

Primary autonomic insufficiency

*Data from Online Mendelian Inheritance in Man (www.ncbi.nlm.nih.gov/omim). Does not include hypovolemia, obstruction of blood flow, and cardiogeneic causes of hypotension, each of which subsumes numerous hereditary disorders as primary causes.

REFERENCES GENETIC FACTORS IN DISEASE 1.

Childs B: Genetic Medicine: A Logic of Disease. Baltimore, Johns Hopkins University Press, 1999.

Murphy EA, Pyeritz RE. Pathogenetics. In Rimoin DL, Connor JM, Pyeritz RE (eds): Principles and Practice of Medical Genetics. 3rd ed. New York, Churchill Livingstone, 1997, pp 359-370. 2.

Gardner RJ, Sutherland GR: Chromosome Abnormalities and Genetic Counseling. New York, Oxford University Press, 1989. 3.

4.

Borgaonkar D: Chromosomal Variation in Man. 8th ed. New York, John Wiley & Sons, 1997.

Ledbetter DH, Ballabio A: Molecular cytogenetics of continuous gene syndromes: Mechanisms and consequences of gene dosage imbalance. In Scriver CR, Beaudet AL, Sly WA, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill, 1995, p 811. 5.

Collins FS: Shattuck Lecture--Medical and societal consequences of the Human Genome Project. N Engl J Med 341: 28-37, 1999. 6.

Pyeritz RE: Genetic approaches to cardiovascular disease. In Chien KR, Breslow JL, Leiden JM, et al (eds): Molecular Basis of Cardiovascular Disease. Philadelphia, WB Saunders, 1999, pp 19-36. 7.

8.

Online Mendelian Inheritance in Man. www.ncbi.nlm.nih.gov/omim

9.

Pyeritz RE: Marfan syndrome and related disorders of connective tissue. Annu Rev Med (in press).

Wallace DC, Brown MD, Lott MT: Mitochondrial genetics. In Rimoin DL, Connor JM, Pyeritz RE (eds): Principles and Practice of Medical Genetics. 3rd ed. New York, Churchill Livingstone, 1997, pp 277-332. 10.

11.

Johns DR: The other human genome: Mitochondrial DNA and disease. Nat Med 2:1065-1068, 1996.

Pyeritz RE: Pleiotropy revisited: Molecular explanations of a classic concept. Am J Med Genet 34:124, 1989. 12.

Pyeritz RE: Homocystinuria. In Beighton P (ed): McKusick's Heritable Disorders of Connective Tissue. 5th ed. St. Louis, CV Mosby, 1993, p 137. 13.

Byers PH: Disorders of collagen biosynthesis and structure. In Scriver CR, Beaudet AL, Sly WA, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill, 1995. p 4029. 14.

Diano R, Bouchard C, Dumesnil J, et al: Parent-child resemblance in left ventricular echocardiographic measurements. Can J Appl Sport Sci 5:4, 1980. 15.

Adams TD, Yanowitz FG, Fisher AG, et al: Heritability of cardiac size: An echocardiographic and electrocardiographic study of monozygotic and dizygotic twins. Circulation 71:39, 1985. 16.

Herrington DM, Pearson TA: Clinical and angiographic similarities in twins with coronary artery disease. Am J Cardiol 59:366, 1987. 17.

Vlodaver Z, Kahn HA, Neufeld HN: The coronary arteries in early life in three different ethnic groups. Circulation 39:541, 1969. 18.

Moller P, Heiberg A: Atrioventricular conduction time--a heritable trait? II. Family studies. Clin Genet 18:454, 1980. 19.

19A. Friedlander

Y, Lapidos T, Sinnreich R, Kark JD: Genetic and environmental sources of QT interval variability in Israeli families: The kibbutz settlements family study. Clin Genet 56:200-209, 1999. Moller P, Heiberg A, Berg K: The atrioventricular conduction time--a heritable trait? III. Twin studies. Clin Genet 21:181, 1982. 20.

Hawlik RJ, Garrison RJ, Fabsitz R, et al: Variability of heart rate, P-R, QRS and QT durations in twins. J Electrocardiol 13:45, 1980. 21.

2011

Dinerman JL, Mehta JL: Endothelial, platelet and leukocyte interactions in ischemic heart disease: Insights into potential mechanisms and their clinical relevance. J Am Coll Cardiol 16:207, 1990. 22.

Wang XL, Mahaney MC, Sim AS, et at: Genetic contribution of the endothelial constitutive nitric oxide synthase gene to plasma nitric oxide levels. Arterioscler Thromb Vasc Biol 17:3147-3153, 1997. 23.

Rudic RD, Sessa WC: Human Genetics '99: The cardiovascular system: Nitric oxide in endothelial dysfunction and vascular remodeling: Clinical correlates and experimental links. Am J Hum Genet 64:673-377, 1999. 24.

Zannad F, Visvikis S, Gueguen R, et al: Genetics strongly determines the wall thickness of the left and right carotid arteries. Hum Genet 103:183-188, 1998. 25.

CARDIOVASCULAR DISORDERS ASSOCIATED WITH CHROMOSOME ABERRATIONS Popescu NC, Zimonjic DB: Molecular cytogenetic characterization of cancer cell alterations. Cancer Genet Cytogene 93:10-21, 1997. 26.

Ferencz C, Neill CA, Boughman JA, et al: Congenital cardiovascular malformations associated with chromosome abnormalities: An epidemiologic study. J Pediatr 114:79, 1989. 27.

Berg KA, Clark EB, Astemborski JA, et al: Prenatal detection of cardiovascular malformations by echocardiography: An indication for cytogenetic evaluation. Am J Obstet Gynecol 159:477, 1988. 28.

van Karnebeek CDM, Hennekam RCM: Associations between chromosomal anomalies and congenital heart defects: A database search. Am J Med Genet 84:158-166, 1999. 29.

De Biase L, Di Ciommo V, Ballerini L, et al: Prevalence of left-sided obstructive lesions in patients with atrioventricular canal without Down syndrome. J Thorac Cardiovasc Surg 91:467, 1986. 30.

Tolmie JL: Down syndrome and other autosomal trisomies. In Rimoin DL, Connor JM, Pyeritz RE (eds): Principles and Practice of Medical Genetics. 3rd ed. New York, Churchill Livingstone, 1997, pp 925-972. 31.

Freeman SB, Taft LF, Dooley KJ, et al: Population-based study of congenital heart defects in Down syndrome. Am J Med Genet 80:213-217, 1998. 32.

Clapp S, Perry BL, Farooki ZQ, et al: Down's syndrome, complete atrioventricular canal, and pulmonary vascular obstructive disease. J Thorac Cardiovasc Surg 100:115, 1990. 33.

Goldhaber SZ, Rubin IL, Brown W, et al: Valvular heart disease (aortic regurgitation and mitral valve prolapse) among institutionalized adults with Down's syndrome. Am J Cardiol 57:278, 1986. 34.

Korenberg J, Bradley C, Disteche C: Down syndrome: Molecular mapping of congenital heart disease and duodenal stenosis. Am J Hum Genet 50:294-302, 1992. 35.

Schneider DS, Zahka KG, Clark EB, et al: Patterns of cardiac care in infants with Down syndrome. Am J Dis Child 143:363, 1989. 36.

Van Dyck DC, Allen M: Clinical management considerations in long-term survivors with trisomy 18. Pediatrics 58:893, 1976. 37.

Musewe NN, Alexander DJ, Teshima I, et al: Echocardiographic evaluation of the spectrum of cardiac anomalies associated with trisomy 13 and trisomy 18. J Am Coll Cardiol 15:673, 1990. 38.

Van Praagh S, Truman T, Firpo A, et al: Cardiac malformations in trisomy-18: A study of 41 postmortem cases. J Am Coll Cardiol 13:1586, 1989. 39.

40.

Saenger P: Turner's syndrome. N Engl J Med 335:1749-1754, 1996.

41.

Lacro RV, Lyons Jones K, Benirschke K: Coarctation of the aorta in Turner syndrome: A pathologic

study of fetuses with nuchal cystic hygromas, hydrops fetalis and female genitalia. Pediatrics 81:445, 1988. 42.

Allen DB, Hendricks SA, Levy JM: Aortic dilation in Turner syndrome. J Pediatr 109:302, 1986.

Natowicz M, Kelley RI: Association of Turner syndrome with hypoplastic left-heart syndrome. Am J Dis Child 141:218, 1987. 43.

Moore JW, Kirby WC, Rogers WM, et al: Partial anomalous pulmonary venous drainage associated with 45,X Turner's syndrome. Pediatrics 86:273, 1990. 44.

Sapienza C, Hall JG: Genetic imprinting in human disease. In Scriver CR, Beaudet AL, Sly WA, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill, 1995, p 437. 45.

Jacobs P, Dalton P, James R, et al: Turner syndrome: A cytogenetic and molecular study. Ann Hum Genet 61:471-483, 1997. 46.

Zinn AR, Tonk VS, Chen Z, et al: Evidence for a Turner syndrome locus or loci at Xp11.2-p22.1. Am J Hum Genet 63:1757-1766, 1998. 47.

CONGENITAL HEART DISEASE Fixler DE, Pastor P, Chamberlin M, et al: Trends in congenital heart disease in Dallas County births: 1971-1984. Circulation 81:137, 1990. 48.

Helmcke F, de Souza A, Nanda NC, et al: Two-dimensional and color Doppler assessment of ventricular septal defect of congenital origin. Am J Cardiol 63:1112, 1989. 49.

Hanna EJ, Nevin NC, Nelson J: Genetic study of congenital heart defects in Northern Ireland (1974-1978). J Med Genet 31:858, 1994. 50.

Simpson IA, Sahn DJ, Valdes-Cruz LM, et al: Color Doppler flow mapping in patients with coarctation of the aorta: New observations and improved evaluation with color flow diameter and proximal acceleration as predictors of severity. Circulation 77:736, 1988. 51.

Ferencz C, Loffredo CA, Correa-Villasenor A, Wilson P: Genetic and Environmental Risk Factors of Major Cardiovascular Malformations: The Baltimore-Washington Infant Study 1981-1989. Armonk, NY, Futura, 1997. 52.

Lin AE, Herring AH, Scharenberg K, et al: Cardiovascular malformations: Changes in prevalence and birth status, 1972-1990. Am J Med Genet 84:102-110, 1999. 53.

Brenner JL, Berg KA, Schneider DS, et al: Cardiac malformations in relatives of infants with hypoplastic left-heart syndrome. Am J Dis Child 143:1492, 1989. 54.

Pyeritz RE, Murphy EA: The genetics of congenital heart disease: Perspectives and prospects. J Am Coll Cardiol 13:1458, 1989. 55.

Ursell PC, Byrne JM, Strombino BA: Significance of cardiac defects in the developing fetus: A study of spontaneous abortuses. Circulation 72:1232, 1985. 56.

57.

Devriendt K, Matthijs G, Dael RV, et al: Delineation of the critical deletion region for congenital heart

defects on chromosome 8p23.1. Am J Hum Genet 64:1119-1126, 1999. Clayton-Smith J, Donnai D: Human malformations. In Rimoin DL, Connor JM, Pyeritz RE (eds): Principles and Practice of Medical Genetics. 3rd ed. New York, Churchill Livingstone, 1997, pp 383-394. 58.

Sadiq M, Stumper O, Wright JGC, et al: Influence of ethnic origin on the pattern of congenital heart defects in the first year of life. Br Heart J 73:173, 1995. 59.

Whittemore R, Hobbins JC, Engle MA: Pregnancy and its outcome in women with and without surgical treatment of congenital heart disease. In Engle MA, Perloff JK (eds): Congenital Heart Disease After Surgery. New York, Yorke Medical Books, 1983, p 362. 60.

Rose VR, Gold JM, Lindsay G, et al: A possible increase in the incidence of congenital heart defects among the offspring of affected parents. J Am Coll Cardiol 6:376, 1985. 61.

Nora JJ, Berg K, Nora AH: Cardiovascular disease--genetics, epidemiology and prevention. Am J Hum Genet 50:450, 1992. 62.

63.

Boughman JA: Familial risks of congenital heart defects [letter]. Am J Med Genet 29:233, 1988.

Murphy JG, Gersh BJ, McGoon MG, et al: Long-term outcome after surgical repair of isolated atrial septal defect: Follow-up at 27 to 32 years. N Engl J Med 323:1645, 1990. 64.

Gold RJM, Rose V, Yau Y: Severity and recurrence risk of congenital heart defects exemplified by atrial septal defect secundum. Clin Genet 32:148, 1987. 65.

66.

Sanchez-Cascos A: The recurrence risk in congenital heart disease. Eur J Cardiol 7:197, 1978.

Lathrop GM, Terwilliger JD, Weeks DE: Multifactorial inheritance and genetic analysis of multifactorial disease. In Rimoin DL, Connor JM, Pyeritz RE (eds): Principles and Practice of Medical Genetics. 3rd ed. New York, Churchill Livingstone, 1997, pp 333-346. 67.

Digilio MC, Marino B, Toscanno A, et al: Atrioventricular canal defect without Down syndrome: A heterogeneous malformation. Am J Med Genet 85:140-146, 1999. 68.

Marino B, Digilio MC: Inlet ventricular septal defect is not a partial atrioventricular septal defect. Am J Med Genet 87:195, 1999. 69.

Corone P, Bonaiti C, Feingold J, et al: Familial congenital heart disease: How are the various types related? Am J Cardiol 51:942, 1983. 70.

Clark EB: Mechanisms in the pathogenesis of congenital cardiac malformations. In Pierpont MEM, Moller JH (eds): Genetics of Cardiovascular Disease. Boston, Martinus Nihjoff, 1986, p 3. 71.

Maestri NE, Beaty TH, Liang K-Y, et al: Assessing familial aggregation of congenital cardiovascular malformations in case-control studies: Genet Epidemiol 5:343, 1988. 72.

Pierpont MEM, Gobel JW, Moller JH, et al: Cardiac malformations in relatives of children with truncus arteriosus or interruption of the aortic arch. Am J Cardiol 61:423, 1988. 73.

Goldmuntz E, Clark BJ, Mitchell LE, et al: Frequency of 22q11 deletions in patients with conotruncal defects. J Am Coll Cardiol 32:492-498, 1998. 74.

Krantz ID, Smith R, Colliton RP, et al: Jagged1 mutationsin patients ascertained with isolated congenital heart defects. Am J Med Genet 84:56-60, 1999. 75.

Ewing CK, Loffredo CA, Beaty TH: Paternal risk factors for isolated membranous ventricular septal defects. Am J Med Genet 71:42-46, 1997. 76.

Desmaze C, Prieur M, Amblard F, et al: Physical mapping by FISH of the DiGeorge critical region (DGCR): Involvement of the region in familial cases. Am J Hum Genet 53:1239, 1993. 77.

Matsuoka R, Takao A, Kimura M, et al: Confirmation that the conotruncal anomaly face syndrome is associated with a deletion within 22q11.2. Am J Med Genet 53:285, 1994. 78.

Funke B, Puech A, Saint-Jore B, et al: Isolation and characterization of a human gene containing a nuclear localization signal from the critical region for velo-cardiofacial syndrome on 22q11. Genomics 53:146-154, 1998. 79.

Goodship J, Cross I, LiLing J, Wren C: A populations study of chromosome 22q11 deletions in infancy. Arch Dis Child 79:348-351, 1998. 80.

Patterson DF, Pexieder T, Schnarr WR, et al: A single major-gene defect underlying cardiac conotruncal malformations interferes with myocardial growth during embryonic development: Studies in the CTD line of Keeshond dogs. Am J Hum Genet 52:388, 1993. 81.

Beekman RH, Robinow M: Coarctation of the aorta inherited as an autosomal dominant trait. Am J Cardiol 56:818, 1985. 82.

Lindsay J Jr: Coarctation of the aorta, bicuspid aortic valve and abnormal ascending aortic wall. Am J Cardiol 61:182, 1988. 83.

2012

Wright TC, Orkin RW, Destrempes M, et al: Increased adhesiveness of Down syndrome fetal fibroblasts in vitro. Proc Natl Acad Sci U S A 81:2426, 1984. 84.

Ferencz C, Boughman JA, Neill CA, et al: Congenital cardiovascular malformations: Questions on inheritance. J Am Coll Cardiol 14:756, 1989. 85.

86.

Moreno A, Murphy EA: Inheritance of Kartagener syndrome. Am J Med Genet 8:305, 1981.

Afzelius BA, Mossberg B: Immotile-cilia syndrome (primary ciliary dyskinesia), including Kartagener syndrome. In Scriver CR, Beaudet AL, Sly WA, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill, 1995, p 3943. 87.

Alonso S, Pierpont ME, Radtke W: Geterotaxia syndrome and autosomal dominant inheritance. Am J Med Genet 56:12, 1995. 88.

Casey B, Devoto M, Jones KL, et al: Mapping a gene for familial situs abnormalities to human chromosome Xq24-q27.1. Nature Genet 5:403, 1993. 89.

Anderson C, Devine WA, Anderson RH, et al: Abnormalities of the spleen in relation to congenital malformation of the heart: A survey of necropsy findings in children. Br Heart J 63:122, 1990. 90.

Phoon CK, Neill CA: Asplenia syndrome: Insight into embryology through an analysis of cardiac and extracardiac anomalies. Am J Cardiol 73:581, 1994. 91.

Olson EN, Srivastava D: Molecular pathways controlling heart development. Science 272:671-676, 1996. 92.

Casey B: Two rights make a wrong: Human left-right malformations. Hum Mol Genet 7:1565-1571, 1998. 93.

Towbin JA, Casey B, Belmont J: Human Genetics '99: The cardiovascular system: The molecular basis of vascular disorders. Am J Hum Genet 64:678-684, 1999. 94.

Mochizuki T, Saijoh U, Tsuchiya K, et al: Cloning of inv, a gene that controls left/right asymmetry and kidney development. Nature Genet 395:177-181, 1998. 95.

Kosaki R, Gebbia M, Kosaki K, et al: Left-right axis malformations associated with mutations in ACVR2B, the gene for human activin receptor type IIB. Am J Med Genet 82:70-76, 1999. 96.

Britz-Cunningham SH, Shah MM, Zuppan CW, et al: Mutations of the Connexin43 gap-junction gene in patients with heart malformations and defects of laterality. N Engl J Med 332:1323-1329, 1995. 97.

Cyran SE, Martinez R, Daniels S, et al: Spectrum of congenital heart disease in CHARGE association. J Pediatr 110:576, 1987. 98.

Oley CA, Baraitser M, Grant DB: A reappraisal of the CHARGE association. J Med Genet 25:147, 1988. 99.

Weaver DD, Mapstone CL, Yu P: The VATER association: Analysis of 46 patients. Am J Dis Child 140:225, 1986. 100.

Nezarati MM, McLeod DR: VACTERL manifestations in two generations of a family. Am J Med Genet 82:40-42, 1999. 101.

Woods CG, Sheffield LJ: Further family with autosomal dominant patent ductus arteriosus. J Med Genet 31:659, 1994. 102.

Davidson HR: A large family with patent ductus arteriosus and unusual face. J Med Genet 30:503, 1992. 103.

Slavotinek A, Clayton-Smith J, Super M: Familial patent ductus arteriosus: A further case of CHAR syndrome. Am J Med Genet 71:229-232, 1997. 104.

Lynch HT, Bachenberg K, Harris RE, et al: Hereditary atrial septal defect: Update of a large kindred. Am J Dis Child 132:600, 1978. 105.

Basson CT, Solomon SD, Weissman B, et al: Genetic heterogeneity of heart-hand syndromes. Circulation 91:1326-1329, 1995. 106.

Schott J-J, Benson DW, Basson CT, et al: Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science 281:108-111, 1998. 107.

Gall JC, Stern AM, Cohen MM, et al: Holt-Oram syndrome: Clinical and genetic study of a large family. Am J Hum Genet 18:187, 1966. 108.

Sletten LJ, Pierpont MEM: Variation in severity of cardiac diseases in Holt-Oram syndrome. Am J Med Genet 65:128-132, 1996. 109.

Basson CT, Cowley GS, Solomon SD, et al: The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome). N Engl J Med 330:885, 1994. 110.

Basson CT, Huang T, Lin RC, et al: Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations. Proc Natl Acad Sci U S A 96:2919-2924, 1999. 111.

Terrett JA, Newbury-Ecob R, Cross GS, et al: Holt-Oram syndrome is a genetically heterogeneous disease with one locus mapping to human chromosome 12q. Nature Genet 6:401, 1994. 112.

Fryns JP, Bonnet D, De Smet L: Holt-Oram syndrome with associated postaxial and central polysyndactyly: Further evidence for genetic heterogeneity in the Holt-Oram syndrome. Genet Counsel 7:323-324, 1996. 113.

McKusick VA, Egeland JA, Eldridge R, et al: Dwarfism in the Amish: I. The Ellis-van Creveld syndrome. Bull Johns Hopkins Hosp 115:306, 1964. 114.

Polymeropoulos MH, Ide SE, Wright M, et al: The gene for Ellis-van Creveld syndrome is located on chromosome 4p16. Genomics 35:1-5, 1996. 115.

Ruiz-Perez VL, Ide SE, Strom TM, et al: Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis. Nature Genet 24:283-286, 2000. 115A.

Sheffield VC, Pierpont ME, Nishimura D, et al: Identification of a complex congenital heart defect susceptibility locus by using DNA pooling and shared segment analysis. Hum Mol Genet 6:117-121, 1997. 116.

117.

Preus M: The Williams syndrome: Objective definition and diagnosis. Clin Genet 25:422, 1984.

Maisuls H, Alday LE, Thuer O: Cardiovascular findings in the Williams-Beuren syndrome. Am Heart J 114:897, 1987. 118.

Hallidie-Smith KA, Karas S: Cardiac anomalies in Williams-Beuren syndrome. Arch Dis Child 63:809, 1988. 119.

Morris CA, Demsey SA, Leonard CO, et al: Natural history of Williams syndrome: Physical characteristics. J Pediatr 113:318, 1988. 120.

Morris CA, Leonard CO, Dilts C, et al: Adults with Williams syndrome. Am J Med Genet 6 (Suppl):102-107, 1990. 121.

Broder K, Reinhardt E, Ahern J, et al: Elevated ambulatory blood pressure in 20 subjects with Williams syndrome. Am J Med Genet 83:356-360, 1999. 122.

Wessel A, Pankau R, Kececioglu D, et al: Three decades of follow-up of aortic and pulmonary vascular lesions in the Williams-Beuren syndrome. Am J Med Genet 52:297, 1994. 123.

Ardinger RH Jr, Goertz KK, Mattioli LF: Cerebrovascular stenoses with cerebral infarction in a child with Williams syndrome. Am J Med Genet 51:200, 1994. 124.

van Son JAM, Edwards WD, Danielson GK: Pathology of coronary arteries, myocardium, and great arteries in supravalvular aortic stenosis: Report of five cases with implications for surgical treatment. J Thorac Cardiovasc Surg 108:21, 1994. 125.

Tassabehji M, Metcalfe K, Karmiloff-Smith A, et al: Williams syndrome: Use of chromosomal microdeletions as a tool to dissect cognitive and physical phenotypes. Am J Hum Genet 64:118-125, 1999. 126.

Francke U: Williams-Beuren syndrome: Genes and mechanisms. Hum Mol Genet 8:1947-1954, 1999. 127.

Chiarella F, Bricarelli FD, Lupi G: Familial supravalvular aortic stenosis: A genetic study. J Med Genet 26:86, 1989. 128.

Ensing GJ, Schmidt MA, Hagler DJ, et al: Spectrum of findings in a family with nonsyndromic autosomal dominant supravalvular aortic stenosis: A Doppler echocardiographic study. J Am Coll Cardiol 13:413, 1989. 129.

Schmidt MA, Ensing GJ, Michels VV, et al: Autosomal dominant supravalvular aortic stenosis: Large three-generation family. Am J Med Genet 32:384, 1989. 130.

Devereux RB, Kramer-Fox R, Shear MK, et al: Diagnosis and classification of severity of mitral valve prolapse: Methodologic, biologic, and prognostic considerations. Am Heart J 113:1265, 1987. 131.

132.

Nishimura RA, McGoon MD: Perspectives on mitral-valve prolapse. N Engl J Med 341:48-50, 1999.

Freed LA, Levy D, Levine RA, et al: Prevalence and clinical outcome of mitral-valve prolapse. N Engl J Med 341:1-7, 1999. 133.

Devereux RB, Kramer-Fox R: Inheritance and phenotypic features of mitral valve prolapse. In Boudoulas H, Wooley CF (eds): Mitral Valve Prolapse and the Mitral Valve Prolapse Syndrome. Mt. Kisco, NY, Futura, 1988, p 109. 134.

Strahan NV, Murphy EA, Fortuin NJ, et al: Inheritance of the mitral valve prolapse syndrome. Discussion of a three-dimensional penetrance model. Am J Med 74:967, 1983. 135.

Pini R, Greppi B, Kramer-Fox R, et al: Mitral valve dimensions and motion and familial transmission of mitral valve prolapse with and without mitral leaflet billowing. J Am Coll Cardiol 12:1423, 1988. 136.

Hickey AJ, Narunsky L, Wilcken DEL: Bodily habitus and mitral valve prolapse. Aust N Z J Med 15:326, 1985. 137.

Devereux RB, Brown WT, Lutas EM, et al: Association of mitral valve prolapse with low body weight and low blood pressure. Lancet 2:792, 1982. 138.

139.

Kyndt F, Schott JJ, Trochu JN, et al: Mapping of X-linked myxomatous valvular dystrophy to

chromosome Xq28. Am J Hum Genet 62:627-632, 1998. Beighton P, de Paepe A, Danks D, et al: International nosology of heritable disorders of connective tissue, Berlin, 1986. Am J Med Genet 29:581, 1988. 140.

DePaepe A, Deitz HC, Devereux RB, et al: Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 62:417-426, 1996. 141.

Roman MJ, Devereux RB, Kramer-Fox R, et al: Comparison of cardiovascular and skeletal features of primary mitral valve prolapse and the Marfan syndrome. Am J Cardiol 3:317, 1989. 142.

Glesby MJ, Pyeritz RE: Association of mitral valve prolapse and systemic abnormalities of connective tissue: A phenotypic continuum. JAMA 262:523, 1989. 143.

Shamberger RC, Welch KJ, Sanders SP: Mitral valve prolapse associated with pectus excavatum. J Pediatr 111:404, 1987. 144.

Rogan K, Sears-Rogan P, Vermani R, et al: Familial myxomatous valvular disease. Am J Cardiol 63:1149, 1989. 145.

146.

Mendez HMM, Opitz JM: Noonan syndrome: A review. Am J Med Genet 21:493, 1985.

Allanson JE, Hall JG, Hughes HE, et al: Noonan syndrome: The changing phenotype. Am J Med Genet 21:507, 1985. 147.

Noonan JA, Ehmke DA: Associated noncardiac malformations in children with congenital heart disease. J Pediatr 63:468, 1963. 148.

Battisle CE, Feldt RH, Lie JT: Congestive cardiomyopathy in Noonan's syndrome. Mayo Clin Proc 52:661, 1977. 149.

Miller M, Motulsky AG: Noonan syndrome in an adult family presenting with chronic lymphedema. Am J Med 65:379, 1978. 150.

Brady AF, Jamieson CR, van der Burgt I, et al: Further delineation of the critical region for Noonan sysndrome on the long arm of chromosome 12. Eur J Hum Genet 5:336-337, 1997. 151.

2013

Legius E, Schollen E, Matthijs G, Fryns J-P: Fine mapping of Noonan/cardiofacio-cutaneous syndrome in a large family. Eur J Hum Genet 6:32-37, 1998. 152.

Quattrin T, McPherson E, Putnam T: Vertical transmission of the neurofibromatosis/Noonan syndrome. Am J Med Genet 26:645, 1987. 153.

van der Burgt I, Berends E, Lommen E, et al: Clinical and molecular studies in a large Dutch family with Noonan syndrome. Am J Med Genet 53:187, 1994. 154.

155.

Kitchens CS, Alexander JA: Partial deficiency of coagulation factor XI as a newly recognized feature

of Noonan syndrome. J Pediatr 102:224, 1983. Hanson JW: Human teratology. In Rimoin DL, Connor JM, Pyeritz RE (eds): Principles and Practice of Medical Genetics. 3rd ed. New York, Churchill Livingstone, 1997, pp. 697-724. 156.

Khoury MJ, Becerra JE, Cordero JF, et al: Clinical-epidemiologic assessment of patterns of birth defects associated with human teratogens: Application to diabetic embryopathy. Pediatrics 83:658, 1989. 157.

158.

Beckman DA. Brent RL: Mechanisms of teratogenesis. Annu Rev Pharmacol Toxicol 24:483, 1984.

159.

Shepard TH: Catalog of Teratogenic Agents. 9th ed. Baltimore, Johns Hopkins Press, 1998.

160.

Jones KL: Fetal alcohol syndrome. Pediatr Rev 8:122, 1986.

161.

Bagheri MM, Burd L, Martsolf JT, Klug MG: Fetal alcohol syndrome. J Perinat Med 26:263-269, 1998.

Finnell RH, Chernoff GF: Genetic background. The elusive component in the fetal hydantoin syndrome. Am J Med Genet 19:459, 1984. 162.

Strickler SM, Dansky LV, Miller MA, et al: Genetic predisposition to phenytoin-induced birth defects. Lancet 2:746, 1985. 163.

164.

Lammer EJ: Retinoic acid embryopathy. N Engl J Med 313:837, 1985.

Hall JG, Pauli RM, Wilson KM: Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 68:122, 1980. 165.

Scriver CR, Kaufman S, Eisensmith RC, et al: The hyperphenylalaninemias. In Scriver CR, Beaudet AL, Sly WA, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill, 1995, p 1015. 166.

Lenke RR, Levy HL: Maternal phenylketonuria and hyperphenylalaninemia. N Engl J Med 303:1202, 1980. 167.

CARDIOMYOPATHIES Vosberg H-P, McKenna WJ. Cardiomyopathies. In Rimoin DL, Connor JM, Pyeritz RE (eds): Principles and Practice of Medical Genetics. 3rd ed. New York, Churchill Livingstone, 1997, pp. 843-878. 168.

Seidman CE, Seidman JG: Molecular genetics of inherited cardiomyopathies. In Chien KR, Breslow JL, Leiden JM, et al: (eds). Molecular Basis of Cardiovascular Disease. Philadelphia, WB Saunders, 1999, pp 251-263. 169.

Fung DCY, Yu B, Littlejohn T, et al: An online locus-specific mutation database for familial hypertrophic cardiomyopathy. Hum Mutat 14:326-332, 1999. 170.

Watkins H, Thierfelder L, Hwang DS, et al: Sporadic hypertrophic cardiomyopathy due to de novo myosin mutations. J Clin Invest 90:1666, 1992. 171.

171A.

Forissier J-F, Richard P, Briault S, et al: First description of germline mosaicism in familial

hypertrophic cardiomyopathy. J Med Genet 37:132-134, 2000. Jeschke B, Uhl K, Weist B, et al: A high risk phenotype of hypertrophic cardiomyopathy associated with a compound genotype of two mulated beta-myosin heavy chain genes. Hum Genet 102:299-304, 1998. 172.

Tesson F, Richard P, Charron P, et al: Genotype-phenotype analysis in four families with mutations in beta-myosin heavy chain gene responsible for familial hypertrophic cardiomyopathy. Hum Mutat 12:385-392, 1998. 173.

Richard P, Isnard R, Carrier L, et al: Double heterozygosity for mutations in the beta-myosin heavy chain and in the cardiac myosin binding protein C genes in a family with hypertrophic cardiomyopathy. J Med Genet 36:542-545, 1999. 174.

Yu B, French JA, Jeremy RW, et al: Counseling issues in familial hypertrophic cardiomyopathy. J Med Genet 35:183-188, 1998. 175.

Maron BJ, Moller JH, Seidman CE, et al: Impact of laboratory molecular diagnosis on contemporary diagnostic criteria for genetically transmitted cardiovascular diseases: Hypertrophic cardiomyopathy, long-QT syndrome, and Marfan syndrome. Circulation 98:1460-1471, 1998. 176.

Cuda G. Fannapazir L, Zhu WS, et al: Skeletal muscle expression and abnormal function of beta-myosin in hypertrophic cardiomyopathy. J Clin Invest 91:2861, 1993. 177.

Lechin M, Quinones MA, Omran A, et al: Angiotensin I converting enzyme genotypes and left ventricular hypertrophy in patients with hypertrophic cardiomyopathy. Circulation 92:1808, 1995. 178.

Maron BJ, Shen W-K, Link MS, et al: Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med 342:365-373, 2000. 178A.

Codd MB, Sugrue DD, Gersh BJ, et al: Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy: A population-based study in Olmsted County, Minnesota, 1975-1984. Circulation 80:564, 1989. 179.

180.

Dec GW, Fuster V: Idiopathic dilated cardiomyopathy. N Engl J Med 331:1564, 1994.

Manolio TA, Baughman KL, Rodeheffer R, et al: Prevalence and etiology of idiopathic dilated cardiomyopathy. Am J Cardiol 69:1458, 1992. 181.

Michels VV, Moll PP, Miller FA, et al: The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N Engl J Med 326:77, 1992. 182.

Maeda M, Holder E, Lowes B, et al: Dilated cardiomyopathy associated with deficiency of the cytoskeletal protein metavinculin. Circulation 95:17-20, 1997. 183.

Jung M, Poepping I, Perrot A, et al: Investigation of a family with autosomal dominant dilated cardiomyopathy defines a novel locus on chromosome 2q14-q22. Am J Hum Genet 65:1068-1077, 1997. 184.

Vilarinho L, Santorelli FM, Rosas MJ, et al: The mitochondrial A3243G mutation presenting as severe cardiomyopathy. J Med Genet 34:607-609, 1997. 185.

186.

Mayosi BM, Khogali SS, Zhang B, et al: Cardiac and skeletal actin gene mutations are not a common

cause of dilated cardiomypathy. J Med Genet 36:796-797, 1999. Caforio ALP, Rossi B, Risaliti R: Type 1 fiber abnormalities in skeletal muscle of patients with hypertrophic and dilated cardiomyopathy: Evidence of subclinical myogenic myopathy. J Am Coll Cardiol 14:1464, 1989. 187.

188.

Voss EG, Reddy CVR, Detremo R, et al: Familial dilated cardiomyopathy. Am J Cardiol 54:456, 1984.

Barth PG, Scholte JA, Berden JA, et al: An X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leukocytes. J Neurol Sci 62:327, 1983. 189.

Bione S, D'Adamo P, Maestrini E, et al: A novel X-linked gene, G4.5. is responsible for Barth syndrome. Nat Genet 12:385-389, 1996. 190.

Digilio MC, Marino B, Bevilacqua M, et al: Genetic heterogeneity of isolated noncompaction of the left ventricular myocardium. Am J Med Genet 85:90-91, 1999. 191.

Emery AEH: Duchenne and other X-linked muscular dystrophies. In Rimoin DL, Connor JM, Pyeritz RE (eds): Principles and Practice of Medical Genetics. 3rd ed. New York, Churchill Livingstone, 1997, pp 2337-2354. 192.

Melacini P, Fanin M, Danieli GA, et al: Cardiac involvement in Becker muscular dystrophy. J Am Coll Cardiol 22:1927, 1993. 193.

Muntoni F, Cau M, Ganau A, et al: Deletion of the dystrophin muscle-promoter region associated with X-linked dilated cardiomyopathy. N Engl J Med 329:921, 1993. 194.

Towbin JA, Hejtmancik JF, Brink P, et al: X-linked dilated cardiomyopathy: Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus. Circulation 87:1854, 1993. 195.

Bushby KMD: Autosomally inherited muscular dystrophies. In Rimoin DL, Connor JM, Pyeritz RE (eds): Principles and Practice of Medical Genetics. 3rd ed. New York, Churchill Livingstone, 1997, pp 2355-2366. 196.

Fishbein MC, Siegel RJ, Thompson CE, et al: Sudden death of a carrier of X-linked Emery-Dreifuss muscular dystrophy. Ann Intern Med 119:900, 1993. 197.

Bione S, Maestrini E, Rivella S, et al: Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy. Nat Genet 8:323, 1994. 198.

Morris GE, Manilal S: Heart to heart: From nuclear proteins to Emery-Dreifuss muscular dystrophy. Hum Mol Genet 8:1847-1851, 1999. 199.

Barresi R, Di Blasi C, Negri T, et al: Disruption of heart sarcoglycan complex and severe cardiomyopathy caused by beta sarcoglycan mutations. J Med Genet 37:102-107, 2000. 200.

Dalakas MC, Park K-Y, Semino-Mora C, et al: Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene. N Engl J Med 342:770-780, 2000. 200A.

201.

Aroney C, Bett N, Radford D: Familial restrictive cardiomyopathy. Aust N Z J Med 18:877, 1988.

Fitzpatrick AP, Shapiro LM, Richards AF, et al: Familial restrictive cardiomyopathy with atrioventricular block and skeletal myopathy. Br Heart J 63:114, 1990. 202.

Hodgson S, Child A, Dyson M: Endocardial fibroelastosis: Possible X-linked inheritance. J Med Genet 24:210, 1987. 203.

204.

Opitz JM: Genetic aspects of endocardial fibroelastosis. Am J Med Genet 11:92, 1982.

Devi AS, Eisenfeld L, Uphoff D, et al: New syndrome of hydrocephalus, endocardial fibroelastosis, and cataracts (HEC) syndrome. Am J Med Genet 56:62, 1995. 205.

Ross RS, Bulkley BH, Hutchins GM, et al: Idiopathic familial myocardiopathy in three generations: A clinical and pathologic study. Am Heart J 96:170, 1978. 206.

Voorhees ML, Hussan GS, Blackman MS: Growth failure with pericardial constriction: The syndrome of mulibrey nanism. Am J Dis Child 130:1146, 1976. 207.

Avela K, Lipsanen-Nyman M, Perheentupa J, et al: Assignment of the mulibrey nanism gene to 17q by linkage and linkage-disequilibrium analysis. Am J Hum Genet 60:896-902, 1997. 208.

Martinez-Lavin M, Buendia A, Delgado E, et al: A familial syndrome of pericarditis, arthritis and camptodactyly. N Engl J Med 309:224, 1983. 209.

Bahabri SA, Suwairi WM, Laxer RM, et al: The camptodactyly-arthropathy-coxa vara-pericarditis syndrome: Clinical features and genetic mapping to human chromosome 1. Arthritis Rheum 41:730-735, 1998. 210.

Marcelino J, Carpten JD, Suwairi WM, et al: CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Nat Genet 23:319-322, 1999. 211.

2014

Fitzpatrick AP, Emanuel RW: Familial neurofibromatosis and hypertrophic cardiomyopathy. Br Heart J 60:247, 1988. 212.

Sommer A, Contras SB, Craenen JM, et al: A family study of the LEOPARD syndrome. Am J Dis Child 121:520, 1971. 213.

Coppin BD, Temple IK: Multiple lentigines syndrome (LEOPARD) syndrome or progressive cardiomyopathic lentiginosis. J Med Genet 24:582-586, 1997. 214.

PRIMARY DISORDERS OF RHYTHM AND CONDUCTION Marks ML, Keating MT: Familial dysrhythmias. In Rimoin DL, Connor JM, Pyeritz RE (eds): Principles and Practice of Medical Genetics. 3rd ed. New York, Churchill Livingstone, 1997, pp. 879-898. 215.

Priori SG, Barhanin J, Hauer RNW, et al: Genetic and molecular basis of cardiac arrhythmias: Impact on clinical management Part I and II. Circulation 99:518-528, 1999. 216.

Gambetta M, Weese J, Ginsburg M. et al: Sick sinus syndrome in a patient with familial PR prolongation. Chest 64:520, 1973. 217.

Surawicz B, Hariman RJ: Follow-up of the family with congenital absence of sinus rhythm. Am J Cardiol 61:467, 1988. 218.

Balderston SM, Shaffer EM, Sondheimer HM, et al: Hereditary atrioventricular conduction defect in a child. Pediatr Cardiol 10:37, 1989. 219.

220.

Wolkowicz J, Burgess JH: Complete heart block in an Inuit family. Can J Cardiol 4:352, 1988.

Stephan E: Hereditary bundle branch system defect: Survey of a family with four affected generations. Am Heart J 95:89, 1978. 221.

Lorber A, Maisuls E, Naschitz J: Hereditary right axis deviation: Electrocardiographic pattern of pseudo left posterior hemiblock and incomplete right bundle branch block. Int J Cardiol 20:399, 1988 222.

Van Der Merwe P-L, Weymar HW, Torrington M, et al: Progressive familial heart block (type I): A follow up study after 10 years. S Afr Med J 73:275, 1988. 223.

Torrington M, Weymar HW, van der Merwe PL, et al: Progressive familial heart block: Pt I. Extent of the disease. S Afr Med J 70:354, 1986. 224.

Kothari SS, Agrawal SM, and Kirshnaswami S: Familial complete heart block in hypertrophic cardiomyopathy. Int J Cardiol 20:294, 1988. 225.

Stables RH, Bailey C, Ormerod OJM: Idiopathic familial atrial cardiomyopathy with diffuse conduction block, Q J Med 264:325, 1989. 226.

Olofsson B-V, Eriksson P, Eriksson A: The sick sinus syndrome in familial amyloidosis with polyneuropathy. Int J Cardiol 4:71, 1983. 227.

Winkler RB, Nora AH, Nora JJ: Familial congenital complete heart block and maternal systemic lupus erythematosus. Circulation 56:1103, 1977. 228.

McCue CM, Mantakas ME, Tingelstad JB, et al: Congenital heart block in newborns of mothers with connective tissue disease. Circulation 56:82, 1977. 229.

Chameides L, Truex RC, Vetter V, et al: Association of maternal systemic lupus erythematosus with congenital complete heart block. N Engl J Med 297:1204, 1977. 230.

Scott JS, Maddison PJ, Taylor PV, et al: Connective-tissue disease, antibodies to ribonucleoprotein, and congenital heart block. N Engl J Med 309:209, 1983. 231.

Lockshin MD, Gibofsky A, Peebles CL, et al: Neonatal lupus erythematosus with heart block: Familial study of a patient with anti-SS-A and SS-B antibodies. Arthritis Rheum 26:210, 1983. 232.

233.

Bergfeldt L: HLA-B27-Associated cardiac disease. Ann Intern Med 127:621-629, 1997.

234.

Bacos JM, Eagan JT, Orgain ES: Congenital familial nodal rhythm. Circulation 22:887, 1960.

Chen Q, Kirsch GE, Zhang D, et al: Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 392:293-296, 1998. 235.

Chia BL, Yew FC, Chay SO, et al: Familial Wolff-Parkinson-White syndrome. J Electrocardiol 15:195, 1982. 236.

Vidaillet HJ, Pressley JC, Henke E, et al: Familial occurrence of accessory atrioventricular pathways: Preexcitation syndrome. N Engl J Med 317:65, 1987. 237.

Brugada R, Tapscott T, Czernuszewicz GZ, et al: Identification of a genetic locus for familial atrial fibrillation. N Engl J Med 336:905-911, 1997. 238.

Stoll C, Kieny JR, Dott B, et al: Ventricular extrasystoles with syncopal episodes, perodactyly, and Robin sequence in three generations: A new inherited MCA syndrome? Am J Med Genet 42:480, 1992. 239.

Laurent M, Descases C, Biron Y, et al: Familial form of arrhythmogenic right ventricular dysplasia. Am Heart J 113:827, 1987. 240.

Ruder MA, Winston SA, Davis JC, et al: Arrhythmogenic right ventricular dysplasia in a family. Am J Cardiol 56:799, 1985. 241.

Wiesfeld ACP, Crijns JGM, Van Dijk RB, et al: Potential role for endomyocardial biopsy in the clinical characterization of patients with idiopathic ventricular fibrillation. Am Heart J 127:1421, 1993. 242.

McKenna WJ, Thiene G, Nava A, et al: Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Br Heart J 72:215, 1994. 243.

243A.

Watzinger N, Lercher P, Kern R, et al: Biventricular dysplasia. Circulation 101:1479-1482, 2000.

Severini GM, Krajinovic M, Pinamonti B, et al: A new locus for arrhythmogenic right ventricular dysplasia on the long arm of chromosome 14. Genomics 31:193-200, 1996. 244.

Li D, Ahmad F, Gardner MJ, et al: The locus of a novel gene responsible for arrhythmogenic right-ventricular dysplasia characterized by early onset and high penetrance maps to chromosome 10p12-p14. Am J Hum Genet 66:148-156, 2000. 244A.

245.

Ward OC: A new familial cardiac syndrome in children. J Ir Med Assoc 54:103, 1964.

246.

Romano C: Congenital cardiac arrhythmia. Lancet 1:658, 1965.

Greenspon AJ, Kidwell GA, Barrasse LD, et al: Hereditary long QT syndrome associated with cardiac conduction system disease. PACE 12:479, 1989. 247.

Marks ML, Whisler SL, Clericuzio C, et al: A new form of long QT syndrome associated with syndactyly. J Am Coll Cardiol 25:59, 1995. 248.

Vincent GM: The molecular genetics of the long QT syndrome: Genes causing fainting and sudden death. Annu Rev Med 49:263-274. 1998. 249.

Wattanasirichaigoon D, Vesely MR, Duggal P, et al: Sodium channel abnormalities are infrequent in patients with long QT syndrome: Identification of two novel SCN5A mutations. Am J Med Genet 86:470-476, 1999. 250.

Ackerman MJ, Tester DJ, Porter CJ, et al: Molecular diagnosis of the inherited long-QT syndrome in a woman who died after near-drowning. N Engl J Med 341:121-125, 1999. 251.

Priori SG, Napolitano C, Schwartz PJ: Low penetrance in the long-QT syndrome. Circulation 99:529-533, 1999. 252.

Vincent GM, Timothy KW, Leppert M, et al: The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome. N Engl J Med 327:846, 1992. 253.

Zareba W, Moss AJ, Schwartz PJ, et al: Influence of the genotype on the clinical course of the long-QT syndrome. N Engl J Med 339:690-695, 1998. 254.

Priori SG, Barhanin J, Hauer RNW, et al: Genetic and molecular basis of cardiac arrhythmias: Impact on clinical management. Part III. Circulation 99:674-681, 1999. 255.

Jervell A, Lange-Nielsen F: Congenital deaf-mutism, functional heart disease with prolongation of Q-T interval and sudden death. Am Heart J 54:59, 1957. 256.

Splawski I, Timothy KW, Vincent GM, et al: Molecular basis of the long-QT syndrome associated with deafness. N Engl J Med 336:1562-1567, 1997. 257.

DISORDERS OF CONNECTIVE TISSUE 258.

McKusick VA: Heritable Disorders of Connective Tissue. St. Louis, CV Mosby, 1956.

Royce PM, Steinmann B (eds): Connective Tissue and Its Heritable Disorders: Molecular, Genetic and Medical Aspects. New York, Wiley-Liss, 1993. 259.

Pyeritz RE: Heritable disorders of connective tissue. In Pierpont ME, Moller JH (eds): The Genetics of Cardiovascular Disease. Boston, Martinus Nijhoff, 1987, p 265. 260.

Beighton P (ed): McKusick's Heritable Disorders of Connective Tissue. 5th ed. St. Louis, CV Mosby, 1993. 261.

Pyeritz RE: Disorders of fibrillins and microfibrilogenesis: Marfan syndrome, MASS phenotype, contractural arachnodactyly and related conditions. In Rimoin DL, Connor JM, Pyeritz RE (eds): Principles and Practice of Medical Genetics. 3rd ed. New York, Churchill Livingstone, 1997, pp 1027-1066. 262.

262A.

Pyeritz RE: The Marfan syndrome. Ann Rev Med 51:481-510, 2000.

McKusick VA: The cardiovascular aspects of Marfan's syndrome: A heritable disorder of connective tissue. Circulation 11:321, 1955. 263.

Marsalese DL, Moodie DS, Vacante M, et al: Marfan's syndrome: Natural history and long-term follow-up of cardiovascular involvement. J Am Coll Cardiol 14:422, 1989. 264.

Murdoch JL, Walker BA, Halpern BL, et al: Life expectancy and causes of death in the Marfan syndrome. N Engl J Med 286:804, 1972. 265.

266.

Sisk HE, Zahka KG, Pyeritz RE: The Marfan syndrome in early childhood: Analysis of 15 patients

diagnosed less than 4 years of age. Am J Cardiol 52:353, 1983. Morse RP, Rockenmacher S, Pyeritz RE, et al: Diagnosis and management of Marfan syndrome in infants. Pediatrics 86:888, 1990. 267.

268.

Pyeritz RE, Wappel MA: Mitral valve dysfunction in the Marfan syndrome. Am J Med 74:797, 1983.

Gillinov AM, Hulyalkar A, Cameron DE, et al: Mitral valve operation in patients with the Marfan syndrome. J Thorac Cardiovasc Surg 107:724, 1994. 269.

Gott VL, Greene PS, Alejo DE, et al: Surgery for ascending aortic disease in Marfan patients: A multi-center study. N Engl J Med 340:1307-1313, 1999. 270.

Lima SD, Lima JAC, Pyeritz RE, et al: Relationship of mitral valve prolapse to left ventricular size in Marfan's syndrome. Am J Cardiol 55:739, 1985. 271.

Roman MJ, Rosen SE, Kramer-Fox R, et al: Prognostic significance of the pattern of aortic root dilation in the Marfan syndrome. J Am Coll Cardiol 22:1470, 1993. 272.

Crawford ES: Marfan's syndrome: Broad spectral surgical treatment: Cardiovascular manifestations. Ann Surg 198:487, 1983. 273.

Svensson LG, Crawford ES, Coselli JS, et al: Impact of cardiovascular operation on survival in the Marfan patient. Circulation 80:233, 1988. 274.

Silverman DI, Burton KJ, Gray J, et al: Life expectancy in the Marfan syndrome. Am J Cardiol 75:157, 1995. 275.

David TE: Aortic valve repair in patients with Marfan syndrome and ascending aorta aneurysms due to degenerative disease. J Card Surg 9(Suppl):182-187, 1994. 276.

Birks EJ, Webb C, Child A, et al: Early and long-term results of a valve-sparing operation for Marfan syndrome. Circulation 100(suppl II):29-35, 1999. 276A.

2015

Arn PH, Scherer LR, Haller JA Jr, et al: Outcome of pectus excavatum in patients with Marfan syndrome and in the general population. J Pediatr 115:954, 1989. 277.

Schaefer S, Peshock RM, Malloy CR, et al: Nuclear magnetic resonance imaging in Marfan's syndrome. J Am Coll Cardiol 9:70, 1987. 278.

Soulen RL, Fishman E, Pyeritz RE, et al: Evaluation of the Marfan syndrome: MR imaging versus CT. Radiology 165:697, 1987. 279.

Crawford ES, Crawford JL, Stowe CL, et al: Total aortic replacement for chronic aortic dissection occurring in patients with and without Marfan's syndrome. Ann Surg 199:358, 1984. 280.

281.

Shores J, Borger KR, Murphy EA, et al: Chronic beta-adrenergic blockade protects the aorta in the

Marfan syndrome: A prospective, randomized trial of propranolol. N Engl J Med 330:1335, 1994. Salim MA, Alpert BS, Ward JC, et al: Effect of beta-adrenergic blockade on aortic root rate of dilation in the Marfan syndrome. Am J Cardiol 74:629, 1994. 282.

Yin FCP, Brin KP, Ting C-T, et al: Arterial hemodynamics in the Marfan syndrome. Circulation 79:854, 1989. 283.

Jondeau G, Boutouyrie P, Lacolley P, et al: Central pulse pressure is a major determinant of ascending aorta dilatation in Marfan syndrome. Circulation 99:2677-2681, 1999. 284.

Pyeritz RE: Maternal and fetal complications of pregnancy in the Marfan syndrome. Am J Med 71:784, 1981. 285.

Rossiter JP, Morales AJ, Repke JT, et al: A prospective longitudinal evaluation of pregnancy in the Marfan syndrome. Am J Obstet Gynecol 173:1599, 1995. 286.

Lipscomb KJ, Clayton-Smith J, Clarke B, et al: Outcome of pregnancy in women with Marfan's syndrome. Br J Obstet Gynaecol 104:210-216, 1997. 287.

Hollister DW, Godfrey M, Sakai LY, et al: Marfan syndrome: Immunohistologic abnormalities of the elastin-associated microfibrillar fiber system. N Engl J Med 323:152, 1990. 288.

Sakai LY, Keene DR, Engvall E: Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils. J Cell Biol 103:2499, 1986. 289.

Pyeritz RE, Dietz HC: The Marfan syndrome and other fibrillinopathies. In Royce PM, Steinmann B (eds): Connective Tissue and Its Heritable Disorders: Molecular, Genetic and Medical Aspects. 2nd ed. New York, Wiley-Liss (in press). 290.

Collod-Beroud G, Beroud C, Ades L: Marfan Database (3rd ed): New mutations and new routines for the software. Nucl Acids Res 26:229-233, 1998. 291.

Yuan B, Thomas JP, von Kodolitsch Y, Pyeritz RE: Comparison of heteroduplex analysis, direct sequencing and enzyme mismatch cleavage for detecting mutations in a large gene, FBN1. Hum Mutat 14:440-446, 1999. 292.

Milewicz DMcG, Pyeritz RE, Crawford ES, et al: Marfan syndrome: Defective synthesis, secretion and extracellular matrix formation of fibrillin by cultured dermal fibroblasts. J Clin Invest 89:79, 1992. 293.

Aoyama T, Francke U, Dietz H, et al: Quantitative differences in biosynthesis and extracellular deposition of fibrillin in cultured fibroblasts distinguish five groups of Marfan syndrome patients and suggest distinct pathogenetic mechanisms. J Clin Invest 94:130, 1994. 294.

Beighton P, De Paepe A, Steinmann B, et al: Ehlers-Danlos syndromes: Revised nosology, Villefranche, 1997. Am J Med Genet 77:31-37, 1998. 295.

Leier CV, Call TD, Fulkerson PK, et al: The spectrum of cardiac defects in the Ehlers-Danlos syndrome, types I and III. Ann Intern Med 92:171, 1980. 296.

296A.

Pyeritz RE: Ehlers-Danlos syndrome. N Engl J Med 342:730-732, 2000.

Gilchrist D, Schwarze U, Shields K, et al: Large kindred with Ehlers-Danlos syndrome type IV due to a point mutation (G571S) in the COL3A1 gene of type III procollagen: Low risk of pregnancy complications and unexpected longevity in some affected relatives. Am J Med Genet 82:305-311, 1999. 297.

Fox R, Pope FM, Narcisi P, et al: Spontaneous carotid cavernous fistula in Ehlers-Danlos syndrome. J Neurol Neurosurg Psychiatry 51:984, 1988. 298.

Pepin M, Schwarze U, Superti-Furga A, Byers PH: Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med 342:673-680, 2000. 298A.

Rudd NL, Nimrod C, Holbrook KA, et al: Pregnancy complications in type IV Ehlers-Danlos syndrome. Lancet 1:50, 1983. 299.

Pope FM: Pseudoxanthoma elasticum, cutis laxa, and other disorders of elastic tissue. In Rimoin DL, Connor JM, Pyeritz RE (eds): Principles and Practice of Medical Genetics. 3rd ed. New York, Churchill Livingstone, 1997, pp 1083-1120. 300.

Cunningham JR, Lippman SM, Renie WA, et al: Pseudoxanthoma elasticum: Treatment of gastrointestinal hemorrhage by arterial embolization and observations of autosomal dominant inheritance. Johns Hopkins Med J 147:168, 1980. 301.

Lebwohl MG, Distefano D, Prioleau PG, et al: Pseudoxanthoma elasticum and mitral-valve prolapse. N Engl J Med 307:228, 1982. 302.

Pyeritz RE, Weiss JL, Renie WA, et al: Pseudoxanthoma elasticum and mitral-valve prolapse. N Engl J Med 307:1451, 1982. 303.

Goodman RM, Smith EW, Paton D, et al: Pseudoxanthoma elasticum: A clinical and histopathological study. Medicine 42:297, 1963. 304.

Lebwohl M, Halperin J, Phelps RG: Occult pseudoxanthoma elasticum in patients with premature cardiovascular disease. N Engl J Med 329:1237, 1993. 305.

Challenor VF, Conway N, Monro JL: The surgical treatment of restrictive cardiomyopathy in pseudoxanthoma elasticum. Br Heart J 59:266, 1988. 306.

Renie WA, Pyeritz RE, Combs J, et al: Pseudoxanthoma elasticum: High calcium intake in early life correlates with severity. Am J Med Genet 19:235, 1984. 307.

Struk B, Neldner KH, Rao VS, et al: Mapping of both autosomal recessive and dominant variants of pseudoxanthoma elasticum to chromosome 16p13.1. Hum Mol Genet 6:1823, 1997. 308.

Maharaj B, Hammond MG, Appadoo B, et al: HLA-A, B, DR, and DQ antigens in black patients with severe chronic rheumatic heart disease. Circulation 76:259, 1987. 309.

INBORN ERRORS OF METABOLISM THAT AFFECT THE CARDIOVASCULAR SYSTEM La Du BN: Alkaptonuria: In Scriver CR, Beaudet AL, Sly WA, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill, 1995, p 1371. 310.

311.

Mudd SH, Levy HL, Skovby F: Disorders of transsulfuration. In Scriver CR, Beaudet AL, Sly WA,

Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill, 1995, p 1279. Kraus JP, Janosik M, Kozich V, et al: Cystathionine beta-synthase mutations in homocystinuria. Hum Mutat 13:362-375, 1999. 312.

Mudd SH, Skovby F, Levy HL, et al: The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 37:1, 1985. 313.

Wilcken DEL, Wilcken B: The natural history of vascular disease in homocystinuria and the effects of treatment. J Inher Metab Dis 20:295-300, 1997. 313A.

Hill-Zobel RL, Pyeritz RE, Scheffel U, et al: Kinetics and biodistribution of 122 In-labeled platelets in homocystinuria. N Engl J Med 307:781, 1982. 314.

Selhub J, Jacques PF, Bostom AG, et al: Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 332:286, 1995. 315.

Kang S-S, Passen EL, Ruggie N, et al: Thermolabile defect of methylenetetrahydrofolate reductase in coronary artery disease. Circulation 88:1463, 1993. 316.

Eikelboom JW, Lonn E, Genest J Jr, et al: Homocyst(e)ine and cardiovascular disease: A critical review of the epidemiologic evidence. Ann Intern Med 131:363-375, 1999. 317.

Hajjar KA: Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J Clin Invest 91:2873, 1993. 318.

Majors A, Ehrhart LA, Pezacka EH: Homocysteine as a risk factor for vascular disease. Enhanced collagen production and accumulation by smooth muscle cells. Arterioscler Thromb Vasc Biol 17:2074-2081, 1997. 319.

Stampfer MJ, Manilow MR: Can lowering homocysteine levels reduce cardiovascular risk? N Engl J Med 332:328, 1995. 320.

Roe CR, Coates PM: Mitochondrial fatty acid oxidation disorders. In Scriver CR, Beaudet AL, Sly WA, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill, 1995, p 1501. 321.

Treem WR, Stanley CA, Finegold DN, et al: Primary carnitine deficiency due to a failure of carnitine transport in kidney, muscle, and fibroblasts. N Engl J Med 319:1331, 1988. 322.

Waber LJ, Valle D, Neill C, et al: Carnitine deficiency presenting as familial cardiomyopathy: A treatable defect in carnitine transport. J Pediatr 101:700, 1982. 323.

Tripp ME, Katcher ML, Peters HA, et al: Systemic carnitine deficiency presenting as familial endocardial fibroelastosis. N Engl J Med 305:385, 1981. 324.

Goodman SI: Organic acid metabolism. In Rimoin DL, Connor JM, Pyeritz RE (eds): Principles and Practice of Medical Genetics. 3rd ed. New York, Churchill Livingstone, 1997, pp 1977-1990. 325.

Brackett JC, Sims HF, Steiner RD, et al: A novel mutation in medium chain Acyl-CoA dehydrogenase causes sudden neonatal death. J Clin Invest 94:1477, 1994. 326.

de Vries HG, Niezen-Koning K, Kliphuis JW, et al: Prevalence of carriers of the most common medium-chain acyl-CoA dehydrogenase (MCAD) deficiency mutation (G985A) in The Netherlands. Hum Genet 98:1-2, 1996. 327.

Anan R, Nakagawa M, Miyata M, et al: Cardiac involvement in mitochondrial diseases. A study of 17 patients with documented mitochondrial DNA defects. Circulation 91:955, 1995. 328.

Merante F, Tein L, Benson L, et al: Maternally inherited hypertrophic cardiomyopathy due to a novel T-to-C transition at nucleotide 9997 in the mitochondrial tRNA glycine gene. Am J Hum Genet 55:437, 1994. 329.

Van Hove JLK, Shanske S, Ciacci F, et al: Mitochondrial myopathy with anemia, cardiomyopathy and lactic acidosis: A distinct late onset mitochondrial disorder. Am J Med Genet 51:115, 1994. 330.

Ogashara S, Engel AG, Frens D, et al: Muscle coenzyme Q deficiency in familial mitochondrial encephalomyopathy. Proc Natl Acad Sci U S A 86:2379, 1989. 331.

Channer KS, Channer JL, Campbell MJ, et al: Cardiomyopathy in the Kearns-Sayre syndrome. Br Heart J 59:486, 1988. 332.

Chen Y-T, Burchell A: Glycogen storage diseases. In Scriver CR, Beaudet AL, Sly WA, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill, 1995, p 935. 333.

Ehlers KH, Hagstrom JWC, Lukas DS, et al: Glycogen-storage disease of the myocardium with obstruction to left ventricular outflow. Circulation 25:96, 1962. 334.

2016

Bharati S, Serratto M, Du Brow I, et al: The conduction system in Pompe's disease. Pediatr Cardiol 2:25, 1982. 335.

Bonnici F, Shapiro R, Joffe HS, et al: Angiocardiographic and enzyme studies in a patient with type II glycogenosis. S Afr Med J 58:860, 1980. 336.

Robinson WF, Howell JM, Dorling PR: Cardiomyopathy is generalised glycogenosis type II in cattle. Cardiovasc Res 17:238, 1982. 337.

Suzuki Y, Tsuji A, Omura K, et al: Km mutant of acid alpha-glucosidase in a case of cardiomyopathy without signs of skeletal muscle involvement. Clin Genet 33:376, 1988. 338.

Makos MM, McComb RD, Hart MN, et al: Alpha-glucosidase deficiency and basilar artery aneurysm: Report of a sibship. Ann Neurol 22:629, 1987. 339.

Kretzschmar HA, Wagner H, Hubner G, et al: Aneurysm and vacuolar degeneration of cerebral arteries in late-onset acid maltase deficiency. J Neurol Sci 98:169, 1990. 340.

Martiniuk F, Mehler M, Tzall S, et al: Extensive genetic heterogeneity in patients with acid alpha glucosidase deficiency as detected by abnormalities of DNA and mRNA. Am J Hum Genet 47:73, 1990. 341.

Olson LJ, Reeder GS, Noller KL, et al: Cardiac involvement in glycogen storage disease III. Morphologic and biochemical characterization with endomyocardial biopsy. Am J Cardiol 53:980, 1984. 342.

Coleman RA, Winter HS, Wolf B, et al: Glycogen debranching enzyme deficiency: Long-term study of serum enzyme activities and clinical features. J Inherit Metab Dis 15:869, 1992. 343.

Talente GM, Coleman RA, Alter C, et al: Glycogen storage diseases in adults. Ann Intern Med 120:218, 1994. 344.

Cox PM, Brueton LA, Murphy KW, et al: Early-onset fetal hydrops and muscle degeneration in siblings due to a novel variant of type IV glycogenosis. Am J Med Genet 86:187-193, 1999. 345.

Servidei S, Metlay LA, Chodosh J, et al: Fatal infantile cardiopathy caused by phosphorylase b kinase deficiency. J Pediatr 113:82, 1988. 346.

Schroder JM, May R, Shin YS, et al: Juvenile hereditary polyglucosan body disease with complete branching enzyme deficiency (type IV glycogenosis). Acta Neuropathol 85:419, 1993. 347.

Howell RR: Continuing lessons from glycogen storage diseases [editorial]. N Engl J Med 324:55, 1991. 348.

Selby R, Starzl TE, Yunis E, et al: Liver transplantation for type IV glycogen storage disease. N Engl J Med 324:39, 1991. 349.

Eishi Y, Takemura T, Sone R, et al: Glycogen storage disease confined to the heart with deficient activity of cardiac phosphorylase kinase: A new type of glycogen storage disease. Hum Pathol 16:193, 1987. 350.

Elleder M, Shin YS, Zuntova A, et al: Fatal infantile hypertrophic cardiomyopathy secondary to deficiency of heart specific phosphorylase b kinase. Virchows Arch A 423:303, 1993. 351.

Leroy JG: Oligosaccharidoses. In Rimoin DL, Connor JM, Pyeritz RE (eds): Principles and Practice of Medical Genetics. 3rd ed. New York, Churchill Livingstone, 1997, pp 2081-2104. 352.

Bothwell TH, Charlton RW, Motulsky AG: Hemochromatosis. In Scriver CR, Beaudet AL, Sly WA, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill, 1995, p 2237. 353.

Olynyk JK, Cullen DJ, Aquilia S, et al: A population-based study of the clinical expression of the hemochromatosis gene. N Engl J Med 341:718-724, 1999. 354.

Burke W, Thomson E, Khoury MJ, et al: Hereditary hemochromatosis: Gene discovery and its implications for population-based screening. JAMA 280:172-178, 1998. 355.

356.

Edwards CQ: Early detection of hereditary hemochromatosis. Ann Intern Med 101:707, 1984.

Olson LJ, Baldus WP, Tajik AJ, Echocardiographic features of idiopathic hemochromatosis. Am J Cardiol 60:885, 1987. 357.

Porter J, Cary N, Schofield P: Haemochromatosis presenting as congestive cardiac failure. Br Heart J 73:73, 1995. 358.

Cutler DJ, Isner JM, Bracey AW, et al: Hemochromatosis heart disease: An unemphasized cause of potentially reversible restrictive cardiomyopathy. Am J Med 69:923, 1980. 359.

360.

Adams RJ: Sickle cell disease and stroke. J Child Neurol 10:75-76, 1995.

Weatherall DJ, Clegg JB, Higgs DR, et al: The hemoglobinopathies. In Scriver CR, Beaudet AL, Sly WA, Valley D (eds): The Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill, 1995, p 3417. 361.

Sutton LL, Castro O, Cross DJ, et al: Pulmonary hypertension in sickle cell disease. Am J Cardiol 74:626, 1994. 362.

Brittenham GM, Griffith PM, Nienhuis AW, et al: Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med 331:567, 1994. 363.

364.

Steinberg MH: Management of sickle cell disease. N Engl J Med 340:1021-1030, 1999.

Olivieri NF, Liu PP, Sher GD, et al: Combination liver and heart transplantation for end-stage iron-induced organ failure in an adult with homozygous beta-thalassemia. N Engl J Med 330:1125, 1994. 365.

Spranger J: Mucopolysaccharidoses. In Rimoin DL, Connor JM, Pyeritz RE (eds): Principles and Practice of Medical Genetics. 3rd ed. New York, Churchill Livingstone, 1997, pp 2071-2080. 366.

Johnson GL, Vine DL, Cottrill CM, et al: Echocardiographic mitral valve deformity in the mucopolysaccharidoses. Pediatrics 67:401, 1981. 367.

Gross DM, Williams JC, Caprioli C, et al: Echocardiographic abnormalities in the mucopolysaccharide storage diseases. Am J Cardiol 61:170, 1988. 368.

John RM, Hunter D, Swanton RH: Echocardiographic abnormalities in type IV mucopolysaccharidosis. Arch Dis Child 65:746, 1990. 369.

Pyeritz RE: Storage disorders. In Pierpont ME, Moller JH (eds): The Genetics of Cardiovascular Disease. Boston, Martinus Nijhoff Publishing, 1987, p 215. 370.

Nelson J, Shields MD, Mulholland HC: Cardiovascular studies in the mucopolysaccharidoses. J Med Genet 27:94, 1990. 371.

Brosius FC III, Roberts WC: Coronary artery disease in the Hurler syndrome: Qualitative and quantitative analysis of the extent of coronary narrowing at necropsy in six children. Am J Cardiol 47:649, 1981. 372.

Renteria VG, Ferrans VJ, Roberts WC: The heart in the Hurler syndrome: Gross, histologic and ultrastructural observations in five necropsy cases. Am J Cardiol 38:487, 1976. 373.

Semenza GL, Pyeritz RE: Respiratory complications of the mucopolysaccharide storage disorders. Medicine 67:209, 1988. 374.

375.

Young ID, Harper PS: Long-term complications in Hunter's syndrome. Clin Genet 16:125, 1979.

376.

Armitage JO: Bone marrow transplantation. N Engl J Med 330:827, 1994.

Whitley CB, Belani KG, Chang P-N, et al: Long-term outcome of Hurler syndrome following bone marrow transplantation. Am J Med Genet 46:209, 1993. 377.

Rutledge SL, Percy AK: Gangliosidoses and related lipid storage diseases. In Rimoin DL, Connor JM, Pyeritz RE (eds): Principles and Practice of Medical Genetics. 3rd ed. New York, Churchill Livingstone, 1997, pp 2105-2130. 378.

Spence MW, MacKinnon KE, Burgess JK, et al: Failure to correct the metabolic defect by renal allotransplantation in Fabry's disease. Ann Intern Med 84:13, 1976. 379.

Kramer W, Thormann J, Mueller K, et al: Progressive cardiac involvement by Fabry's disease despite successful renal allotransplantation. Int J Cardiol 7:72, 1985. 380.

Schiffmann R, Murray GJ, Treco D, et al: Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease. Proc Natl Acad Sci U S A 97:365-370, 2000. 380A.

Colucci WS, Lorell BH, Schoen FJ, et al: Hypertrophic obstructive cardiomyopathy due to Fabry's disease. N Engl J Med 307:926, 1982. 381.

von Scheidt W, Eng CM, Fitzmaurice TF, et al: An atypical variant of Fabry's disease with manifestations confined to the myocardium. N Engl J Med 324:395, 1991. 382.

Hillsley RE, Hernandez E, Steenbergen C, et al: Inherited restrictive cardiomyopathy in a 74-year-old woman: A case of Fabry's disease. Am Heart J 129:199-202, 1995. 383.

Nakao S, Takenaka T, Maeda M, et al: An atypical variant of Fabry's disease in men with left ventricular hypertrophy. N Engl J Med 333:288-293, 1995. 384.

Goldman ME, Cantor R, Schwartz MF, et al: Echocardiographic abnormalities and disease severity in Fabry's disease. J Am Coll Cardiol 7:1157, 1986. 385.

Sakuraba H, Yanagawa Y, Igarashi T, et al: Cardiovascular manifestations in Fabry's disease: A high incidence of mitral valve prolapse in hemizygotes and heterozygotes. Clin Genet 29:276, 1986. 386.

Mutoh T, Senda Y, Sugimura K, et al: Severe orthostatic hypotension in a female carrier of Fabry's disease. Arch Neurol 34:468, 1988. 387.

Bernstein HS, Bishop DF, Astrin KH, et al: Fabry disease: Six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene. J Clin Invest 83:1390, 1989. 388.

Thomas PK, Harding AE. Hereditary motor and sensory neuropathies. In Rimoin DL, Connor JM, Pyeritz RE (eds): Principles and Practice of Medical Genetics. 3rd ed. New York, Churchill Livingstone, 1997, pp 2249-2268. 389.

Backman C, Olofsson BO: Echocardioraphic features in familial amyloidosis with polyneuropathy. Acta Med Scand 214:273, 1983. 390.

Eriksson A, Eriksson P, Olofsson B-O, et al: The cardiac atrioventricular conduction system in familial amyloidosis with polyneuropathy: A clinico-pathologic study of six cases from Northern Sweden. Acta Pathol Microbiol Immunol Scand 91:343, 1983. 391.

Booth DR, Tan SY, Hawkins PN, et al: A novel variant of transthyretin, 59Thr-Lys , associated with autosomal dominant cardiac amyloidosis in an Italian family. Circulation 91:962, 1995. 392.

Skinner M, Lewis WD, Jones LA, et al: Liver transplantation as a treatment for familial amyloidotic polyneuropathy. Ann Intern Med 120:133, 1994. 393.

394.

Vidaillet HJ Jr: Cardiac tumors associated with hereditary syndromes. Am J Cardiol 61:1355, 1988.

Burke AP, Rosado-de-Christenson M, Templeton PA, et al: Cardiac fibroma: Clinicopathologic correlates and surgical treatment. J Thorac Cardiovasc Surg 108:862, 1994. 395.

Roach ES, DiMario FJ, Kandt RS, Northrup H: Tuberous sclerosis complex consensus conference: Recommendations for diagnostic evaluation. J Child Neurol 14:401-407, 1999. 396.

Sperling D, Smith M: Novel 23-base-pair duplication mutation in TSC1 exon 15 in an infant presenting with cardiac rhabdomyomas. Am J Med Genet 84:346-349, 1999. 397.

Harding CO, Pagon RA: Incidence of tuberous sclerosis in patients with cardiac rhabdomyoma. Am J Med Genet 37:443, 1990. 398.

Astrinidis A, Khare L, Carsillo T, et al: Mutational analysis of the tuberous sclerosis gene TSC2 in patients with pulmonary lymphangioleiomyomatosis. J Med Genet 37:55-57, 2000. 398A.

2017

Liebler GA, Magovern GJ, Park SB, et al: Familial myxomas in four siblings. J Thorac Cardiovasc Surg 71:605, 1976. 399.

Carney JA, Gordon H, Carpenter PC, et al: The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine 64:270, 1985. 400.

Handley J, Carson D, Sloan J, et al: Multiple lentigines, myxoid tumours and endocrine overactivity: Four cases of Carney's complex. Br J Dermatol 126:367, 1992. 401.

Goldstein MM, Casey M, Carney JA, et al: Molecular genetic diagnosis of the familial myxoma syndrome (Carney complex). Am J Med Genet 86:62-65, 1999. 402.

INHERITED DISORDERS OF THE CIRCULATION Basson CT, MacRae CA, Korf B, Merliss A: Genetic heterogeneity of familial atrial myxoma syndromes (Carney complex). Am J Cardiol 79:994-995, 1997. 403.

Stratakis CA, Carney JA, Lin J-P, et al: Carney complex, a familial multiple neoplasia and lentiginosis syndrome: Analysis of 11 kindreds and linkage to the short arm of chromosome 2. J Clin Invest 97:699-705, 1996. 404.

Peery WH: Clinical specturm of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease). Am J Med 82:989, 1987. 405.

Haitjema T, Disch F, Overtoom TTC, Westermann CJJ: Screening family members of patients with hereditary hemorrhagic telangiectasia. Am J Med 99:519-524, 1995. 406.

Shovlin CL, Guttmacher AE, Buscarini E, et al: Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 91:66-67, 2000. 406A.

Guillen B, Guizar J, de la Cruz J, et al: Hereditary hemorrhagic telangiectasia: Report of 15 affected cases in a Mexican family. Clin Genet 39:214, 1991. 407.

Fulbright RK, Chaloupka JC, Putman CM, et al: MR of hereditary hemorrhagic telangiectasia: Prevalence and spectrum of cerebrovascular malformations. Am J Neuroradiol 19:477-484, 1998. 408.

Nikolopoulos N, Xynos E, Vassilakis JS: Familial occurrence of hyperdynamic circulation status due to intrahepatic fistulae in hereditary hemorrhagic telangiectasia. Hepatogastroenterology 35:167, 1988. 409.

Cooke DAP: Renal arteriovenous malformation demonstrated angiographically in hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease). J R Soc Med 79:744, 1986. 410.

Kurnik PB, Heymann WR: Coronary artery ectasia associated with hereditary hemorrhagic telangiectasia. Arch Intern Med 149:2357, 1989. 411.

Kopel L, Lage SG: Cardiac tamponade in hereditary hemorrhagic telangiectasia. Am J Med 105:252-253, 1998. 412.

Braverman IM, Keh A, Jacobson BS: Ultrastructure and three-dimensional organization of the telangiectases of hereditary hemorrhagic telangiectasia. J Invest Dermatol 95:422, 1990. 413.

Lee DW, White RI Jr, Egglin TK, et al: Embolotherapy of large pulmonary arteriovenous malformations: Long-term results. Ann Thorac Surg 64:930-940, 1997. 414.

Haq AU, Glass J, Netchvolodoff CV, et al: Hereditary hemorrhagic telangiectasia and danazol. Ann Intern Med 109:171, 1988. 415.

Saba HI, Morelli GA, Logrono LA: Treatment of bleeding in hereditary hemorrhagic telangiectasia with aminocaproic acid. N Engl J Med 330:1789, 1994. 416.

417.

Phillips MD: Stopping bleeding in hereditary telangiectasia. N Engl J Med 330:1822, 1994.

McAllister KA, Grogg KMM, Johnson DW, et al: Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 8:345, 1994. 418.

Johnson DW, Berg JN, Baldwin MA, et al: Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 13:189-195, 1996. 419.

Piantanida M, Buscarini E, Dellavecchia C, et al: Hereditary haemorrhagic telangiectasia with extensive liver involvement is not caused by either HHT1 or HHT2. J Med Genet 33:441-443, 1996. 420.

Jennings AM, Smith C, Cole DR, et al: Von Hippel-Lindau disease in a large British family: Clinicopathological features and recommendations for screening and follow-up. Q J Med 66:233, 1988. 421.

422.

Lamiell JM, Salazar FG, Hsia YE: Von Hippel-Lindau disease affecting 43 members of a single

kindred. Medicine 68:1, 1989. Latif F, Troy K, Gnarra J, et al: Identification of the von Hippel-Landau disease tumor suppressor gene. Science 260:1317, 1993. 423.

Zbar B, Kishida T, Chen F, et al: Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat 8:348-357, 1996. 424.

Prowse AH, Webster AR, Richards FM, et al: Somatic inactivation of the VHL gene in Von Hippel-Lindau disease tumors. Am J Hum Genet 60:765-771, 1997. 425.

Parfrey PS, Bear JC, Morgan J, et al: The diagnosis and prognosis of autosomal dominant polycystic kidney disease. N Engl J Med 323:1085, 1990. 426.

427.

Gabow PA: Autosomal dominant polycystic kidney disease. N Engl J Med 329:332, 1993.

Chapman AB, Johnson A, Gabow PA, et al: The renin-angiotensin aldosterone system and autosomal dominant polycystic kidney disease. N Engl J Med 323:1091, 1990. 428.

Leier CV, Baker PB, Kilman JW, et al: Cardiovascular abnormalities associated with adult polycystic kidney disease. Ann Intern Med 100:683, 1984. 429.

Hossack KF, Leddy CL, Johnson AM, et al: Echocardiographic findings in autosomal dominant polycystic kidney disease. N Engl J Med 319:907, 1988. 430.

431.

Chapman JR, Hilson AJW: Polycystic kidneys and abdominal aortic aneurysms. Lancet 1:646, 1980.

Chapman AB, Rubinstein D, Hughes R, et al: Intracranial aneurysms in autosomal dominant polycystic kidney disease. N Engl J Med 327:916, 1992. 432.

Watnick T, Phakdeekitcharoen B, Johnson A, et al: Mutation detection of PKD1 identifies a novel mutation common to three families with aneurysms and/or very-early-onset disease. Am J Hum Genet 65:1561-1571, 1999. 432A.

Hateboer N, van Dijk MA, Bogdanova N, et al: Comparison of phenotypes of polycystic kidney disease types 1 and 2. Lancet 353:103-107, 1999. 433.

Koptides M, Hadjimichael C. Koupepidou P, et al: Germinal and somatic mutations in the PKD2 gene of renal cysts in autosomal dominant polycystic kidney disease. Hum Mol Genet 8:509-513, 1999. 434.

Qian F, Watnick TJ, Onuchic LF, et al: The molecular basis of focal cyst formation in human autsomal dominant polycystic kidney disease type I. Cell 87:979-987, 1996. 435.

Daoust MC, Reynold DM, Bichet DG, et al: Evidence for a third genetic locus for autosomal dominant polycystic kidney disease. Genomics 25:733, 1995. 436.

Shulman SA, Hyams JS, Gunta R, et al: Arteriohepatic dysplasia (Alagille syndrome): Extreme variability among affected family members. Am J Med Genet 19:325, 1984. 437.

Dhorne-Pollet S, Deleuze J-F, Hadchouel M, et al: Segregation analysis of Alagille syndrome. J Med Genet 31:453, 1994. 438.

Woolfenden AR, Albers GW, Steinberg GK, et al: Moyamoya syndrome in children with Alagille syndrome: Additional evidence of a vasculopathy. Pediatrics 103:505-508, 1999. 439.

Yuan Z-R, Kohsak T, Ikegaya T, et al: Mutational analysis of the Jagged 1 gene in Alagille syndrome families. Hum Mol Genet 7:1363-1369, 1998. 440.

Li L, Krantz ID, Deng Y, et al: Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 16:243-251, 1997. 441.

Nicod P, Bloor C, Godfrey M, et al: Familial aortic dissecting aneurysms. J Am Coll Cardiol 13:811, 1989. 442.

Biddinger A, Rocklin M, Coselli J, Milewicz DM: Familial thoracic aortic dilatations and dissections: A case control study. J Vasc Surg 25:506-511, 1997. 443.

Milewicz DM, Chen H, Park E-S, et al: Reduced penetrance and variable expressivity of familial thoracic aortic aneurysms/dissections. Am J Cardiol 82:474-479, 1998. 444.

Roberts CS, Roberts WC: Dissection of the aorta associated with congenital malformation of the aortic valve. J Am Coll Cardiol 17:712, 1994. 445.

Kontusaari S, Tromp G, Kuivaniemi H, et al: Inheritance of RNA splicing mutation (G +1 IVS 20 ) in the type III procollagen gene (COL3AI) in a family having aortic aneurysms and easy bruisability: Phenotypic overlap between familial arterial aneurysms and Ehlers-Danlos syndrome type IV. Am J Hum Genet 47:112, 1990. 446.

Kontusaari S, Tromp G, Kuivaniemi H, et al: A mutation in the gene for type III procollagen (COL3AI) in a family with aortic aneurysms. J Clin Invest 86:1465, 1990. 447.

Tromp G, Wu Y, Prockop DJ, et al: Sequencing of cDNA from 50 unrelated patients reveals that mutations in the triple-helical domain of type III procollagen are an infrequent cause of aortic aneurysms. J Clin Invest 91:2539, 1993. 448.

Schievink WI, Michaels VV, Mokri B, et al: A familial syndrome of arterial dissections with lentiginosis. N Engl J Med 332:576, 1995. 449.

Majamaa K, Portimojarvi H, Sotaniemi KA, et al: Familial aggregation of cervical artery dissection and cerebral aneurysm. Stroke 25:1704, 1994. 450.

Schievink WI, Mokri B, Piepgras DG, et al: Intracranial aneurysms and cervicocephalic arterial dissections associated with congenital heart disease. J Neurosurg 39:685-690, 1996. 451.

Majumder PP, St. Jean PL, Ferrell RE, et al: On the inheritance of abdominal aortic aneurysm. Am J Hum Genet 48:164, 1991. 452.

Fitzgerald P, Ramsbottom D, Burke P, et al: Abdominal aortic aneurysm in the Irish population. Br J Surg 82:483-486, 1995. 453.

Pletcher BA, Fox JE, Boxer RA, et al: Four sibs with arterial tortuosity. Am J Med Genet 66:121-128, 1996. 454.

455.

Halal F, Mohr G, Toussi T, et al: Intracranial aneurysms: A report of a large pedigree. Am J Med

Genet 15:89, 1983. Caplan LR: Should intracranial aneurysms be treated before they rupture? N Engl J Med 339:1774-1775, 1998. 456.

Magnetic Resonance Angiography Study Group: Risks and benefits of screening for intracranial aneurysms in first-degree relatives of patients with sporadic subarachnoid hemorrhage. N Engl J Med 241:1344-1350, 1999. 457.

Gaist D, Vaeth M, Tsiropoulos I, et al: Risk of subarachnoid haemorrhage in first degree relatives of patients with subarachnoid haemorrhage: Follow up study based on national registries in Denmark. BMJ 320:141-145, 2000. 457A.

2018

Kuivaniemi H, Prockop DJ, Wu Y, et al: Exclusion of mutations in the gene for type III collagen (COL3A1) as a common cause of intracranial aneurysms or cervical artery dissections: Results from sequence analysis of the coding sequences of type III collagen from 55 unrelated patients. Neurology 43:2652, 1993. 458.

Abrahamson M: Human cysteine proteinase inhibitors: Isolation, physiological importance, inhibitory mechanism, gene structure and relation to hereditary cerebral hemorrhage. Scand J Clin Lab Invest 48:21, 1988. 459.

Wattendorf AR, Bots GTAM, Went LN, et al: Familial cerebral amyloid angiopathy presenting as recurrent cerebral haemorrhage. J Neurol Sci 55:121, 1982. 460.

Pasyk KA, Argenta LC, Erickson RP: Familial vascular malformations: Report of 25 members of one family. Clin Genet 26:221, 1984. 461.

Walter JW, Blei F, Anderson JL, et al: Genetic mapping of a novel familial form of infantile hemangioma. Am J Med Genet 82:77-83, 1999. 462.

463.

Iadecola C: Genetics of cerebrovascular disease. N Engl J Med 339:216, 1998.

464.

Stanley JC: Arterial fibrodysplasia. Arch Surg 110:561, 1975.

Kousseff BG, Gilbert-Barness EF: Vascular neurofibromatosis and infantile gangrene. Am J Med Genet 34:221, 1989. 465.

Schievink WI, Bjornsson J, Parisi JE, et al: Arterial fibromuscular dysplasia associated with severe alpha 1 -antitrypsin deficiency. Mayo Clin Proc 69:1040, 1994. 466.

Petit H, Bouchez B, Destee A, et al: Familial form of fibromuscular dysplasia of the internal carotid artery. J Neuroradiol 10:15, 1983. 467.

468.

Rushton AR: The genetics of fibromuscular dysplasia. Arch Intern Med 140:233, 1980.

469.

Austin JG, Stear JC: Familial hypoplasia of both internal carotid arteries. Arch Neurol 24:1, 1971.

McDonald AH, Gerlis LM, Somerville J: Familial arteriopathy with associated pulmonary and systemic arterial stenoses. Br Heart J 31:375, 1969. 470.

Ikeda H, Sasaki T, Yoshimoto T, et al: Mapping of a familial Moyamoya disease gene to chromosome 3p24.2-p26. Am J Hum Genet 64:533-537, 1999. 471.

Van Dyck M, Proesmans W, VanHollebeke E, et al: Idiopathic infantile arterial calcification with cardiac, renal and central nervous system involvement. Eur J Pediatr 148:374, 1989. 472.

De Lange RPJ, Bolt J, Reid E, et al: Screening British CADASIL families for mutations in the NOTCH3 gene. J Med Genet 37:224-225, 2000. 472A.

Ophoff RA, Terwindt GM, Vergouwe MN, et al: Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca 2+ channel gene CACNL1A4. Cell 87:543-552, 1996. 473.

Ducros A, Denier C, Joutel A, et al: Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia. Am J Hum Genet 64:89-98, 1999. 474.

Joutel A, Ducros A, Vahedi K, et al: Genetic heterogeneity of familial hemiplegic migraine. Am J Hum Genet 55:1166, 1994. 475.

Hovatta I, Kallela M, Farkkila M, et al: Familial migraine: Exclusion of the susceptibility gene from the reported locus of familial hemiplegic migraine on 19p. Genomics 23:707, 1994. 476.

Tournier-Lasserve E, Joutel A, Melki I, et al: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosone 19q12. Nat Genet 3:256, 1993. 477.

478.

Melmon KL, Braunwald E: Familial pulmonary hypertension. N Engl J Med 269:770, 1963.

Kingdon HS, Cohen LS, Roberts WC, et al: Familial occurrence of primary pulmonary hypertension. Arch Intern Med 118:422, 1966. 479.

Loyd JE, Primm RK, Newman JH: Familial primary pulmonary hypertension: Clinical patterns. Am Rev Respir Dis 129:194, 1984. 480.

Nichols WC, Koller DL, Slovis B, et al: Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31-32. Nat Genet 15:277-280, 1997. 481.

Morse JH, Jones AC, Barst RJ, et al: Mapping of familial primary pulmonary hypertension locus (PPH1) to chromosome 2q31-q32. Circulation 95:2603-2606, 1997. 482.

Lee S-D, Shroyer KR, Markham NE, et al: Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest 101:927-934, 1998. 483.

Porterfield JK, Pyeritz RE, Traill TA: Pulmonary hypertension and interstitial fibrosis in von Recklinghausen neurofibromatosis. Am J Med Genet 25:531, 1986. 484.

Goldstein S, Qazi QH, Fitzgerald J, et al: Distichiasis, congenital heart defects and mixed peripheral vascular anomalies. Am J Med Genet 20:283, 1985. 485.

Lindenauer SM: The Klippel-Trenaunay-Weber syndrome: Varicosity, hypertrophy and hemangioma with no arteriovenous fistula. Ann Surg 162:303, 1965. 486.

Campistol JM, Agusti C, Torras A, et al: Renal hemangioma and renal artery aneurysm in the Klippel-Trenaunay syndrome. J Urol 140:134, 1988. 487.

Dellemijn PLI, Vanneste JAL: Cavernous angiomatosis of the central nervous system: Usefulness of screening the family. Acta Neurol Scand 88:259, 1993. 488.

Drigo P, Mammi I, Battistella PA, et al: Familial cerebral, hepatic, and retinal cavernous angiomas: A new syndrome. Childs Nerv Syst 10:205, 1994. 489.

Craig HD, Gunel M, Cepeda O, et al: Multilocus linkage identifies two new loci for a Mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27. Hum Mol Genet 7:1851-1858, 1998. 490.

Gunel M, Awad IA, Finberg K, et al: A founder mutation as a cause of cerebral cavernous malformation in Hispanic Americans. N Engl J Med 334:946-951, 1996. 491.

Laberge-le Couteulux S, Jung HH, Labauge P, et al: Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet 23:189-193, 1999.

492.

Duong DH, Hartmann A, Isaacson S, et al: Arteriovenous malformations of the brain in adults. N Engl J Med 340:1812-1818, 340. 493.

Herbert FA, Bowen PA: Hereditary late-onset lymphedema with pleural effusion and laryngeal edema. Arch Intern Med 143:913, 1983. 494.

Ferrell RE, Levinson KL, Esman JH, et al: Hereditary lymphedema: Evidence for linkage and genetic heterogeneity. Hum Mol Genet 7:2073-2078, 1998. 495.

Evans AL, Brice G, Sotirova V, et al: Mapping of primary congenital lymphedema to the 5q35.3 region. Am J Hum Genet 64:547-555, 1999. 496.

Cambien F, Poirier O, Lecerf L, et al: Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 359:641, 1992. 497.

Fowkes FGR, Connor, JM, Smith FB, et al: Fibrinogen genotype and risk for peripheral atherosclerosis. Lancet 339:693, 1992. 498.

Ishigami T, Umemura S, Iwamoto T, et al: Molecular variant of angiotensinogen gene is associated with coronary atherosclerosis. Circulation 91:951, 1995. 499.

von Kodolitsch Y, Pyeritz RE, Rogan PK: Splice site mutations in atherosclerosis candidate genes: Relating individual information to phenotype. Circulation 100:693-699, 1999. 500.

Hacia JG, Collins FS: Mutational anaysis using oligonucleotide microarrays. J Med Genet 36:730-736, 1999. 501.

502.

Elston RC: Linkage and association. Genet Epidemiol 15:565-576, 1998.

503.

Burke W, Motulsky AG: Hypertension. In King RA, Rotter JI, Motulsky AG (eds): The Genetic Basis of

Common Diseases. New York, Oxford University Press, 1992, p 170. 504.

Murphy EA, Pyeritz RD: Homeostasis: VII. A conspectus. Am J Med Genet 24:735, 1986.

Corvol P, Soubrier F, Jeunemaitre X: Molecular genetics of hypertension. In Rimoin DL, Connor JM, Pyeritz RE (eds): Principles and Practice of Medical Genetics. 3rd ed. New York, Churchill Livingstone, 1997, pp 899-908. 505.

Parmer RJ, Cervenka JH, Stone RA: Baroflex sensitivity and heredity in essential hypertension. Circulation 85:497, 1992. 506.

507.

Lindpainter K: Genes, hypertension and cardiac hypertrophy. N Engl J Med 330:1678, 1994.

508.

Lifton RP: Molecular genetics of human blood pressure variation. Science 272:676-680, 1996.

Halushka MK, Fan JB, Bentley K, et al: Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nat Genet 22:239-247, 1999. 509.

Shimkets RA, Warnock DG, Bositis CM, et al: Liddle's syndrome: Heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell 79:407, 1994. 510.

Gordon RG, Klemm SA, Tunny TJ, et al: Primary aldosteronism: Hypertension with a genetic basis. Lancet 340:159, 1992. 511.

512.

Gordon RD: Heterogeneous hypertension. Nat Genet 11:6, 1995.

Lifton RP, Dluhy RG, Powers M, et al: A chimeric 11beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 355:262, 1992. 513.

Hata A, Namikawa C, Sasaki M, et al: Angiotensinogen as a risk factor for essential hypertension in Japan. J Clin Invest 93:1285, 1994. 514.

Jeunemaitre X, Soubrier F, Kotelevtsev YV, et al: Molecular basis of human hypertension: Role of angiotensinogen. Cell 71:169, 1992. 515.

Caulfield M, Lavendar P, Farral M, et al: Linkage of the angiotensinogen gene to essential hypertension. N Engl J Med 33:1629, 1994. 516.

Niu T, Xu X, Rogus J, et al: Angiotensinogen gene and hypertension in Chinese. J Clin Invest 101:188-194, 1998. 517.

Barley J, Carter N, Crews D, et al: Angiotensin 1 converting enzyme (ACE) polymorphism in different groups and its association with hypertension, plasma renin activity and aldosterone. J Med Genet 31:172, 1994. 518.

Morris BJ, Zee RYL, Schrader AP: Different frequencies of angiotensin-converting enzyme genotypes in older hypertensive individuals. J Clin Invest 94:1085, 1994. 519.

Arngrimsson R, Hayward C, Nadaud S, et al: Evidence for a familial pregnancy-induced hypertension locus in the eNOS-gene region. Am J Hum Genet 61:354-362, 1997. 520.

521.

Arngrimsson R, Siguroardottir S, Frigge ML, et al: A genome-wide scan reveals a maternal

susceptibility locus for pre-eclampsia on chromosome 2p13. Hum Mol Genet 8:1799-1805, 1999. DeStefano AL, Baldwin CT, Burzstyn M, et al: Autosomal dominant orthostatic hypotensive disorder maps to chromosome 18q. Am J Hum Genet 63:1425-1430, 1998. 522.

Schwartz F, Baldwin CT, Baima J, Gavras H: Mitochondrial DNA mutations in patients with orthostatic hypotension. Am J Med Genet 86:145-150, 1999. 523.

Jacob HJ, Lindpainter K, Lincoln SE, et al: Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat. Cell 67:213, 1991. 524.

John SWM, Krege JH, Oliver PM, et al: Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension. Science 267:679, 1995. 525.

Cohen LS, Friedman JM, Jefferson JW, et al: A reevaluation of risk of in utero exposure to lithium. JAMA 271:146, 1994. 526.




Part VII - CARDIOVASCULAR DISEASE IN SPECIAL POPULATIONS

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Chapter 57 - Cardiovascular Disease in the Elderly MELVIN D. CHEITLIN DOUGLAS P. ZIPES

PATHOPHYSIOLOGY The age at which patients become "elderly" is difficult to define because aging is a continuum, with blurred boundaries between middle and old age. Ideally, the term "elderly" should be marked by distinct changes in physiology, but the rate of physiological aging varies and may not advance in lock step with chronological changes, so that one can be physiologically young but chronologically old, and vice versa. In some reports the elderly are defined by eligibility for Medicare benefits (65

years). In others, age cutoffs of 70 or even 75 years are used. Aging is characterized by a gradual loss of function in many organ systems, unrelated to a pathological condition. Certainly, in many old individuals comorbid diseases complicate the aging process; but independent of associated diseases, aging produces major cardiovascular changes, including decreased elasticity and compliance of the aorta and great arteries.[1] These alterations result in a higher systolic arterial pressure and an increased impedance to left ventricular (LV) ejection, and subsequent mild LV hypertrophy and interstitial fibrosis.[2] A decrease in the rate of myocardial relaxation also occurs. As a result, the LV becomes stiffer and takes longer to relax and fill in diastole, thus increasing the importance of a properly timed atrial contraction in contributing to a normal LV end-diastolic volume (Fig. 57-1) and forming the basis for diastolic dysfunction and congestive heart failure (CHF).[3] There is also a 50 to 75 percent loss of pacemaker cells in the sinus node, accompanied by a decrease in intrinsic and maximum sinus rate. The number of atrioventricular (AV) nodal cells seems to be preserved, although an increase in AV nodal delay (PR interval) is common. Increased fibrosis of the fibrous skeleton of the AV annuli occur, along with fibrosis and loss of specialized cells in the His bundle and bundle branches that can result in heart block. Heart valves thicken, and calcification results at the base of the aortic valve and mitral annulus.[4] Aging causes a decreased sensitivity of the heart to beta-adrenergic agonists and a diminished reactivity to chemoreceptors and baroreceptors.[5] There is no decrease in myocardial contractility solely as a result of aging, but diseases that do result in decreased contractility, such as hypertension (HTN) and coronary artery disease (CAD), are common in this age group.

Figure 57-1 Effect of age on early diastolic filling and on atrial contribution to diastolic filling by echo-Doppler in healthy Baltimore Longitudinal Study on Aging (BLSA) participants. (From Geokas MC, Lakatta EG, Makinodon T, et al: The aging process. Ann Intern Med 113:455-466, 1990.)

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Figure 57-2 Exercise-related changes in heart rate (A), end-diastolic volume (B), end-systolic volume (C), and stroke volume (D) in young (ages 25-44 years) (triangles), middle-aged (ages 45-64 years) (open circles), and elderly (ages 65-80 years) (closed circles) healthy men, according to increasing cardiac output with exercise. All groups had similar increase in cardiac output up to a workload of 150 watts. Note that the elderly increase cardiac output by increasing end-diastolic volume and stroke volume with exercise. (From Gerstenblith G, Renlund DG, Lakatta EG: Cardiovascular response to exercise in younger and older men. Fed Proc 46:1834-1839, 1987.)

Cardiac output remains normal at rest, but with a slower heart rate there is an increased reliance on the Frank-Starling mechanism to increase stroke volume and keep the cardiac output normal.[6] With exercise, a decrease in the ability to achieve maximum heart rate and oxygen consumption is seen in older as compared with younger patients. However, ejection fraction (EF) is kept normal by the increased stroke volume sustained

by the larger LV diastolic volume seen with exercise[6] (Fig. 57-2) . Many of these alterations can be explained at cellular and subcellular levels. Cardiac fibrosis, reduction in the number of cardiac myocytes, increase in cell size and capacitance by 20 to 80 percent, and decreased responsiveness to beta-adrenergic receptor stimulation are typical changes found in older animal hearts. Interestingly, some of the same structural alterations parallel those that occur during development of myocardial hypertrophy. Aging hearts recapitulate the fetal phenotype in many aspects. Aging increases the magnitude of the L-type calcium current (ICa-L) in parallel with enlargement of cardiac myocytes, which may be important to help preserve contractile function (see Chaps. 14 and 15) . The increase in ICa-L is balanced by the enlarged cell size in aged myocytes so that, despite the increase in the numbers of ICa-L channels, the overall density becomes normalized by the increase in cell size and capacitance. However, ICa-L inactivation is slowed so that larger calcium influx can occur with each heartbeat.[7] Altered calcium homeostasis predisposes to calcium overload. Both the amplitude and the density of the transient outward current (Ito) are decreased with aging.[8] These changes in Ito, together with the delay in ICa-L inactivation, may largely account for prolongation in action potential duration as hearts age. Drug Metabolism

The elderly consume a large percentage of all drugs prescribed. Three fourths of those 75 years of age and older receive drugs of some kind. Elderly outpatients in the community take 2 or 3 medications per day, and institutionalized geriatric patients take 3 to 8 or as many as 15 per day.[9] The pharmacokinetics of drugs have been evaluated mostly in the 65- to 75-year age group, and this information is extrapolated to old and very old patients of ages 80 to 85, because few studies in this age group have been done. Aging affects both the pharmacodynamics and pharmacokinetics of drugs (see Chap. 23) . PHARMACOKINETICS

ABSORPTION.

Although drugs can be given intravenously, subcutaneously, or intramuscularly, most cardiovascular drugs are given orally and are absorbed by passive diffusion through the intestinal mucosa rather than by active transport. Aging decreases gastric acidity, slows intestinal motility, and decreases by 30 percent the mucosal area for absorption in, and decreases the blood flow to, the small intestine; yet none of these seems to affect cardiovascular drug absorption significantly. DISTRIBUTION.

With aging, there is a decrease in lean body mass, and therefore a decrease in the volume of total body water. Diuretics, by decreasing the extracellular fluid, further decrease the volume of distribution and reduce the loading dose of the drug needed to

achieve therapeutic levels. With illness comes a decrease in serum albumin level, counterbalanced partly by an increase in alpha-acid glycoprotein.[10] Although these changes may not be of major importance to a drug's effect, diseases that result in the loss of all plasma proteins such as renal failure can have a major effect. Furthermore, highly protein-bound drugs that compete for binding sites on the albumin can displace other drugs, increasing the free-drug plasma concentration and increasing the effect of the drug. This explains why warfarin, which is 98 percent protein bound, has so many drug-drug interactions. ELIMINATION.

The major sites of drug elimination are through the kidney and metabolism by liver enzymes. Hepatic metabolism biotransforms the drug to a biologically inactive or a hydrophilic polar compound, cleared by the kidney. There are two phases of liver metabolism: Phase I reactions are discrete oxidative pathways of cytochrome P450 (CYP) occurring in the endoplasmic reticulum, whereas phase II reactions, those of conjugation, including glucuronidation, sulfation, and acetylation, occur in the cytosome. Aging results in a

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decrease in liver mass, and often also in the activity of the most important CYP enzymes involved in drug metabolism. Phase II conjugative reactions do not decrease with age.[11] Obviously, liver disease can affect the capacity of the liver to metabolize drugs. Biotransformation can be influenced by drugs that either inhibit or cause induction of the CYP syndrome. Common drugs such as cimetidine, macrolide antibiotics, and quinidine inhibit the system, and drugs such as phenytoin and glucocorticoids induce the enzymes. For drugs metabolized by this CYP system, inhibition causes an increase in the plasma concentration and half-life, whereas induction causes a decrease. Aging results in a decrease in the number of renal glomeruli and tubules, as well as in renal blood flow and glomerular filtration rate (GFR).[12] With a decrease in GFR, the dose of renally excreted drugs must be reduced parallel to this decline in GFR. Digoxin is an excellent example of a renally excreted drug. Another important renal effect of aging involve angiotensin-converting enzyme (ACE) inhibitors and non-steroidal anti-inflammatory agents (NSAIDs). ACE inhibitors reduce conversion to angiotensin II and increase levels of bradykinin; aldosterone excretion is also decreased. This serves to decrease the constriction of the glomerular efferent arterioles and can result in decreasing renal function and even renal failure in the presence of renal artery stenosis. The decrease in aldosterone secretion with ACE inhibitors can increase serum potassium levels and result in hyperkalemia. These

effects are exaggerated in the elderly patient. NSAIDs inhibit the synthesis of prostaglandins, which are responsible in part for regulating renal blood flow. In elderly patients with a low GFR, CHF, or liver disease, NSAIDs can further reduce renal function, causing hyperkalemia or frank renal failure from tubular necrosis or interstitial nephritis.[13] In the elderly patient using ACE inhibitors or NSAIDs, reduced doses of these drugs, with careful monitoring of renal function and serum electrolytes, are required. PHARMACODYNAMICS.

Aging is associated with a decrease in cardiovascular responsiveness to beta1 -adrenergic stimulation, probably related to a decrease in adrenergic receptors[5] and in baroreceptor sensitivity. In the elderly patient, this accounts for less bradycardia with beta blockers than is seen in younger patients. The decrease in baroreceptor and beta1 -adrenergic responsiveness can result in a lack of compensatory tachycardia and exaggerated hypotension with the use of vasodilators and nitrates in elderly patients. Sensitivity to various calcium channel blockers appears to be increased in elderly patients, with a greater decrease in heart rate and blood pressure (BP) to the same serum concentration of verapamil or diltiazem than seen in the younger patient.[14] Drug Interactions and Adverse Drug Effects

Age brings an increased incidence of adverse drug effects, occurring in one fourth of older patients and accounting for 3 to l0 percent of all hospital admissions for elderly patients.[15] Elderly patients often take multiple drugs; the number of medications taken is the most important risk factor for adverse drug reactions.[16] This polypharmacy results in noncompliance, because the elderly often confuse the drug schedule, especially for drugs given more than once a day. Another reason for noncompliance is the high cost of drugs, which may result in patients electing not to have prescriptions filled. Polypharmacy also results in adverse drug reactions from drug-drug interactions, owing to the interference of the pharmacokinetics of one drug on another. Another common reason for drug-drug interaction is competition between two highly protein-bound drugs for receptor sites, with displacement of one drug and a resultant increase in free drug in the plasma and drug effectiveness. Other factors predicting poor compliance include a complicated drug regimen, multiple drugs, noncomprehension of instructions, mental impairment, visual or hearing disabilities, and no helper or relative at home. Legible instructions in the patient's language on easily opened bottles, certain memory aids, and the aid of visiting nurses can all improve compliance. Drugs with similar effect can produce an additive pharmacological action (e.g., excessive bradycardia from a combination of verapamil and digoxin). Cardiovascular drugs that cause the most drug interactions are digoxin, warfarin, lidocaine, quinidine, and amiodarone.[17]

Basic principles of therapeutics in the elderly are as follows: 1. Know all the drugs the patient is taking. 2. Regularly review the drug regimen; insist that the patient bring all medicines to the next visit. 3. Take a careful drug history because of multiple drugs from multiple sources, including self-medication with over-the-counter drugs. 4. Know the pharmacokinetics and side effects of the drugs. 5. Start the drugs in the elderly at a low dose and increase in small increments and larger intervals than in younger patients until the desired effect is obtained. 6. Use the simplest drug regimen possible. 7. Adjust the dose by the patient's response. 8. Educate patient, family, and friends about the medicines, what they are for, and how to take them; also tell them about the major side effects. Be alert to drug-induced illness; in the elderly, this can be subtle or mistaken for symptoms due to the patient's disease. Drug-related effects can present as somnolence, confusion and even delirium, nausea, frequent falls, or urinary incontinence. 9. Expect noncompliance, and tell the patient what to do if the dose is missed or in cases of confusion about whether or not the drug was taken. EPIDEMIOLOGY Average life expectancy has risen from 47 years in the United States in 1890 to 72 years for men and 79 years for women by the end of the 20th century. At present, a person reaching the age of 65 has an average life expectancy of 18 more years; at age 85, this is 7 years.[18] The average maximum length of life, however, is 85 to 90 years and has not changed much.[19] The population 65 years and older has grown from 20 million in 1970 to 35 million in 2000, and it is estimated that there will be 69 million by the year 2030 (20 percent of the U.S. population, up from 13 percent in 1997). By 2030, the fastest-growing segment of that elderly population will be those aged 85 and older,[18] growing from 2 million in 1970 to 4.5 million in 2000, and 8 million (estimated) by 2030.[18] The number of persons in the world who are 60 years old or older is estimated to be nearly 600 million in 1999 and is projected to be about 2 billion by 2050. At that time, the elderly population will exceed that of children from birth to 14 years of age for the first time in human history. At present, one in every 10 people is 60 years or older. By 2050, this is projected to become 1 in every 5. The percentage is growing fastest in the developed regions of the world. The older population itself is aging: currently, the oldest old (80 years or older) comprise 11 percent of the population 60 and older; by 2050, they are projected to comprise 19 percent. The number of those 100 years and older is projected to increase from 145,000 in 1999 to 2.2 million by 2050.[19] The aging pyramid, instead of becoming smaller in number as the age groups increase, will become more of a trapezoid, especially as the "baby boomers" become the elderly population. In this older population cardiovascular disease plays a significant role and is the most common cause of morbidity and mortality.[20] Heart failure (HF) is the most common

diagnostic-related group in the Medicare population 65 years old and older. In the Framingham Heart Study, 44 percent of men and 28 percent of women aged 75 to 84 had cardiovascular disease; in the 85 to 94 age group, the prevalence was 48 percent in men and 43 percent in women.[21] CAD and HTN (especially isolated systolic HTN) increase as the population ages. In the United States, in people older than 65, HTN is present in about half the patients (Fig. 57-3) .[22] The overall cost of treating cardiac disease in people older than the age of 65 years was estimated at $58 billion in 1995.[18] Hospital and nursing home care is the largest proportion of this cost. A recent study in 80- to 98-year olds found that most would rather extend their lives in

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Figure 57-3 Prevalence of isolated systolic hypertension by the midpoint of the age classes reported in various studies. As shown by the unweighted regression line, the prevalence of systolic hypertension increases curvilinearly with age. The 95 percent confidence interval for the prediction of individual points is presented for the age range of 50 to 90 years. (From Staessen J, Amery A, Fagard R: Isolated systolic hypertension in the elderly. J Hypertens 8:393-405, 1990.)

their present state of compromised health than live shorter lives in excellent health. [23] VALVULAR HEART DISEASE (see also Chap. 46) Although any valve lesion can be seen in the elderly population, the most common valve diseases are calcific aortic stenosis (AS) and mitral regurgitation (MR) due to myxomatous mitral valve. MR due to ischemia, or previous myocardial infarction, resulting in a failure of the papillary muscle/LV complex to allow proper coaptation of the mitral leaflets, is also a common cause, along with LV failure for any reason. Mild to moderate MR usually occurs in patients with calcification of the mitral annulus. Ruptured chordae, endocarditis, trauma, and aortic dissection are other causes of aortic regurgitation (AR) and MR. Aortic valve sclerosis, as a result of stiffening and calcification of the aortic annulus and base of the semilunar cusps, causes an early-peaking systolic ejection murmur that is short and grade III-VI or less in loudness. It does not represent significant obstruction. No physical findings of obstruction are present, nor is LV hypertrophy, but it is associated with other manifestations of atherosclerotic disease, especially CAD,[24] and indeed it may result from the atherosclerotic process. It can be found in about 30 percent of the elderly, whereas significant AS is seen in 2 to 3 percent.[24] The cause of AS in the older age group is calcific or degenerative, almost always on a normally tricuspid semilunar valve. Calcification is at the base and body of the semilunar cusps, and the commissures are not fused. Rheumatic heart disease is much less common, as is congenital AS. Patients with a bicuspid aortic valve are seen in the elderly age group, but most who develop calcification and severe obstruction do so between the ages of 40

and 60.[25] In the elderly AR can be due to rheumatic heart disease, but more often it is due to myxomatous changes and prolapse of the aortic cusp, aneurysmal aortic root dilation, infective endocarditis (possibly on a bicuspid aortic valve), or dissecting aorta. Primary valve disease in the elderly rarely causes tricuspid and pulmonic valve regurgitation, which is usually secondary to pulmonary HTN and dilatation of the right ventricle. Pulmonary HTN can be due to LV diseases such as ischemia or cardiomyopathy, mitral stenosis, or intrinsic pulmonary disease. Primary tricuspid regurgitation due to infective endocarditis almost always occurs in intravenous drug users, who are rare in this age group. Primary tricuspid valve regurgitation (TR) can rarely be seen in elderly patients after trauma. Infrequently, an elderly patient is found with Ebstein disease and TR, or pulmonic valve regurgitation after tetralogy of Fallot repair with a patchenlarged pulmonary outflow tract and annulus. DIAGNOSIS.

The diagnosis of significant valve disease can be difficult in the elderly population; echocardiographic-Doppler imaging can be of great help (see Chap. 7) . The loudness of an aortic stenotic murmur depends on the generated LV systolic pressure as well as on the stroke volume and the loudness of MR murmur on the regurgitant volume. If the cardiac output is low, the murmur of AS or MR may be soft or even absent. The loudness of the murmur also depends on the nearness of the site of origin of

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the murmur to the chest wall. Accompanying clues to severity can also be absent or confusing in the elderly. For instance, an S4 gallop or the presence of LV hypertrophy in a young person with AS is a sign strongly suggesting hemodynamic severity of the AS. In the older patient, an S4 is often present without AS, as is LV hypertrophy, especially in those patients who have had a long history of systolic HTN. In the elderly, the carotid upstroke can feel normal in severe AS because of the stiff aorta. The severity of AR can be difficult to judge by physical examination in the elderly because of the frequent occurrence of a wide pulse pressure due to a stiff atherosclerotic aorta rather than to severe AR. Acute AR masks many of the peripheral signs of severe AR, because the LV filling pressure is high and the forward effective stroke volume is low, thus decreasing the rise of the systolic aortic pressure, increasing the diastolic pressure, and narrowing the pulse pressure. If the AR is very severe, the diastolic regurgitant gradient between the aorta and LV is small, and with tachycardia there may be little or no diastolic murmur. The collapsing quality of the carotid pulse and Duroziez sign, that is, the systolic and diastolic bruit heard on compression of the femoral artery by the bell of the stethoscope, remain as signs of severe AR. Treatment

A problem with selecting therapy for the elderly is that, until recently, they have been excluded from most controlled trials, and information about treatment comes mostly from registries and observational studies. Medical therapy for elderly patients with valve disease is generally similar to that for younger patients.[26] In elderly patients, even with mild mitral valve disease, atrial fibrillation (AF) is common, and represents a markedly increased threat of systemic embolization and stroke. Anticoagulation, unless absolutely contraindicated, is essential. VALVE SURGERY.

Deciding to send an elderly patient with significant valvular stenosis or regurgitation to surgery can be difficult and must be individualized because of the diversity of problems found in this age group. Generally, the patient younger than 75 has a similar morbidity and mortality to a younger patient with a similar problem. As the patient enters the late 60s and early 70s, a higher prevalence of comorbidity exists, with increased coronary, cerebrovascular, renal, hepatic, and pulmonary disease that add to surgical morbidity and mortality.[27] After age 75 to 80, surgical morbidity and mortality are increased, even beyond the impact of comorbidities, because age per se becomes an increasing risk factor for valvular surgery. In patients older than 75, the risk of neurological problems and stroke with cardiopulmonary bypass surgery increases.[28] The elderly have more problems than younger patients with mechanical valve replacement, mostly because of the increased complications from anticoagulation.[29] The goals of valve surgery in the elderly are somewhat different from those in younger patients. In the older patient the major goal becomes relief of symptoms, with improvement in activity and quality of life rather than prolongation of life. Aortic Stenosis.

After the occurrence of symptoms of HF, exertional syncope, angina, or myocardial infarction without obstructive CAD, mortality in patients with severe AS increases rapidly, so that the mean survival is 3 years for symptomatic patients, shorter with HF symptoms, and somewhat longer with angina. In all probability, survival is even less in the elderly. Also, the incidence of sudden death increases in the symptomatic patient with AS, accounting for one fifth to one fourth of all deaths (see Chap. 46) . Surgery should be recommended once symptoms begin, depending on the overall status of the patient and the number and severity of comorbidities. Only in the presence of a decreasing EF, or possibly with increasing runs of nonsustained ventricular tachycardia, should a patient not complaining of symptoms be offered surgery. [26] Patients with AR who undergo aortic valve replacement do not fare as well as patients with AS, especially if they are in New York Heart Association (NYHA) Class III or IV or have a decreased LV EF.[30] Long-term morbidity and mortality are increased in patients with moderate to severe AR if they have symptoms, an EF less than 50 to 55 percent, comorbidities, or an increased LV end-systolic diameter by echocardiography (>25

mm/m2 ).[26] [31] Surgery is, therefore, indicated in these patients. Aortic Valve Replacement.

In younger patients who have pliable valves and AS due to commissural fusion, successful commissurotomy, either surgically or by balloon valvotomy, is possible, with good results lasting 15 to 30 years.[32] In elderly patients with AS of whatever cause, the aortic valve is always severely calcified, and valvotomy, either by surgery or balloon, has a limited, short-lived success. With severe AR, valve replacement is the rule, except for ascending aortic aneurysm or AR with aortic dissection, in which ascending aortic grafting with valve resuspension can be done with long-term success.[33] In most series of patients older than 70 years, perioperative mortality varies from 2.4 to 12.4 percent, depending on comorbid conditions, increasing patient age, the presence of other cardiac lesions or concomitant operations such as mitral valve repair or replacement, or coronary artery bypass graft (CABG).[34] As experience has increased, perioperative mortality has fallen to 6 to 10 percent for aortic replacement and CABG[35] and 4 to 7 percent with isolated aortic replacement. Factors that predict perioperative mortality in patients older than 75 years are NYHA functional therapeutic Class IV, decreased LV EF, chronic HF, the presence of comorbid diseases such as pulmonary or renal disease or diabetes, and concomitant procedures such as mitral valve surgery, coronary artery surgery, or surgery performed as an urgent procedure. Other independent predictors of hospital mortality include cardiomegaly, serum creatinine level greater than 150 mmol, and operation as an emergency procedure. Predictors of late mortality are comorbid diseases such as severe renal, pulmonary, or coronary disease and poor LV function.[30] [36] Patients with coexisting minimal-to-moderate AS or AR who have cardiac surgery for other than aortic valve disease (e.g., coronary surgery or mitral valve replacement) generally experience very slow progression of the aortic valve disease. Consequently, there is no indication to replace the aortic valve at that time. [37] However, the higher the aortic valve gradient and the heavier the aortic valve calcification, the more likely the AS will progress, and therefore the more reasonable it becomes to replace the aortic valve at the time of the primary surgery. As many as 40 percent of patients with AS in the elderly age group have at least one significantly obstructed coronary artery.[38] The presence of atheromas in the descending aorta by transesophageal echocardiography is a good predictor of CAD.[39] Although stress echocardiography has been recommended to detect CAD in patients with AS,[40] stress testing is generally unnecessary, because in this age group coronary arteriography is justified preoperatively to assess the status of the coronary arteries [26] (see Chaps. 6 and 7) . Aortic valve debridement can result in relief of severe calcific AS; however, it has been abandoned by most surgeons because there is a rapid restenosis and, with some techniques, a high incidence of increased AR (see Chap. 46) . Occasionally it can be beneficial. [41] A biological tissue valve, rather than a mechanical valve, is most often placed in this elderly age group because of their shorter life expectancy, because biological valves are

less subject to tissue failure in elderly patients,[27] [42] and because of the dangers of anticoagulants in the elderly.[29] For most tissue valves, even in younger patients, there is no significant failure for 5 to 10 years, long enough to last the natural life of the elderly patient.[42] With aortic valve replacement, operative mortality is slightly increased with age and more markedly increased with comorbidity and severity of disease; however, the results of surgery are excellent, with a definite increase in quality of life. Mitral Valve Repair/Replacement.

With MR, because of multiple causes and especially CAD causing severe MR, the results of valve replacement are not as good as with AS; 5-year survival after both coronary surgery and mitral valve replacement is only about 50 percent.[43] With mitral valve replacement, the major risk factor for mortality is the presence of CAD. [44] Patients do well after repair of MR, with

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perioperative mortality of 4 percent and 25 months late mortality of 6 percent.[45] Thus, the elderly undergoing mitral valve surgery do not do as well as those having aortic valve replacement or younger patients and fare better with mitral valve repair than with replacement. Balloon Valvotomy.

For calcific AS, balloon valvotomy increases aortic valve area, but rapid restenosis follows. Because balloon valvotomy is not an alternative to valve replacement, its use is restricted to very old, extremely symptomatic patients who are poor candidates for surgery, where the procedure might improve cardiac output and peripheral organ perfusion, and relieve afterload on the LV enough to allow surgical valve replacement at a later time. It can also be useful in those patients who are not candidates for surgery because of comorbid problems and who are repeatedly hospitalized for HF. Balloon valvotomy can keep these patients out of the hospital for a variable period of time, and improve quality of life.[46] Balloon valvotomy for MS has become the procedure of choice when the valve is not heavily calcified and MR is absent or minimal. The results of balloon valvotomy are equivalent to those of open commissurotomy, and both are better than closed commissurotomy.[47] Mitral valve calcification, frequent in the elderly, reduces the success rate and increases mortality and complications.[48] CORONARY ARTERY DISEASE (see also Chaps. 35 , 36 , and 37) PREVALENCE AND INCIDENCE.

As the population ages, the prevalence and annual incidence of the development of overt CAD increases substantially with age, as does the total number of people with clinical CAD (Fig. 57-4) . The severity and diffuse distribution of the coronary obstruction

also increases, presumably as a result of prolonged exposure to atherosclerotic risk factors. There is a striking gender difference, with men developing CAD at a younger age than women (37 percent in men aged 65 to 74 vs. 22 percent in women of the same age range). The prevalence of CAD in the Framingham cohort aged 75 to 84 years was 44 percent in men and 28 percent in women. In the 85- to 94-year age range, the prevalence of CAD was 48 percent in men and 43 percent in women.[49] The lifetime risk of developing CAD at age 40 is 49 percent for men and 32 percent for women, decreasing to 35 percent for men and 24 percent for women at age 70, or 1 in 3 for men and 1 in 4 for women.[50] MORTALITY.

Almost 85 percent of people who die of CAD are age 65 or older. According to data from the Health Care Financing Administration, in 1995, $98 billion ($3,769 to $11,110 per discharge) was paid by Medicare to Medicare beneficiaries for CAD. Of 2.3 million Americans discharged from hospitals with a first-listed diagnosis of CAD in 1996, 57 percent were 65 years of age or older.[51] CAD mortality is about twice as high in men as in women and higher in blacks than in whites. After age 70, mortality in white men is higher than in black men. In women, mortality in blacks exceeds that in whites until age 85.[52] Although mortality from CAD has been declining since 1970, the decline is greater in white men and women than in blacks (average annual percentage change 3 to 4 percent vs. 2 to 3 percent), more robust than in the age groups up to 85 but still 1 to 2 percent in even the oldest age groups.[52] After adjustment for major risk factors, with each decade of advancing age, a twofold to threefold increase in coronary vascular mortality persists. RISK FACTORS (See Chaps. 31 , 32 , and 39)

The impact of many risk factors for CAD, such as HTN, diabetes, and LV hypertrophy, increases with age. Although the benefits of risk-factor reduction in the elderly for some risk factors is incomplete, excellent evidence exists that control of BP, for example, reduces cardiovascular events even in the older age group. HYPERTENSION (see Chaps. 28 & 29).

Because HTN is so common in the older population, and the number and type of effective drugs so numerous, this is one of the most controllable of the risk factors. Fifty-seven percent of men and 61 percent of women aged 65 to 74 and 64 percent of men and 77 percent of women aged 75 and older have HTN, as defined by at least one ambulatory BP reading of 140 mm Hg systolic or 90 mm Hg diastolic or higher.[18] Both systolic and diastolic elevation of BP is associated with an increased risk of CAD in men and women. People older than 65 years with systolic pressure greater than 180 mm Hg have a threefold to fourfold increase in risk of CAD compared with people with a systolic pressure of less than 120 mm Hg. A diastolic pressure greater than 105 mm Hg increased the risk two to three times compared with a diastolic pressure of less than 75 mm Hg.[53]

Isolated systolic HTN (systolic pressure greater than 140 mm Hg with a diastolic pressure less than 90 mm Hg)[54] is very frequent in the elderly and is partially related to the loss of elasticity and compliance of the aorta and arterial branches. The risk of stroke, CHF, renal disease, renal insufficiency, and probably coronary artery events decreases with a decrease in the degree of systolic HTN, as shown in the Systolic Hypertension in the Elderly Program (SHEP trial) (see Chap. 29) . Treatment of HTN in the elderly population reduces the risk of cardiovascular events, especially stroke and CHF, and probably decreases the incidence of myocardial infarction.[55]

Figure 57-4 Prevalence of coronary heart disease by age and sex. (NHAHES III, US 1988-1991.) (From Kannel WB, Wilson WF, Larson MG, et al: Coronary risk factors and coronary prevention in octogenarians. In Wenger NK [ed]: Cardiovascular Disease in the Octogenarian and Beyond. 1st ed. London, Martin Dunitz, 1999, p. 143.)

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SMOKING (see Chaps. 31 , 32 , and 39) .

Cigarette smoking declines in prevalence with advancing age to about 15 percent of men and 11.5 percent of women age 65 and older.[56] Although smoking is a powerful risk factor in the younger patient, it is unclear if smoking exerts the same risk in the older population[57] and whether smoking cessation in elderly patients decreases the incidence of coronary events. In the Coronary Artery Surgery Study (CASS) registry, patients older than age 70, all of whom had CAD, who continued to smoke, had three times the risk of death or myocardial infarction during a 60-year follow-up period compared with those who stopped smoking. In the British Physicians' Study[58] and the U.S. Nurses' Health Study,[59] smoking was an independent risk factor for coronary events in both younger and older age groups. However, the Framingham Heart Study showed that in individuals older than age 65 the incidence of lung cancer is accelerated, but there was no correlation between the incidence of smoking and CAD.[60] The explanation for the latter may be that, although there is increased risk of CAD from smoking, there is increased mortality from other smoking-related diseases in this age group. It is also possible that those susceptible to CAD from smoking died at a younger age, and among the persons who survive to age 65, fewer patients are susceptible to CAD from smoking. HYPERLIPIDEMIA (see Chap. 31) .

Serum cholesterol concentration increases progressively until age 50 in men and age 65 in women and then begins to decline. High-density lipoprotein value is higher in both men and women and stays constant with aging.[61] Among people 65 to 74 years of age, 22 percent of men and 41 percent of women have a total serum cholesterol value of greater than 240 mg/dl; for those older than 75 years, 20 percent of men and 38 percent of women have cholesterol levels greater than 240 mg/dl.[18] Although the association

between the risk factor of an elevated serum cholesterol level and the development of CAD is less striking in the elderly, the ratio of total to high-density lipoprotein cholesterol remains a strong predictor of CAD in the elderly.[62] Elevated triglycerides have been independently associated with an increased risk of CAD in elderly women but not men.[63] Treatment with HMG-CoA reductase drugs can reduce the incidence of acute cardiac events in patients up to 75 years of age; older patients have not been studied.[64] DIABETES MELLITUS (see Chap. 63) .

In 1996, there were 503,000 Americans discharged from the hospital with a first-listed diagnosis of diabetes mellitus. Of these, 39 percent were older than 65 years of age. The prevalence of physician-diagnosed diabetes in patients aged 60 and older is 12 to 13 percent for men and women. The vast majority of patients older than age 70 have non-insulin-dependent (type II) diabetes. Its presence doubles the risk of CAD and, when combined with hyperlipidemia, increases the risk 15-fold.[65] PHYSICAL INACTIVITY.

Approximately one third of men and women aged 65 to 74, and 38 percent of men and 51 percent of women aged older than 75 years, report no leisure-time physical activity. Frequent exercise raises high-density lipoprotein cholesterol, controls obesity, and lowers systolic and diastolic BP even in patients 60 to 80 years old and reduces insulin resistance.[66] Even moderate amounts of exercise have been shown to protect against CAD events in middle-aged and older men in the Framingham Heart Study.[67] Other risk factors for CAD, such as lipoprotein (a) and other apolipoproteins, are still being investigated. A high homocystine level is not uncommon in elderly men and is strongly associated with increased prevalence of coronary heart disease and cerebrovascular disease.[68] After an acute myocardial infarction (AMI), patients with depression who are socially isolated have an increased recurrence rate and mortality[69] (see Chaps. 39 and 70) . This social isolation is more common in the elderly. Clinical Presentation

Elderly patients have more multivessel disease and lower EF than do younger patients.[70] Although angina pectoris is a common first presentation of CAD in the elderly, angina may not occur until the CAD is well advanced because of often markedly decreased activity. For this reason, acute ischemic syndromes are common initial presentations of CAD.[70] Also, many symptoms of discomfort that would alert a younger person are explained away in the elderly patient as a consequence of "getting old." When angina occurs, the precipitating factors and the description, with radiation and its relief by rest, are similar to that in younger patients. However, with advancing age, a frequent presenting symptom is increasing fatigability and shortness of breath during activity because of the ischemic effects on systolic and diastolic myocardial function. In patients with documented CAD, anginal pain without dyspnea is reported in 25 to 43 percent of persons older than age 65, dyspnea without chest discomfort in 8 to 25

percent, and both dyspnea and angina in almost 50 percent. [71] Others have reported the initial manifestation of CAD in the elderly to be angina in 80 percent.[72] As many as 30 percent have silent ischemia. With increasing age, the gender composition of patients with AMI changes from 80 percent men younger than 55 to about 50 percent men aged 75 to 84 and only one third men aged older than 83.[73] Sudden pulmonary edema is a common presentation of AMI in the elderly, but chest pain is still the most common, as it is in younger patients. Neurological symptoms as a presentation of AMI, such as syncope, stroke, or confusion, are more likely seen in the elderly, as is painless AMI. Non-Q-wave myocardial infarctions are more common in the elderly. Physical examination, especially during the ischemic episode, can be very helpful. Unlike younger patients, an S4 gallop rhythm is very common in elderly patients with and without CAD; however, the appearance or increase in the loudness of an S4 or S3 gallop or MR murmur during the chest discomfort or dyspnea and its disappearance with relief of the chest discomfort or dyspnea are strong evidence in favor of a transient decrease in diastolic ventricular function, the most common cause of which is CAD. For the same reason, an electrocardiogram (ECG) taken during the time of the discomfort that shows definite ST segment elevation or depression, or marked T wave inversion, which reverses after the discomfort abates, is excellent evidence of severe CAD. Because LV hypertrophy is common in elderly patients, ST segment/T wave changes can be present chronically on a resting ECG and are of limited help in diagnosing myocardial ischemia unless the ST segment/T wave changes are transient and associated with chest discomfort. SILENT ISCHEMIA.

The presence of significant CAD without symptoms increases with age. Because only about 20 percent of people older than 80 have clinically evident CAD[74] and over 50 percent have significant CAD at autopsy,[75] a large number of elderly people must have significant CAD without symptoms. About one third of asymptomatic hypertensive elderly patients have a myocardial infarction discovered incidentally on ECG. An equal number have silent ischemia. The reason for increased silent ischemia in the elderly patient is not known, but it may be related to mental status changes impairing perception or recall of ischemic pain, to the development of collaterals that reduce the severity of the myocardial ischemia, to autonomic dysfunction, or to increased sensitivity to endogenous endomorphins.[76] Although the presence of silent ischemia may not predict a worse prognosis for the patient with CAD than its absence, most people with silent ischemia have a positive exercise test result and so probably have more extensive CAD. Diagnosis

The diagnosis of CAD in the elderly can be suspected by finding a history of typical angina or atypical symptoms related to exertion, and by a careful physical examination, as indicated earlier. Stress testing is done to establish the diagnosis and to determine risk stratification and prognosis (see Chap. 6) . The high prevalence and increased severity of CAD in the elderly, by Bayesian principles, increases the sensitivity of stress

testing but makes it harder to exclude significant disease because of more false-negative test results.[77] The criteria for a positive exercise test result in the elderly do not differ significantly from those in the younger patient.[77] As in younger patients, the test is less likely to be positive with single-vessel disease but is 80 to 85 percent sensitive in identifying patients with three-vessel or left main CAD. In patients older than 60 to 65 years, the sensitivity for diagnosing the presence of significant CAD varies from 62 to 84 percent, and the specificity from 56 to 93 percent, depending on the population studied. The ability to walk through the second stage of Bruce protocol (>6 minutes) predicts low risk.[77]

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The increased number of false-positive test results seen in the elderly is probably attributable to an abnormal resting ECG, the presence of LV hypertrophy from HTN or valve disease, or intraventricular conduction defects. Prognosis depends on the amount of ischemic and nonfunctioning myocardium, reflecting the effect of severity and extent of CAD on LV function. For risk stratification, attention should be paid to the chronotropic and inotropic responses to exercise, exercise-induced arrhythmias, and the duration of exercise. Arrhythmias are common in the elderly, especially at high workloads, but are not necessarily an adverse feature unless they occur with other signs of ischemia.[77] Inability to increase the heart rate to 85 percent of age-predicted maximum, or a hypotensive response to exercise, are poor prognostic factors, similar to those seen in younger patients. PROGNOSTIC VALUE OF STRESS TESTING.

Stress testing offers challenges to the elderly. Many have orthopedic or neurological problems that prevent active walking on a treadmill. Many are physically deconditioned and may have an abnormal resting ECG, making criteria of ST segment shifts for positivity less reliable. In a study of patients older than 65 years observed for 2 years, those with ST segment depression during stress testing had a 17 percent cardiac death rate, whereas the incidence was only 2 percent in those without ST segment depression. [78] In patients older than 70 years who had exercise stress testing 3 weeks after an AMI and were observed for a mean of 4.5 years, of those who failed to increase double product from rest to exercise by more than 1500, and also developed ventricular arrhythmias with exercise, only 25 percent were still alive at the end of the follow-up time, whereas in the absence of either response, 77 percent were still alive.[78A] Patients after AMI who are unable to increase systolic BP with exercise greater than 30 mm Hg have a 1-year mortality of 15 percent compared with 2 percent for those who did increase their BP.[78B] Using the Duke treadmill score combining ST segment depression, chest pain, and exercise duration is useful to predict significant (>75 percent) stenosis and severe three-vessel or left main disease. [77] When the patient can exercise, but the resting ECG is abnormal or has a feature that

makes it impossible to diagnose ischemia (left bundle branch block, pacemaker, or marked ST segment changes), then myocardial perfusion study at rest and after exercise, using tracers such as thallium-201, technetium-99m sestamibi or technetium-99m tetrofosmin single-photon emission computed tomographic imaging (see Chap. 9) , or stress echocardiography (see Chap. 7) can be used to detect areas of scarring or ischemia. When exercise cannot be done, pharmacological tests using dipyridamole or adenosine to vasodilate coronary arterioles and increase coronary blood flow maximally to areas without stenotic arteries, or dobutamine to increase myocardial oxygen demand and create ischemia, can be used. Dobutamine stress testing is safe in the elderly. These techniques are more sensitive than exercise testing in identifying single- and two-vessel disease, and, like exercise testing, are also useful for risk stratification. With the use of thallium-201 perfusion tests on 120 patients older than 70 years with known or suspected CAD, three variables were associated with a cardiac event: (1) a maximum ST segment depression of 2 mm (27 percent with vs. 6 percent without), (2) peak exercise beyond stage 1 of the Bruce protocol (18 percent event rate in those who could not go beyond this stage vs. 6 percent in those who could), and (3) the presence of either a fixed or a reversible thallium defect (18 percent event rate with vs. 2 percent without). The combination of inability to attain peak exercise beyond stage 1 and the presence of any thallium defect were the most powerful predictors, with a relative risk of 5.3 at 1 year.[79] Acute Myocardial Infarction (see also Chap. 35)

In the elderly, AMI results in an increase in mortality compared with younger patients. Eighty percent of all deaths due to AMI occur in those 65 years of age and older.[74] In a population-based study over a 20-year period between 1975 and 1995, patients aged 55 to 64 were 2.2 times more likely to die of AMI during hospitalization than were patients younger than 55, whereas patients aged 65 to 74, 75 to 84, and older than 85 years were at 4.2, 7.8, and 10.2 times greater risk of dying.[73] In the Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries (GUSTO)-I study of 41,021 patients, in-hospital mortality from AMI younger than age 65 was 3 percent as opposed to 9.5 percent at age 65 to 74, 19.6 percent at age 75 to 85, and 30.3 percent in those older than 85 (Fig. 57-5) . [80] Age alone can result in changes that increase mortality from AMI due to increasing diastolic dysfunction, altered baroreceptor and beta-adrenergic receptor responsiveness, and age-related decreases in renal and pulmonary function, all of which make the patient vulnerable to increased complications. Older patients have an increased comorbidity with pulmonary, renal, and hepatic disease. A more adverse baseline status in AMI prevails with higher NYHA functional class, prior history of CHF, prior myocardial infarction, angina, HTN or diabetes mellitus, low EF, and cardiovascular disease; and more of the elderly are women.[81] Complications of myocardial infarction are also more frequent in the elderly, including

Figure 57-5 Effects of age on mortality and stroke, GUSTO-1 trial. Of 41,021 patients, 24,708 were younger than 65 years, 11,201 were 65 to 74 years, 4625 were 75 to 85 years, and 412 were older than 85 years. All patients had ST segment elevation and were treated with thrombolytic agents. Postdischarge 1-year mortality remained high in the oldest groups (6.1 percent and 10.3 percent, respectively) and continued to be low (1.5 percent) in the younger than 65 group. (From White HD,

Barbash GI, Califf RM, et al for the GUSTO-1 Investigators: Age and outcome with contemporary thrombolytic therapy: Results from the GUSTO-1 Trial. Circulation 94:1826-1833, 1996.)

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CHF, atrial arrhythmias, cardiogenic shock, and cardiac rupture.[82] Management Management of AMI

MEDICAL TREATMENT.

Treatment of patients with angina, acute ischemic syndromes, and AMI is similar to that in younger patients (see Chaps. 35 and 36) . For angina and acute ischemic syndromes, aspirin, nitrates, beta-blockers, calcium-channel blockers, ACE inhibitors, and anticoagulants such as heparin have all been found to be as effective in elderly as in younger patients.[83] In the older population, attention should be paid to impaired baroreceptor reflexes, decreased beta-adrenergic responsiveness, and stiff aorta. With ACE inhibitors or nitrates, especially short-acting nitroglycerin with venodilatation, postural hypotension can result in falls and injury. Combinations of digoxin, amiodarone, and calcium channel blockers can also produce profound bradycardia more easily in the elderly. These drugs should be initiated cautiously, beginning with lower doses than in younger patients and carefully watching for toxicity.[84] In a study of 10,018 patients older than 65, after an AMI with no absolute contraindication to aspirin use, aspirin was associated with a 22 percent reduction in 30-day mortality.[85] Beta blockers are the antiischemic drugs of choice in elderly patients with stable angina,[86] and all appear to be equally effective in controlling angina.[87] Many studies demonstrate the effectiveness of beta blockers in reducing mortality after AMI, including in patients older than age 65.[88] Beta blockers are often not given to patients with chronic obstructive pulmonary disease, type I diabetes mellitus, a low LV EF, or a history of HF, even though they have been shown to reduce mortality in these groups also. Despite evidence of effectiveness, aspirin and beta blockers are underprescribed in the elderly, and patients with the highest risk for in-hospital death appear to be least likely to receive beta blockers. ACE inhibitors have also been shown to reduce mortality, and to prevent LV remodeling and the onset of CHF in patients after a large AMI[89] (see Chaps. 35 and 39) . Calcium channel blockers are equally effective, as are beta blockers, in controlling anginal pain.[87] Because of the tendency of rapid-acting calcium channel blockers to cause vasodilation, a drop in BP, and increased sympathetic tone, short-acting calcium channel blockers should be avoided. The use of slow-release, or new-generation long-acting, dihydropyridines are the calcium antagonists of choice.[87] After an AMI, however, calcium channel blockers have not been shown to decrease mortality; and in certain patients there is evidence that they are harmful, especially in those with decreased ventricular function, CHF, or bradyarrhythmias. [84] It is a consensus of the American College of Cardiology/American Heart Association AMI

group that calcium channel blockers are used too often in patients with AMI and that beta blockers are the more appropriate choice.[84] [90] Heparin is recommended in acute ischemic syndromes and has been shown to decrease the development of AMI and/or mortality in patients given aspirin compared with those given aspirin alone.[91] Most studies have not investigated patients older than age 75, where the incidence of intracranial bleeding is higher than in younger patients. No trial has specifically investigated fractionated or low-molecular-weight heparin, with varying molecular weights that bind specifically to antithrombin III in patients 75 years of age and older.[91] Two major trials of the platelet glycoprotein IIb-IIIa inhibitors have been reported, with reduction in combined endpoints of myocardial infarction and death, but the number of patients older than 65 was small and no specific comments can be made.[91] FIBRINOLYTIC THERAPY.

There is evidence that the older population with AMI benefits from fibrinolytic drugs with reduced mortality and preserved LV function. Pooled results from five major thrombolytic trials showed an absolute reduction in mortality of 3.5 percent in patients older than age 65 compared with 2.2 percent in the younger population. [92] There was also an absolute excess of strokes and other bleeding complications of less than 1 percent. Elderly patients take longer to reach the hospital after the onset of chest pain and are less likely to receive thrombolysis.[93] [94] Depending on the study, 10 to 50 percent of the elderly are excluded from thrombolytic therapy solely on the basis of age.[95] Observational studies indicate that older patients are at slightly greater risk of hemorrhagic stroke after fibrinolysis than younger patients. [96] In the elderly, especially those older than age 75, the incidence of serious bleeding, especially intracranial bleeding, must be balanced against any possible benefit derived from the use of fibrinolytics during an AMI. THROMBOLYSIS VERSUS PRIMARY ANGIOPLASTY.

Several trials have shown no advantage to early angioplasty compared with medical management in patients with non-ST segment elevation myocardial infarction, except for those with ongoing ischemia.[91] However, none of these has addressed the elderly specifically. In patients with ST segment elevation AMI, percutaneous transluminal coronary angiography (PTCA) can restore antegrade flow in the infarct-related occluded artery, with Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow in 90 percent of patients.[84] In a post-hoc analysis of high-risk patients (those older than age 75 with anterior myocardial infarction or tachycardia on presentation), mortality was only 2 percent in those with primary angioplasty, and 10 percent in those receiving thrombolysis (p < 0.01).[97] The difference was in part related to an excessive incidence of cerebrovascular hemorrhage with death in the thrombolytic group. The cardiac-related deaths were similar in the two groups. Management of CAD

PERCUTANEOUS CORONARY INTERVENTION (PCI).

Coronary arteriography is more likely to be performed in elderly patients who are symptomatic and have CAD than in younger patients.[98] Elderly patients with high-risk CAD or angina not responding to medical management are being sent for PCI in increasing numbers because it is a less invasive procedure than coronary bypass surgery.[99] Although patients in general do very well, some studies document increasing procedural morbidity and mortality with advancing age, particularly past 80 years. Multivessel PCI is successful in patients aged 65 and older, with an overall angioplasty success rate of 96 percent. Complete revascularization was accomplished in 52 percent, and 3.2 percent had a myocardial infarction or other major in-hospital complications. Independent predictors of mortality were EF less than 40 percent (p < 0.001), three-vessel disease (p < 0.01), female gender (p < 0.02), and PTCA from 1985 or earlier.[100] In one study, the octogenarian was more likely to be a woman and have multivessel disease, with high-grade stenoses and more complex lesions than the younger patient.[101] Procedural mortality rose fivefold in those older than 80 years compared with those younger than 60 years. The rate of postprocedural myocardial infarction was also one and one-half times higher in the elderly than in the younger patients. Angiographic success was equal to that in younger patients, and the rate of in-hospital bypass surgery after intervention was less than that in younger patients. [101] CORONARY ARTERY BYPASS SURGERY.

There are no randomized studies comparing surgery to medical management in patients older than 65 years. Although there is limited information from randomized studies of coronary

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surgery compared with angioplasty that have included elderly patients,[102] and many reports of elderly patients from the same institution who had either CABG or angioplasty,[103] the conclusions from such studies are limited. With medical advances in the treatment of CAD, and with more patients with lesser degrees of CAD receiving angioplasty, coronary surgery is being done more often than in the past on older patients with more complicated CAD. As age increases, the proportion of men to women undergoing CABG increases, as does the prevalence of severe angina and CHF. The severity of the distribution of coronary stenoses also increases with age, as well as the incidence of complications, including neurological events, wound infections, and death, increasing in every decade after age 40. In most surgical series, morbidity and mortality are greater in the elderly, particularly in those older than 75 years. [104] Perioperative mortality in the elderly patient varies in different studies, from less than 2 percent to 10 percent.[102] [104] Morbidity and mortality depend on the presence of comorbidity, the EF, and the diffuseness of the CAD but are generally higher in the elderly.[104] The elderly patient also has a higher incidence of complications such as stroke, renal failure,

prolonged ventilation, and postoperative cardiac arrest.[104] [105] Carotid artery disease is also more common in the elderly. In the Bypass Angioplasty Revascularization Investigation (BARI) trial, 709 patients aged 65 to 80 with multivessel CAD were randomized to bypass surgery or angioplasty.[102] Mortality at 30 days was 0.7 percent for PTCA and 1.1 percent for CABG. For patients both older and younger than 65, it was 1.7 percent. CABG resulted in greater angina relief and fewer repeat procedures in both younger and older patients. In older patients compared with younger patients, stroke was more common after CABG than after PTCA (1.7 vs. 0.2 percent), and HF and pulmonary edema were more common after PTCA (4.0 vs. 1.3 percent). The 5-year survival rate was 91.5 percent after CABG and 89.5 percent after PTCA in the younger patients and 85.7 percent after CABG and 81.4 percent after PTCA in the older. Stents [106] and minimally invasive or "off-pump" coronary artery surgery[107] offer advantages in the elderly for low risk revascularization. There is evidence of substantial improvement in health-related quality of life after PTCA in the elderly similar to that seen in the younger patients.[107A] CARDIAC REHABILITATION (see Chap. 39) .

Fewer than half of eligible patients, and most elderly patients after a myocardial infarction or CABG do not participate in rehabilitation programs.[108] Because exercise capacity is reduced in the elderly after a cardiac event, exercise rehabilitation is especially important in this age group. Women and older patients are less likely to participate, as are those with lesser degrees of education and employment.[109] Psychological depression is common after AMI and coronary surgery, especially in the elderly.[69] [110] Education and reinforcement that this reaction is a normal response to a major cardiovascular event, and mostly transient, can be very helpful. Erectile dysfunction is especially common after coronary surgery or AMI and should be inquired about. The energy used during sexual activity is usually less than 5 METs.[111] Most patients can return to normal sexual activity within 3 to 4 weeks after an acute event. If erectile dysfunction is a problem, encouragement to resume sexual activity gradually should be given; and drugs such as sildenafil, or intracavernosal or intraurethral prostacyclin, can be very effective. The patient should be cautioned about the need to avoid taking nitrates within 24 hours of taking sildenafil.[111] Exercise prescriptions designed for the individual show substantial evidence for benefit of exercise in the elderly, with an increase in exercise tolerance and capacity, obesity indices, lipid profile, overall levels of physical fitness, and quality of life.[112] The greatest reduction in mortality with exercise training may occur in elderly men.[113] The benefits of cardiac rehabilitation have been shown to occur equally well in elderly women.[114] Rehabilitation programs for the elderly are safe. Data from 57,000 patients with over 2 million exercise hours identified only 21 cardiac events, including three fatal and eight nonfatal myocardial infarctions, during exercise training, or one cardiac event per 100,000, one AMI per 300,000, and one death per 1 million exercise hours.[115] [116] HEART FAILURE

Heart failure is the leading first-listed diagnosis among hospitalized older adults[117] (Fig. 57-6) . Among an estimated 4 million U.S. residents with HF, 70 percent were older than 60 years. The National Hospital Discharge Survey estimated 871,000 hospital admissions annually with a first-listed diagnosis of HF from 1985 to 1995; the numbers of hospitalizations for any diagnosis of HF increase to 2.6 million, or 53 percent, over the 10-year period in question. About 78 percent of men and 85 percent of women hospitalized with HF were older than 65 years. The etiology of HF in the elderly is the same as that in the younger populations. In the Framingham Heart Study, the prevalence of HF increased from 0.8 percent in the 50- to 59-year age group to 9.1 percent in the population 80 years and older.[118] Also in the Framingham study, the annual incidence of HF in men increased from 0.2 percent in the 45- to 54-year age group to 1.4 percent in the 75- to 84-year age group to 5.4 percent in the 85- to 94-year age group. [118] Whereas the majority of patients with HF younger than 65 years are men, of those over that age 60 percent are women, and the proportion increases with age.[119] Furthermore, there was a 27 percent increase in the incidence of initial hospitalization for HF in those 65 years and older from 1986 to 1993.[120] The mortality from HF is very high in the elderly, particularly with advanced HF, and may be 10 to 15 percent at 1 month and as high as 30 percent or more at 1 year. Mortality rate increases exponentially after age 65 in both men and women.[120A] HF is not only an important reason for

Figure 57-6 Incidence of heart failure by age and sex: 30-year follow-up from the Framingham Heart Study. (From Kannel WB, Belanger AJ: Epidemiology of heart failure. Am Heart J 121:951-957, 1991.)

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hospitalization but also is second only to HTN as a reason for outpatient physician visits, accounting for 12 million office visits per year in the United States.[121] HF in the older population consumes the most resources, with an estimated annual expenditure of $40 billion.[121] PATHOPHYSIOLOGY (see Chap. 16) .

With aging, LV hypertrophy occurs as a result of increased afterload, a slowing of LV muscle relaxation, and stiffening of the LV, all of which lead to diastolic dysfunction as a prominent feature of HF. With a stiff LV, atrial contraction becomes most important in delivering a normal LV diastolic volume and keeping stroke volume normal (see Fig. 57-1) . Therefore, AF often precipitates, or markedly increases, symptoms of HF in the elderly population.[122] In fact, with advancing age, the proportion of people with LV failure but normal systolic function approaches 50 percent or more.[123] Diastolic dysfunction as a pathophysiological function of HF occurs more often in women than in

men and also more often with hypertensive cardiovascular disease and diabetes. DIAGNOSIS.

The diagnosis of HF can be difficult in the older individual. Symptoms of dyspnea on exertion or easy fatigability are often taken as signs of "getting older" or deconditioning or can result from other diseases, especially pulmonary disease, thyroid abnormality, anemia, or depression. Edema of the lower extremity is not unusual in older patients, because the skin turgor decreases and the patient is increasingly sedentary, with legs dependent much of the time. Edema-related liver and renal disease is also not uncommon. Symptoms of increasing orthopnea or development of nocturnal cough, shortness of breath, or paroxysmal nocturnal dyspnea should alert the clinician to the possibility of the diagnosis of HF. Physical examination is particularly helpful with the findings of rales, tachycardia, and an S3 gallop rhythm; with right-sided HF, an elevated jugular venous pressure or positive hepatojugular reflux can be seen, as well as a right-sided S3 gallop rhythm. Chest radiography showing cardiomegaly, pulmonary congestion, or vascular redistribution confirms the diagnosis. Echocardiography is especially helpful in identifying the presence of a dilated, hypokinetic LV. With pure diastolic dysfunction as a cause of HF, the patient often has LV hypertrophy, although LV systolic function may appear to be normal, with normal or near-normal EF. An S4 gallop rhythm and echo-Doppler signs of delayed LV filling and diastolic dysfunction are frequently present. Clinical signs and symptoms of HF in the presence of a normal EF makes the diagnosis of pure diastolic dysfunction. Management (see also Chaps. 18 , 19 , and 21)

The management of HF in the elderly follows the same principles as those in younger patients[124] (see Chaps. 18 and 21) . The goals of therapy are also the same, including a decrease or elimination of symptoms, reduction in rehospitalization, and improvement in quality of life. Prolongation of life is desirable but of lower priority in the aged person with HF. Treatment requires consideration of the etiology of the heart disease, the factors that can precipitate HF, and the medical management. For instance, the patient with HF due to AS requires aortic valve replacement; HF due to ischemic but viable myocardium requires revascularization. Managing problems that precipitate HF in patients with underlying heart disease can be important in their medical management. For example, in the patient with diastolic dysfunction who develops HF along with AF, conversion to normal sinus rhythm or, less desirable, control of ventricular rate is the most important treatment.[125] Noncompliance with medical therapy, excessive salt intake and volume overload in the patient with renal failure, and infection are all causes of exacerbation of HF requiring rehospitalization. These factors contribute to 30 to 50 percent of recurrent episodes of HF in the elderly[126] and are the major reasons why between one third and one half of all

patients hospitalized with HF are readmitted within 3 to 6 months of initial discharge.[126] An effective way of managing elderly patients with HF is through a multidisciplinary approach and follow-up of patients at home through telephone calls, home visits by nursing personnel, and other patient contacts between office visits. Such an approach decreased the 90-day readmission rate by 32 percent in a group of 137 patients 80 to 96 years of age,[127] with improved quality-of-life scores and decreased overall cost. This multidisciplinary approach involves ongoing patient education, dietary consultation, medication review, daily weighings, and help with psychosocial problems and results in better compliance with medication[128] and overall cost reduction due to decreased rehospitalization.[129] Although medications for HF are the same as those for the younger population, care must be taken not to cause hypovolemia, with marked reduction in stroke volume. Also, electrolyte levels should be monitored closely, especially in those patients taking digoxin and ACE inhibitors, because of the danger of renal dysfunction, hypokalemia, and hyperkalemia. A danger of hypovolemia is precipitation of falls in elderly patients, with subsequent hip fracture.[130] Another problem in elderly patients is that many are receiving NSAIDs, which can increase the risk of HF in elderly patients taking diuretics.[131] DRUG THERAPY

ACE inhibitors, underprescribed in the elderly, are as effective in improving quality of life and reducing mortality as in younger patients.[132] Digoxin is useful in patients with HF who are in AF and/or are symptomatic on diuretics and ACE inhibitors.[133] However, in the elderly, lean body mass is decreased and renal function frequently is impaired; digoxin dosage is therefore lower than in the younger patient, and the danger of toxicity is greater. The Digitalis Investigation Group (DIG) reported that there was no decrease in overall mortality, but there was a decrease in hospitalization and mortality due to HF in patients receiving digoxin. Older age was an independent risk factor for all-cause mortality and rehospitalization, as well as for HF rehospitalizations and deaths.[134] Angiotensin II type 1 receptor antagonists are probably as effective as ACE inhibitors, but they are still being evaluated in the elderly, although side effects are probably less often noted.[135] Candesartan was effective in improving exercise tolerance, as well as symptoms and signs of HF.[136] In patients unable to take ACE inhibitors or angiotensin II type 1 receptor blockers, hydralazine and isosorbide have been shown to reduce mortality in patients with HF (see Chap. l8) . Beta blockers, if started in the usual dosage in patients with HF, will worsen the patient's clinical status; however, beta blockers started in small doses with titration upward have been shown to be very effective in improving quality of life of patients with HF, as well as increasing EF and exercise tolerance.[137] In the U.S. carvedilol study, patients with chronic HF and EF less than 35 percent were randomized to carvedilol versus placebo. Mortality was 65 percent lower in the carvedilol group in a 6.5-month follow-up.[138] Patients older than 60 years had results similar to younger patients. In this study, few patients were older than age 75 years. After AMI, beta blockers have been shown to

decrease late mortality in the elderly population.[139] In general, first-generation calcium channel blockers have been associated with adverse effects in patients with HF and as a result are usually contraindicated. If calcium channel blockers are indicated for ischemia, then those with little negative inotropic effect, such as amlodipine or felodipine, should be used. DIASTOLIC DYSFUNCTION

The treatment of diastolic dysfunction in the elderly has not been well studied. If the symptoms are predominantly pulmonary congestion, then treatment with diuretics and/or long-acting nitrates will lower the filling pressure and decrease shortness of breath. However, overdiuresis can markedly drop the stroke volume and cause hypotension and prerenal azotemia. Beta blockers, by slowing the heart rate and increasing the diastolic filling period, can lower the filling pressure and improve LV compliance by decreasing LV hypertrophy. Similar benefits can result from ACE inhibitors and calcium channel blockers, and all of these drugs have been used in patients with HF and EF greater than 40 percent. Verapamil has been shown to improve symptoms in exercise capacity and diastolic function in older patients with HF and EF less than 45 percent.[140] Whether results with spironolactone will be similar in patients older than age 75 years is unknown but likely (see Chap. 18) .

2030

HYPERTENSION (see also Chaps. 28 and 29) Both essential and secondary HTN, especially with renoarterial disease, are found in the elderly (see Fig. 57-3) . Isolated systolic HTN, as defined by a systolic BP greater than 140 mm Hg and a diastolic BP reading less than 90 mm Hg, is especially prominent in the elderly as a result of the decrease in arterial compliance and concomitant LV systolic stiffening.[3] The diagnosis of HTN should be made only after the BP is found to be elevated on three separate occasions. In the elderly, there are several problems in obtaining a correct BP using the BP cuff.[141] With noncompliant arteries, changes in stroke volume can result in wide variations in systolic BP. The patient should therefore be allowed to rest for 3 minutes before BP is taken. [141] Each time, BP should be taken two or three times and the results averaged. The "white coat" effect can be seen in 15 to 20 percent of all hypertensives, and it is especially common in the elderly.[142] Systolic BPs can vary as much as 20 to 40 mm Hg. For this reason, home or ambulatory BP recordings can be helpful in ascertaining the patient's usual BP.[143] Another problem, termed "pseudohypertension," is caused by a brachial artery that is calcified and sclerotic and therefore not easily compressed by the BP cuff. The diagnosis of pseudohypertension can be made for certain only by comparing cuff systolic BPs to intraarterial pressures. Recently, doubt has been cast on the validity and usefulness of "Osler's maneuver," that of continuing to palpate a radial pulse with the BP cuff above auscultated systolic BP.[144] Falsely low systolic BPs can also occur

because of the "auscultatory gap" in 20 percent of the elderly.[145] Here, Korotkoff sounds may be heard at 180 mm Hg, disappear, and then reappear at 130 mm Hg. If the BP cuff is not inflated to more than 180 mm Hg, the systolic BP will be incorrectly read as 130 mm Hg. This auscultatory phenomenon, the cause of which is unknown, is associated with age, female gender, increased arterial stiffness, and increased prevalence of carotid atherosclerotic plaques.[145] Pseudohypotension occurs when the BP is measured in an arm with an atherosclerotic obstruction proximal to the brachial artery. It can be suspected when there is a 30 mm Hg difference in BPs between the arms. A unilateral supraclavicular bruit is often heard. BP should always be taken initially in both arms and followed in the arm with the higher pressure. HYPOTENSION.

Orthostatic hypotension, defined as a drop of more than 20 mm Hg in pressure on going from a supine or sitting to a standing position for 1 to 3 minutes, was present in the Systolic Hypertension in the Elderly Program (SHEP) study before therapy in one of every six elderly patients with HTN.[146] Orthostatic HTN is more likely to occur in an elderly person because of the noncompliant vessels and is especially likely to occur with hypovolemia due to diuretics or drugs interfering with vasoconstriction, such as alpha-adrenergic blockade given for HTN or benign prostatic hypertrophy. Postprandial hypotension is especially common in elderly patients, occurring 30 to 120 minutes after a meal and causing drops in BP of more than 20 mm Hg. It is associated with lightheadedness, syncope, and falls and may be caused by vasodilation associated with excessive insulin response to a glucose load.[147] Decisions regarding BP control or change in therapy for HTN should take into account how long after the last meal the BP is taken. EPIDEMIOLOGY

HTN is more common in blacks than in whites: About 45 percent of white, but 60 percent of black, men and women have HTN at ages 65 to 74.[148] In a study from a university geriatrics practice of 459 men and 1360 women, mean age 80 ± 8 years (range 59 to 101 years), HTN was present in 58 percent.[149] Because of its prevalence in the elderly, isolated systolic HTN was thought to be a natural consequence of aging. To the extent that there are changes in the arterial wall with aging that lead to less compliant vessels, a rise in systolic BP is a consequence of aging. That isolated systolic HTN is not a normal consequence of aging is reflected in the fact that epidemiological studies show a rise in systolic BP with age occurring only infrequently in most nonindustrialized societies. In a study in which participants at ages 50 to 89 were surveyed as to leisure activity (classified into light, moderate, heavy, and no physical activity), BP decreased with increasing levels of activity.[150] It appears, therefore, that there are environmental and life-style influences on the late rise in systolic BP with aging. HTN remains the most common cause of HF, both with systolic and diastolic dysfunction. It is a strong risk factor for the development of CAD in both men and women. The Framingham Heart Study found that people 65 to 94 years of age with

systolic BPs greater than 180 mm Hg had a threefold to fourfold increase in the risk of CAD compared with those whose systolic BP was less than 120 mm Hg.[53] A diastolic BP greater than 105 mm Hg caused a twofold to threefold higher rise in CAD than in those with a diastolic BP less than 75 mm Hg. Mortality is increased in elderly patients with HTN, mainly owing to HF and CAD.[53] In addition to mortality, the complications of HTN can be especially devastating: almost two thirds of those older than age 60 with untreated HTN will have a cerebrovascular accident, HF, myocardial infarction, or aortic dissection within 5 years.[151] Similar morbidity and mortality have been shown to occur in patients with isolated systolic HTN as in those with systolic and diastolic HTN.[152] Although there is no doubt that lowering BP will reduce mortality, in old patients aged 80 to 85, there is paradoxical evidence of higher mortality with lower than with higher systolic or diastolic BP.[153] In one study of 561 people, including 82 percent of women aged older than 85, the 5-year mortality was lower in hypertensive (41 percent) than normotensive (72 percent) patients. It was highest in those with the lowest systolic BP (

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