Section Editors Gerard P. Aurigemma MD
William J. Kostuk MD, FRCPC
Professor of Medicine and Radiology University of Massachusetts Medical School Director of Noninvasive Cardiology Director, Cardiology Fellowship Training Program UMass Memorial Medical Center Worcester, Massachusetts
Emeritus Professor of Medicine Schulich School of Medicine & Dentistry University of Western Ontario Consultant, Cardiology Division University Hospital London, Ontario, Canada
George L. Bakris MD
Gregory Y H Lip MD, FRCP, DFM, FESC, FACC Professor of Cardiovascular Medicine University Department of Medicine City Hospital Birmingham, United Kingdom
Professor of Medicine University of Chicago Pritzker School of Medicine Director, Hypertensive Diseases Unit Section of Endocrinology, Diabetes and Metabolism University of Chicago Medical Center Chicago, Illinois
Helmut Drexler MD Professor of Medicine Chief, Division of Cardiology Medical University of Hannover Hannover, Germany Erling Falk MD, PhD Professor of Cardiovascular Pathology Institute of Clinical Medicine Aarhus University Hospital Skejby Aarhus, Denmark
Michael A. Gatzoulis MD, PhD, FACC, FESC Professor of Cardiology National Heart and Lung Institute Imperial College London Head, Adult Congenital Heart Centre and Centre for Pulmonary Hypertension Royal Brompton Hospital London, United Kingdom
George J. Klein MD, FRCPC, FACC Professor, Department of Medicine University of Western Ontario London, Ontario, Canada
Barry M. Massie MD Professor of Medicine UCSF School of Medicine Chief, Cardiology Division San Francisco VA Medical Center San Francisco, California
David J. Sahn MD, MACC, FAHA Professor of Pediatrics (Cardiology), Diagnostic Radiology, Obstetrics and Gynecology, and Biomedical Engineering Oregon Health & Science University Portland, Oregon
Prediman K. Shah MD, FACC, FACP, FCCP Shapell and Webb Chair and Director Division of Cardiology Oppenheimer Atherosclerosis Research Center Cedars Sinai Medical Center Professor of Medicine David Geffen School of Medicine at UCLA Los Angeles, California David Waters MD Emeritus Professor Department of Medicine UCSF School of Medicine San Francisco, California
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CARDIOLOGY
ISBN: 978-0-7234-3485-6
Copyright # 2010, 2004, 2001 by Elsevier Ltd. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Rights Department: phone: (þ1) 215 239 3804 (US) or (þ44) 1865 843830 (UK); fax: (þ44) 1865 853333; e-mail:
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Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment, and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on his or her experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher
Library of Congress Cataloging-in-Publication Data Cardiology / [edited by] Michael H. Crawford . . . [et al.]. — 3rd ed. p. ; cm. Includes bibliographical references and index. ISBN 978-0-7234-3485-6 1. Cardiology. I. Crawford, Michael H., 1943– [DNLM: 1. Heart Diseases—diagnosis. 2. Heart Diseases—etiology. 3. Heart Diseases—therapy. WG 100 C2655 2010] RC667.C377 2010 2009018142 616.10 2—dc22
Acquisitions Editor: Natasha Andjelkovic Developmental Editor: Pamela Hetherington Publishing Services Manager: Linda Van Pelt Project Manager: Frank Morales Design Direction: Lou Forgione
Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1
Contributors Nicola Abate, MD Professor, Chief Division of Endocrinology, University of Texas Medical Branch, Galveston, Texas, USA
Ahmed Tageldien Abdellah, MD Professor of Cardiology, Hull York Medical School, University of Hull, Castle Hill Hospital, Kingston upon Hull, United Kingdom
Jonathan Abrams, MD Professor of Medicine, Division of Cardiology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
Christophe Acar, MD Professor of Cardiac Surgery, Universite´ Pierre et Marie Curie–Paris VI, Staff Surgeon, CHU Pitie´-Salpeˆtrie`re Hospital, Paris, France
Jean Acar, MD Professor Emeritus of Cardiology, Universite´ Pierre et Marie Curie–Paris VI, Former Chief, Department of Cardiology, CHU Tenon Hospital, Paris, France
Harry Acquatella, MD, FACC, FAHA Professor of Medicine, Faculty of Medicine, Universidad Central de Venezuela, Centro Medico, Caracas, Venezuela
M. Jacob Adams, MD, MPH Assistant Professor of Community and Preventive Medicine, Division of Epidemiology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
Teiji Akagi, MD, PhD, FACC, FAHA Associate Professor, Department of Cardiovascular Surgery, Okayama University Graduate School of Medicine and Dentistry, Attending, Cardiac Intensive Care Unit, Okayama University Hospital, Okayama, Japan
Inder S. Anand, MD, FRCP, DPhil (Oxon) Professor of Medicine, University of Minnesota Medical School, Director, Heart Failure Program, Minneapolis VA Medical Center, Minneapolis, Minnesota, USA
David E. Anderson, PhD Senior Investigator, Cancer research Branch, National Institute on Aging, Baltimore, Maryland, USA
Henning Rud Andersen, MD, DMSc Associate Professor of Cardiology, University of Aarhus Faculty of Health Sciences, Cardiac Electrophysiologist, Aarhus University Hospital Skejby, Aarhus, Denmark
Mark E. Anderson, MD, PhD Professor of Internal Medicine, University of Iowa Carver College of Medicine, Director, Division of Cardiovascular Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA
Christiane E. Angermann, MD Professor of Medicine and Cardiology, University of Wu¨rzburg Faculty of Medicine, Head, Division of Cardiology (Polyclinic), Department of Medicine I, University Hospital Wu¨rzburg, Wu¨rzburg, Germany
Stefan D. Anker, MD, PhD Professor of Cardiology and Cachexia Research, Division of Applied Cachexia Research, Department of Cardiology, Charite´ University Medical School, Campus Virchow-Klinikum, Berlin, Germany
Ramon Arroyo-Espliguero, MD Associate Professor of Cardiology, University of Guadalajara Faculty of Medicine, Consultant Cardiologist, Hospital General Universitario, Guadalajara, Spain
Gerard P. Aurigemma, MD Professor of Medicine and Radiology, University of Massachusetts Medical School, Director of Noninvasive Cardiology, Director, Cardiology Fellowship Training Program, UMass Memorial Medical Center, Worcester, Massachusetts, USA
Sonya V. Babu-Narayan, MBBS, BSc, MRCP Honorary Clinical Research Fellow, National Heart and Lung Institute, Imperial College London, Specialist Registrar, Adult Congenital Heart Disease, Royal Brompton Hospital, London, United Kingdom
George L. Bakris, MD Professor of Medicine, University of Chicago Pritzker School of Medicine, Director, Hypertensive Diseases Unit, Section of Endocrinology, Diabetes and Metabolism University of Chicago Medical Center, Chicago, Illinois, USA
Malcolm Barlow, MBBS, FRACP, FCANZCS Conjoint Senior Lecturer, School of Medicine and Public Health, Faculty of Health, University of Newcastle, Newcastle, Senior Staff Specialist, John Hunter Hospital, New Lambton, New South Wales, Australia
Margot M. Bartelings, MD, PhD Assistant Professor of Cardiac Pathophysiology, Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands
George A. Beller, MD Ruth C. Heede Professor of Cardiology and Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA
Lisa J. Bergerson, MD Assistant Professor in Pediatrics, Harvard Medical School, Associate in Cardiology, Children’s Hospital Boston, Boston, Massachusetts, USA
Sandro Betocchi, MD, FACC, FESC Professor of Cardiology, Department of Clinical Medicine–Cardiovascular and Immunological Sciences, University of Naples Federico II School of Medicine and Surgery, Chief, Cardiology Consultant Service, Federico II University Hospital, Naples, Italy
Ami B. Bhatt, MD Fellow in Cardiology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
Kalkidan G. Bishu, MD Resident, Department of Medicine, Minneapolis VA Medical Center, Minneapolis, Minnesota, USA
Reidar Bjørnerheim, MD, PhD, FESC Head, Department of Cardiology, Oslo University Hospital, Ulleval, Oslo, Norway
Hans Erik Bøtker, MD, PhD, DMSc Professor of Cardiology, University of Aarhus Faculty of Health Sciences, Consultant Interventional Cardiologist, Aarhus University Hospital Skejby, Aarhus, Denmark
v
Contributors
Harm Jan Bosaard, MD, PhD Assistant Professor of Medicine, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Victoria W. Johnson Center for Obstructive Lung Disease Research, VCU Health System, Richmond, Virginia, USA
Jamieson Bourque, MD, MHS (ClinRes) Fellow in Advanced Imaging and Cardiovascular Disease, University of Virginia Health System, Charlottesville, Virginia, USA
Craig Broberg, MD, FACC Assistant Professor of Medicine, Oregon Health & Science University School of Medicine, Director, Adult Congenital Heart Disease Program, OHSU Hospital, Portland, Oregon, USA
Fiona Brodie, MBBS, MRCP(UK) Stroke Research Fellow, University of Leicester College of Medicine, Biological and Psychological Science, Leicester, United Kingdom
W. Virgil Brown, MD Charles Howard Candler Professor of Medicine, Emory University School of Medicine, Chief of Medicine, Atlanta VA Medical Center, Atlanta, Georgia, USA
David A. Calhoun, MD Professor of Medicine, Vascular Biology and Hypertension Program, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA
Francesco P. Cappuccio, MBBS, MD, MSc, FRCP, FFPH, FAHA Professor and Cephalon Chair of Cardiovascular Medicine & Epidemiology, University of Warwick Medical School/ Clinical Sciences Research Institute, Consultant Cardiovascular Physician, University Hospitals Coventry & Warwickshire NHS Trust, Coventry, United Kingdom
Blase A. Carabello, MD, FACC Professor of Medicine, Baylor College of Medicine, Chief of Medicine, Michael E. DeBakey VA Medical Center, Houston, Texas, USA
John G. Carr, MD Assistant Professor of Medicine, Boston University School of Medicine, Cardiac Electrophysiologist, Boston Medical Center, Boston, Massachusetts, USA
John D. Carroll, MD Professor of Medicine, University of Colorado Denver School of Medicine, Director, Section of Interventional Cardiology, University of Colorado Hospital, Aurora, Colorado, USA
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Filip P. Casselman, MD, PhD, FETCS Staff Surgeon, Department of Cardiovascular and Thoracic Surgery, Atrial Fibrillation Clinic, Onze Lieve Vrouw (OLV) Hospital, Aalst, Belgium
David Celermajer, MBBS, PhD, DSc, FRACP Scandrett Professor of Cardiology, University of Sydney Faculty of Medicine, Clinical Academic Cardiologist, Director, Adult Congenital Heart Disease, Royal Prince Albert Hospital, Sydney, New South Wales, Australia
Bojan Cercek, MD, PhD Professor of Medicine, David Geffen School of Medicine at UCLA, Director, Coronary Care Units, Co-Director, Atherosclerosis Research Center at Cedars-Sinai Medical Center, Los Angeles, California, USA
Philippe Charron, MD, PhD Associate Professor, Universite´ Pierre et Marie Curie–Paris VI, Department of Genetics, CHU Pitie´-Salpeˆtrie`re Hospital, Paris, France
Shi-Ann Chen, MD Professor of Medicine, Department of Medicine, Division of Cardiology, National Yang-Ming University School of Medicine, Attending Cardiologist, Taipei Veterans General Hospital, Taipei, Taiwan
Alice Yuk-Yan Cheng, MD, FRCPC Assistant Professor (Adjunct), Department of Medicine, University of Toronto Faculty of Medicine, Staff Endocrinologist, St. Michael’s Hospital, Toronto, Staff Endocrinologist, Credit Valley Hospital, Mississauga, Ontario, Canada
Margaret A. Chesney, PhD Professor of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
Bernard Cheung, PhD, FRCP Professor of Clinical Pharmacology and Therapeutics, College of Medical and Dental Sciences, University of Birmingham, Honorary Consultant, University Hospital Birmingham, Birmingham, United Kingdom
Massimo Chiarello, MD Professor of Cardiology, Department of Clinical Medicine–Cardiovascular and Immunological Sciences, University of Naples Federico II School of Medicine and Surgery, Chief, Cardiology, Federico II University Hospital, Naples, Italy
Dave C.Y. Chua, MD, MS Cardiologist, Dreyer Medical Clinic, Auroa, Illinois, USA
Natali A.Y. Chung, MD, MRCP Specialist Registrar, Adult Congenital Heart Disease, Royal Brompton Hospital, London, United Kingdom
David Churchill, MBChB, MD, FRCOG Consultant Obstetrician, Clinical Director of Governance, The Royal Wolverhampton Hospitals NHS Trust, New Cross Hospital, Wolverhampton, United Kingdom
John G.F. Cleland, MD Professor of Cardiology, Hull York Medical School, University of Hull, Castle Hill Hospital, Kingston upon Hull, United Kingdom
Peter Clemmensen, MD, PhD Associate Professor of Medicine, University of Copenhagen Faculty of Health Sciences, Director, CAO Services, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Laura J. Collins, MD, FACC, FAHA Associate Professor of Medicine, Division of Cardiology, University of Texas Southwestern Medical School, Staff Cardiologist, Dallas VA Medical Center, Parkland Memorial Hospital, and University Hospital St. Paul, Dallas, Texas, USA
Louis S. Constine, MD, FASTRO Professor of Radiation Oncology and Pediatrics, University of Rochester School of Medicine and Dentistry, Vice Chair and Director, Fellowship Program, Department of Radiation Oncology, James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA
Michael H. Crawford, MD Professor of Medicine, Lucie Stern Chair in Cardiology, University of California, San Francisco, Interim Chief of Cardiology, UCSF Medical Center, San Francisco, California, USA
Alain Cribier, MD Professor of Medicine, University of Rouen Medical School, Chief, Department of Cardiology, Charles Nicolle Hospital, Rouen, France
Laura Cupper, BSW Vocational Counselor, Minto Prevention and Rehabilitation Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
William A. Dafoe, MD, FRCPC Associate Professor of Medicine, Division of Cardiology, University of Alberta Faculty of Medicine & Dentistry, Regional Director, Cardiac Rehabilitation, Walter Mackenzie Centre/University of Alberta Hospitals, Edmonton, Alberta, Canada
Jayanta Das, MD Fellow in Cardiovascular Medicine, CedarsSinai Medical Center, Los Angeles, California, USA
Warren Davis, MD Professor of Medicine (retired), Emory University School of Medicine, Atlanta, Georgia, USA
Roman DeSanctis Professor of Medicine, Harvard Medical School, Chief, Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA
Prakash Deedwania, MD, FACC, FACP, FAHA Professor of Medicine, University of California, San Francisco, School of Medicine, San Francisco, Chief, Cardiology Section, VA Medical Center Fresno, Director, Cardiovascular Research, VACCHCS/UCSF Program, Fresno, California, USA
Livio Dei Cas, MD Divisions of Cardiac Surgery and Cardiology, University of Brescia Medical School, Brescia, Italy
Pim J. de Feyter, MD Professor of Cardiac Imaging, Department of Cardiology, Erasmus University Medical Center, Rotterdam, The Netherlands
Gilles de Keulenaer, MD, PhD Professor of Physiology, Department of Pharmaceutical Sciences, University of Antwerp Faculty of Medicine, Director, Laboratory of Physiology, University Hospital of Antwerp, Cardiologist and Specialist in Cardiac Rehabilitation, Middelheim Hospital, Antwerp, Belgium
Marco C. DeRuiter, PhD Associate Professor of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands
Richard B. Devereux, MD Professor of Medicine, Weill Cornell Medical College, Attending Physician, NewYork– Presbyterian Hospital, New York, New York, USA
Abhay J. Dhond, MD, MPH, FACP Associate Professor of Medicine, Drexel University College of Medicine, Attending, Hahnemann University Hospital, Philadelphia, Pennsylvania, USA
John P. DiMarco, MD, PhD Julian R. Beckwith Professor of Medicine, University of Virginia School of Medicine, Director, Cardiac Electrophysiology Laboratory, Cardiovascular Division, University of Virginia Health System, Charlottesville, Virginia, USA
Konstantinos Dimopoulos, MD, MSc, PhD Senior Fellow, National Heart and Lung Institute, Imperial College London, Associate Specialist, Royal Brompton Hospital, London, United Kingdom
Associate Professor of Medicine, University of Montreal Faculty of Medicine, Cardiologist, Adult Congenital Heart Center, Montreal Heart Institute, Montreal, Quebec, Canada
Paul Dorian, MD, MSc, FRCPC Professor of Medicine, Director, Cardiology Division, University of Toronto Faculty of Medicine, Cardiac Electrophysiologist, St. Michael’s Hospital, Toronto, Ontario, Canada
Pamela S. Douglas, MD, FACC Ursula Geller Professor of Research in Cardiovascular Diseases, Professor of Medicine, Division of Neurology, Duke University School of Medicine, Head, Cardiovascular Medicine Section, Duke Clinical Research Institute, Durham, North Carolina, USA
Helmut Drexler, MD Professor of Medicine, Chief, Division of Cardiology, Medical University of Hannover, Hannover, Germany
Jean G. Dumesnil, MD, FRCPC, FACC Professor of Medicine, Laval University Faculty of Medicine, Cardiologist, Quebec Lung and Heart Institute, Quebec City, Quebec, Canada
Amgad El Sherif, MD Clinical Instructor in Cardiothoracic Surgery, UPMC Presbyterian, Pittsburgh, Pennsylvania, USA
Uri Elkayam, MD Professor of Medicine, Division of Cardiovascular Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, California, USA
Perry M. Elliott, MD Reader in Inherited Cardiovascular Disease, University College London Medical School, Consultant Cardiologist, University College London Hospital, London, United Kingdom
William J. Elliott, MD, PhD Professor of Preventive Medicine, Internal Medicine, and Pharmacology, Rush Medical College, Attending Physician, Rush University Medical Center, Chicago, Illinois, USA
Alexander Ellis, MD, MSc, FAAP Assistant Professor of Internal Medicine and Pediatrics, Eastern Virginia Medical School, Pediatric and Adult Congenital Cardiologist, Children’s Hospital of the King’s Daughters, Norfolk, Virginia, USA
He´le`ne Eltchaninoff, MD Professor of Medicine, University of Rouen Medical School, Head, Cardiac Catheterization Unit, Department of Cardiology, Charles Nicolle Hospital, Rouen, France
Jeanette Erdmann, PhD Professor of Genetics, Faculty of Medicine, University of Lu¨beck, Head, Molecular Genetics Laboratory, Lu¨beck University Hospital, Lu¨beck, Germany
Mohammed Rafique Essop, MBBCh, MRCP(UK), FCP(SA), FRCP(Lond), FACC Associate Professor of Medicine–Cardiology, Faculty of Health Sciences, University of the Witwatersrand, Head, Division of Cardiology, Baragwanath Hospital, Johannesburg, South Africa
Contributors
G. William Dec, MD
Annie Dore, MD
Michael D. Ezekowitz, MD, PhD Vice President, Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA
Bengt Fagrell, MD, PhD Professor Emeritus, Department of Internal Medicine, Karolinska Institute, Stockholm, Sweden
Erling Falk, MD, PhD Professor of Cardiovascular Pathology, University of Aarhus Faculty of Health Sciences, Cardiovascular Pathologist, Department of Cardiology, Aarhus University Hospital Skejby, Aarhus, Denmark
William F. Fearon, MD Assistant Professor of Medicine, Stanford University School of Medicine, Associate Director, Interventional Cardiology, Stanford University Medical Center, Stanford, California, USA
Eric O. Feigl, MD Professor, Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington, USA
Craig E. Fleishman, MD Director, Noninvasive Cardiology, Congenital Heart Institute at Miami Children’s Hospital, Miami, Arnold Palmer Hospital for Children, Orlando, Florida, USA
Gerald F. Fletcher, MD Professor of Medicine, Mayo College of Medicine, Cardiologist, Mayo Clinic Jacksonville, Jacksonville, Florida, USA
Andrew S. Flett, MBBS, BSc Clinical Fellow, University College London, London, United Kingdom
Thomas R. Flipse, MD Assistant Professor of Medicine, Mayo College of Medicine, Jacksonville, Florida, USA
Gregory P. Fontana, MD Vice Chairman, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA
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Contributors
Thomas Force, MD James C. Wilson Professor of Medicine, Jefferson Medical College of Thomas Jefferson University, Clinical Director, Center for Translational Medicine, Thomas Jefferson University Hospitals, Philadelphia, Pennsylvania, USA
Anne Fournier, MD Associate Professor, Department of Pediatrics, University of Montreal Faculty of Medicine, Director, Electrophysiology Section, Ste. Justine Hospital, Montreal, Quebec, Canada
Gary S. Francis, MD, FACC Professor of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
Ian J. Franklin, MS, FRCS(GenSurg) Honorary Clinical Senior Lecturer, Imperial College London School of Medicine, Consultant Vascular Surgeon, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
William H. Gaasch, MD Professor of Medicine, University of Massachusetts Medical School, Worcester, Tufts University School of Medicine, Boston, Senior Consultant in Cardiology, Lahey Clinic, Burlington, Massachusetts, USA
Michael A. Gatzoulis, MD, PhD, FACC, FESC Professor of Cardiology, National Heart and Lung Institute, Imperial College London, Head, Adult Congenital Heart Centre and Centre for Pulmonary Hypertension, Royal Brompton Hospital, London, United Kingdom
Peter Geelen, MD, PhD Head, Arrhythmia Unit and Atrial Fibrillation Clinic, Cardiovascular Center, Onze Lieve Vrouw (OLV) Hospital, Aalst, Belgium
Tal Geva, MD Professor of Pediatrics, Harvard Medical School, Chief, Division of Noninvasive Imaging, Senior Associate in Cardiology, Children’s Hospital Boston, Boston, Massachusetts, USA
Marc Gewillig, MD, PhD Professor of Pediatric Cardiology, University of Leuven Faculty of Medicine, Head, Pediatric Cardiology, University Hospital Leuven, Leuven, Belgium
Aziz Ghaly, MD Fellow in Cardiothoracic Surgery, CedarsSinai Medical Center, Los Angeles, California, USA
Adrianna C. Gittenberger-de Groot, PhD
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Professor and Chair, Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands
James A. Goldstein, MD Medical Director, Cardiovascular Research & Education, William Beaumont Hospital, Royal Oak, Michigan, USA
Eric M. Graham, MD Assistant Professor of Pediatric Cardiology, Medical University of South Carolina College of Medicine, Charleston, South Carolina, USA
Peer Grande, MD, PhD Associate Professor of Medicine, University of Copenhagen Faculty of Health Sciences, Chief, Acute Coronary Care Service, Rigshospitalet Heart Center, Copenhagen University Hospital, Copenhagen, Denmark
Paul A. Grayburn, MD Paul J. Thomas Professor of Medicine, Baylor College of Medicine, Director, Cardiology Research, Baylor University Medical Center, Dallas, Texas, USA
Ehud Grossman, MD Professor of Medicine, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Head, Internal Medicine D and Hypertension Unit, Chaim Sheba Medical Center, Tel-Hashomer, Israel
Scott M. Grundy, MD, PhD Director of the Center for Human Nutrition, Chairman of the Department of Clinical Nutrition, University of Texas Southwestern Medical School, Chief of the Metabolic Unit, Veterans Affairs Medical Center, Dallas, Texas, USA
Colette Guiraudon, MD, FRCPC, FACP Emeritus Professor of Pathology, Schulich School of Medicine & Dentistry, University of Western Ontario, Consultant, Department of Pathology, University Hospital, London Health Sciences Centre, London, Ontario, Canada
Lorne J. Gula, MD Assistant Professor of Medicine, Division of Cardiology, Schulich School of Medicine & Dentistry, University of Western Ontario, Cardiologist, University Hospital, London Health Sciences Centre, London, Ontario, Canada
Donald J. Hagler, MD Professor of Pediatrics, Mayo Clinic College of Medicine, Consultant, Pediatric Cardiology–Cardiovascular Diseases, Consultant, Circulatory System Devices Panel, Medical Devices Advisory Committee, Mayo Clinic, Rochester, Minnesota, USA
David E. Haines, MD Chief, Department of Cardiovascular Medicine, Beaumont Hospitals, Royal Oak, Michigan, USA
Sharif A. Halim, MD Resident and House Officer, Department of Internal Medicine, Duke University Medical Center, Durham, North Carolina, USA
Afshan Hameed, MD, FACC Assistant Professor of Cardiology and Maternal Fetal Medicine, University of California, Irvine, School of Medicine, Orange, California, USA
Frank L. Hanley, MD Professor of Cardiothoracic Surgery, Stanford University School of Medicine, Director, Children’s Heart Center, Lucile Packard Children’s Hospital, Stanford, California, USA
Go¨ran K. Hansson, MD, PhD Professor, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden
Peter D. Hart, MD, FACP Associate Professor of Medicine, Rush Medical College, Chair, Division of Nephrology, Stroger Hospital of Cook County, Chicago, Illinois, USA
Gerd Hasenfuss, MD, FAHA Professor of Medicine, Department of Cardiology and Pulmonary Medicine, Faculty of Medicine, Georg August University of Go¨ttingen, Go¨ttingen, Germany
Emily Hass, MD Cardiology Fellow, University of North Carolina at Chapel Hill School of Medicine/ North Carolina Memorial Hospital, Chapel Hill, North Carolina, USA
Harvey S. Hecht, MD Director of Cardiovascular Computed Tomography, Lenox Hill Heart & Vascular Institute, New York, New York, USA
Otto M. Hess, MD, FESC, FAHA Professor of Cardiology, Faculty of Medicine, University of Bern, Bern, University of Zurich, Zurich, Switzerland, Faculty of Medicine and Surgery, University of Bari, Bari, University of Verona, Verona, Italy, Chair, Department of Cardiology, Swiss Cardiovascular Center, Bern University Hospital, Bern, Switzerland
Li-Wei Ho, MD Lecturer in Medicine, Department of Medicine, Division of Cardiology, National Yang-Ming University School of Medicine, Attending Cardiologist, Taipei Veterans General Hospital, Taipei, Taiwan
Richard Hobbs, MBChB, FRCGP, FRCP, FESC, FMedSci Professor and Head, Primary Care Clinical Sciences, School of Medicine, University of Birmingham, Birmingham, United Kingdom
Neil Hobson, MD Consultant Cardiologist, Castle Hill Hospital, Kingston upon Hull, United Kingdom Professor of Medicine, UMDNJ–Robert Wood Johnson Medical School, Director, Coronary Care Unit, Cooper University Hospital, Camden, New Jersey, USA
Babak Hooshmand, MD Aging Research Center, Karolinska Institute, Stockholm, Sweden
Priscilla Y. Hsue, MD Assistant Professor of Medicine, University of California, San Francisco, School of Medicine, Attending, Division of Cardiology, San Francisco General Hospital, San Francisco, California, USA
Judy Hung, MD Assistant Professor of Pathology, Harvard Medical School, Associate Director, Echocardiography, Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA
Stuart J. Hutchison, MD Clinical Professor of Medicine, University of Calgary, Foothills Medical Center, Calgary, Alberta, Canada
Michael Dilou Jacobsen, MD Senior Resident, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Jose A. Joglar, MD Associate Professor of Internal Medicine, Elizabeth Thaxton Page and Ellis Batten Page Professorship in Cardiac Electrophysiology Research, University of Texas Southwestern Medical School, Director, Clinical Cardiac Electrophysiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Monique R.M. Jongbloed, MD, PhD Assistant Professor of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands
Priya Kansal, MD Fellow, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Juan Carlos Kaski, MD, DSc, FRCP, FESC, FACC Professor of Cardiovascular Science, Director, Cardiovascular Research Centre, St. George’s University of London, Consultant Cardiologist, Deputy Head, Division of Cardiac and Vascular Sciences, St. George’s Hospital NHS Trust, London, United Kingdom
Professor of Cardiology, Faculty of Medicine, Albert Ludwigs University of Freiburg, Medical Clinic III, University Medical Center Freiburg, Freiburg, Chief of Cardiology, St. Josef’s Hospital, Wiesbaden, Germany
Hirohisa Kato, MD, PhD, FACC Professor Emeritus of Pediatrics, Kurume University School of Medicine, Honorary President, Cardiovascular Research Institute, Kurume, Japan
Sanjay Kaul, MD Director, Cardiology Training Fellowship Program, Division of Cardiology, CedarsSinai Heart Institute, Director, Vascular Physiology and Thrombosis Research Laboratory, Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
Gautam Kedia, MD Fellow in Cardiology, Cedars-Sinai Medical Center, Los Angeles, California, USA
John A. Kern, MD Associate Professor of Surgery, Department of Surgery, University of Virginia School of Medicine, Medical Director, Non-Invasive Vascular Laboratory, University of Virginia Hospital, Charlottesville, Virginia, USA
Paul Khairy, MD, PhD Associate Professor of Medicine, University of Montreal Faculty of Medicine, Canada Research Chair, Electrophysiology and Adult Congenital Heart Disease, Director, Adult Congenital Heart Center, Montreal Heart Institute, Montreal, Quebec, Canada, Research Director, Boston Adult Congenital Heart Service, Boston, Massachusetts, USA
Apurv Khanna, MD Assistant Professor of Medicine, University of Connecticut School of Medicine, Attending Physician, John Dempsey Hospital, Farmington, Connecticut, USA
Michael S. Kim, MD Chief Fellow, Cardiovascular Diseases, Clinical Fellow, Section of Interventional Cardiology, University of Colorado Denver School of Medicine/University of Colorado Hospital, Aurora, Colorado, USA
Thomas R. Kimball, MD Professor of Pediatrics, University of Cincinnati College of Medicine, Director, Cardiac Ultrasound, Director, Cardiovascular Imaging Core Research Laboratory, Cincinnati Children’s Hospital, Cincinnati, Ohio, USA
Miia Kivipelto, MD, PhD Associate Professor, Department of Neuroscience and Neurology, Faculty of Medicine, University of Kuopio, Kuopio, Finland, Aging Research Center, Department of Neurobiology, Karolinska Institute, Stockholm, Sweden
George J. Klein, MD, FRCPC Professor of Medicine, Division of Cardiology, Schulich School of Medicine & Dentistry, University of Western Ontario, Cardiologist, University Hospital, London Health Sciences Centre, London, Ontario, Canada
Michel Komajda, MD, PhD Professor of Cardiology, Universite´ Pierre et Marie Curie–Paris VI, Head, Department of Cardiology, CHU Pitie´-Salpeˆtrie`re Hospital, INSERM UMR 621, Paris, France
Contributors
Steven Hollenberg, MD
Wolfgang Kasper, MD
Marvin A. Konstam, MD Professor of Medicine, Tufts University School of Medicine, Chief Physician Executive, The Cardiovascular Center, Tufts Medical Center, Boston, Massachusetts, USA
Stavros Konstantinides, MD Professor of Medicine, Department of Cardiology and Pulmonary Medicine, Faculty of Medicine, Georg August University of Go¨ttingen, Go¨ttingen, Germany
Alexander Kopelnik, MD Fellow in Cardiology, University of California, San Diego, School of Medicine/ UCSD Medical Center, San Diego, California, USA
William J. Kostuk, MD, FRCPC, FACC, FACP, FAHA Emeritus Professor of Medicine (Cardiology), Schulich School of Medicine & Dentistry, University of Western Ontario, Cardiologist, University Hospital, London Health Sciences Centre, London, Ontario, Canada
Andrew D. Krahn, MD Professor of Medicine, Division of Cardiology, Schulich School of Medicine & Dentistry, University of Western Ontario, Cardiologist, University Hospital, London Health Sciences Centre, London, Ontario, Canada
Richard Krasuski, MD Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Director, Adult Congenital Heart Disease Services, Cleveland Clinic, Cleveland, Ohio, USA
Jacqueline Kreutzer, MD, FACC, FSCAI Associate Professor of Medicine, University of Pittsburgh School of Medicine, Director, Cardiac Catheterization Laboratory, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA
Henry Krum, MBBS, PhD, FRACP Professor of Medicine, Chair of Medical Therapeutics, Monash University Faculty of Medicine, Nursing and Health Sciences, Head, Clinical Pharmacology, Physician, Heart Centre, Alfred Hospital, Melbourne, Victoria, Australia
ix
Uwe Ku¨hl, MD, PhD
Contributors
Department of Cardiology and Pneumonology, Medical Clinic II, Charite´ University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany
Michael J. Landzberg, MD Assistant Professor of Medicine, Harvard Medical School, Director, Boston Adult Congenital Heart (BACH) and Pulmonary Hypertension Service, Department of Cardiology, Children’s Hospital Boston/ Brigham and Women’s Hospital, Boston, Massachusetts, USA
Chim C. Lang, MD, FRCP(Lond, Edinb) Professor of Cardiology, Division of Medical Sciences, College of Medicine, Dentistry and Nursing, University of Dundee, Honorary Consultant Cardiologist, Ninewells Hospital and Medical School, Dundee, United Kingdom
Mark Langsfeld, MD Professor of Surgery, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
Guido Lastra, MD Endocrinology Fellow, University of Missouri–Columbia School of Medicine/ Harry S. Truman Memorial Veterans’ Hospital, Columbia, Missouri, USA
Decebal-Gabriel Latcu, MD Assistant Specialist, Cardiology Service, Princess Grace Hospital Center, Monaco (Principality)
Chu-Pak Lau, MD Honorary Clinical Assistant Professor, Department of Medicine, Li Ka Shing Faculty of Medicine/Queen Mary Hospital, University of Hong Kong, Director, Institute of Cardiovascular Science & Medicine, Hong Kong, China
Wendy Lau, MBBS, MD Honorary Physician to the Pacemaker Clinic, The Royal Melbourne Hospital, Melbourne, Victoria, Australia
Agnes Y.Y. Lee, MD, MSc, FRCPC Associate Professor of Medicine, University of British Columbia Faculty of Medicine, Medical Director of Thrombosis, Vancouver General Hospital, Vancouver, British Columbia, Canada
Kathy L. Lee, MBBS, MRCP, FRCP, FHKCP, FHKAM, FACC Honorary Clinical Assistant Professor, Li Ka Shing Faculty of Medicine, University of Hong Kong, Senior Medical Officer, Queen Mary Hospital, Hong Kong, China
x
James Leitch, MBBS, FRACP, FCANZCS Conjoint Senior Lecturer, School of Medicine and Public Health, Faculty of Health, University of Newcastle, Newcastle, Senior Staff Specialist, John Hunter Hospital, New Lambton, New South Wales, Australia
Paul LeLorier, MD Assistant Professor of Medicine, Boston University School of Medicine, Director, Electrophysiology Training Program, Boston Medical Center, Boston, Massachusetts, USA
Oren Lev-Ran, MD Department of Cardiothoracic Surgery, Onze Lieve Vrouw Gasthuis (OLVG) Hospital, Amsterdam, The Netherlands
Martin M. LeWinter, MD Professor of Medicine and Molecular Physiology and Biophysics, University of Vermont College of Medicine, Attending Physician and Director, Heart Failure and Cardiomyopathy Program, Fletcher Allen Health Care, Burlington, Vermont, USA
Bertil Lindal, MD, PhD Associate Professor of Cardiology, Department of Medical Sciences, Uppsala University Faculty of Medicine, Co-Director, Uppsala Clinical Research Centre, Uppsala University Hospital, Uppsala, Sweden
Gregory Y.H. Lip, MD, FRCP, DFM, FESC, FACC Professor of Cardiovascular Medicine, School of Medicine, University of Birmingham, Consultant Cardiologist, Director, Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, United Kingdom
Steven E. Lipshultz, MD George E. Batchelor Professor and Chairman, Department of Pediatrics, Associate Executive Dean for Child Health, Professor of Epidemiology and Public Health, Professor of Medicine (Oncology), University of Miami Leonard M. Miller School of Medicine, Chief-of-Staff, Holtz Children’s Hospital, Director, Batchelor Children’s Research Center, Associate Director, Mailman Center for Child Development, Member, Sylvester Comprehensive Cancer Center, University of Miami–Jackson Memorial Medical Center, Miami, Florida, USA
Li-Wei Lo, MD Professor of Medicine, Department of Medicine, Division of Cardiology, National Yang-Ming University School of Medicine, Attending Cardiologist, Taipei Veterans General Hospital, Institute of Clinical Medicine, Taipei, Taiwan
Maria-Angela Losi, MD Assistant Professor of Cardiology, Department of Clinical Medicine– Cardiovascular Sciences, University of Naples Federico II School of Medicine and Surgery, Chief, Echocardiography Laboratory, Federico II University Hospital, Naples, Italy
Nidal Maarouf, MD Consultant Cardiologist, Castle Hill Hospital, Kingston upon Hull, United Kingdom
Malcolm J. MacDonald, MD Clinical Assistant Professor, Department of Cardiothoracic Surgery, Division of Pediatric Cardiac Surgery, Stanford University School of Medicine, Stanford, Attending Surgeon, Pediatric Cardiac Surgery, Children’s Hospital of Central California, Madera, California, USA
Yasuki Maeno, MD Associate Professor of Pediatrics, Department of Pediatrics and Child Health, Kurume University School of Medicine, Staff Neonatologist, Maternal and Perinatal Medical Center, Kurume University Hospital, Kurume, Fukuoka, Japan
Binu Malhotra, MD Clinical Associate of Medicine, Rittenhouse Hospitalist Associates, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA
Efstathios Manios, MD Research Fellow, Department of Cardiovascular Sciences, University of Leicester College of Medicine, Biological and Psychological Science/University Hospitals of Leicester NHS Trust, Leicester, United Kingdom, Consultant, Department of Clinical Therapeutics, University of Athens School of Medicine/Alexandra Hospital, Athens, Greece
Calin V. Maniu, MD Cardiologist, Cardiovascular Specialists, Inc., Portsmouth, Virginia, USA
Barry J. Maron, MD Director, Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, Minnesota, Professor of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA
David Martins, MD, MS Assistant Professor of Medicine, College of Medicine, Charles Drew University of Medicine and Science, Los Angeles, California, USA
Thomas H. Marwick, MBBS, PhD Professor of Medicine, School of Medicine, University of Queensland, Director of Echocardiography, Princess Alexandra Hospital, Brisbane, Queensland, Australia
Gerald R. Marx, MD
Yasmin Masood, MD Assistant Professor of Medicine, Penn State University College of Medicine, Heart and Vascular Institute, Hershey, Pennsylvania, USA
Barry M. Massie, MD Professor of Medicine, University of California, San Francisco, School of Medicine, Chief, Cardiology Division, San Francisco VA Medical Center, San Francisco, California, USA
Henry Masur, MD Chief, Critical Care Medicine, National Institutes of Health Clinical Center, Bethesda, Maryland, USA
David McCarty, MBBCh Research Fellow, Harvard Medical School, Clinical and Research Fellow, Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA
Samy I. McFarlane, MD, MPH Professor of Medicine–Endocrinology, Medical Director of Clinical Research, SUNY Downstate School of Medicine, Chief, Division of Endocrinology, Department of Medicine, SUNY Downstate Medical Center, Attending, University Hospital of Brooklyn and Kings County Hospital, Brooklyn, New York, USA
William J. McKenna, MD, DSc, FRCP, FESC, FACC Professor of Cardiology, Institute of Cardiovascular Science, University College London Medical School, Clinical Director, The Heart Hospital, University College London Hospitals, NHS Foundation Trust, London, United Kingdom
Alison Knauth Meadows, MD, PhD Assistant Professor of Radiology and Pediatric Cardiology, University of California, San Francisco, School of Medicine, San Francisco, California, USA
Lise-Andree´ Mercier, MD Associate Professor of Medicine, University of Montreal Faculty of Medicine, Cardiologist, Adult Congenital Heart Center, Montreal Heart Institute, Montreal, Quebec, Canada
Luc Mertens, MD, PhD Associate Professor of Pediatrics, University of Toronto Faculty of Medicine, Section Head, Echocardiography, Hospital for Sick Children, Toronto, Ontario, Canada, Associate Professor of Pediatrics, University of Leuven Faculty of Medicine, Pediatric Cardiologist, University Hospital Leuven, Leuven, Belgium
Marco Metra, MD Institute of Cardiology, Department of Experimental and Applied Medicine, University of Brescia, Brescia, Italy
Bret Mettler, MD Fellow in Cardiac Surgery, University of Virginia School of Medicine/Medical Center, Charlottesville, Virginia, USA
Theo E. Meyer, MD, DPhil Professor of Medicine, University of Massachusetts Medical School, Chief of Clinical Cardiology, Director, Advanced Heart Failure Program and Heart Failure Wellness Center, UMass Memorial Medical Center, Worcester, Massachusetts, USA
Pierre-Louis Michel, MD Professor of Cardiology, Universite´ Pierre et Marie Curie–Paris VI, Chief, Division of Cardiology, CHU Tenon Hospital, Paris, France
John M. Miller, MD Professor of Medicine, Indiana University School of Medicine, Director, Clinical Cardiac Electrophysiology, Clarian Health System, Indianapolis, Indiana, USA
Mary Minette, MD Assistant Professor, Oregon Health & Science University, Director, Pediatric Echocardiography Laboratory, Doernbecher Children’s Hospital, Portland, Oregon, USA
Michelle C. Montpetit, MD Private Practitioner, Kane Cardiology, Geneva, Illinois, USA
Carlos A. Morillo, MD, FRCPC, FACC, FHRS, FESC Professor of Medicine, McMaster University Faculty of Medicine, Director, Arrhythmia and Pacing Service, Hamilton Health Sciences, Hamilton, Ontario, Canada
Cynthia D. Morris, PhD, MPH Professor of Medical Informatics and Clinical Epidemiology; Medicine (Research), Division of Cardiology; and Public Health and Preventive Medicine, Oregon Health & Science University School of Medicine, Portland, Oregon, USA
Lori Mosca, MD, MPH, PhD Professor of Medicine, Columbia University College of Physicians and Surgeons, Director, Preventive Cardiology, NewYork– Presbyterian Hospital, New York, New York
Barbara J.M. Mulder, MD, PhD Professor of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Francis D. Murgatroyd, MD, FRCP, FACC Director of Cardiac Electrophysiology, King’s College Hospital, London, United Kingdom
Daniel J. Murphy, Jr., MD Associate Professor of Pediatrics (Cardiology), Stanford University School of Medicine, Director, Congenital Cardiac Clinic, Stanford Hospital & Clinics, Stanford, Associate Chief, Pediatric Cardiology, Lucile Packard Children’s Hospital, Palo Alto, California, USA
Katherine T. Murray, MD Associate Professor, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Contributors
Associate Professor of Pediatrics, Harvard Medical School, Senior Associate in Cardiology, Children’s Hospital Boston, Boston, Massachusetts, USA
M.L. Myers, MD, FRCSC Associate Professor, Schulich School of Medicine & Dentistry, University of Western Ontario, Cardiac Surgeon, University Hospital, London Health Sciences Centre, London, Ontario, Canada
Rangadham Nagarakanti, MD Lead Clinical Research Physician, Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA
Shawna D. Nesbitt, MD Associate Professor of Internal Medicine, Division of Hypertension, University of Texas Southwestern Medical School, Dallas, Texas, USA
Pavlo I. Netrebko, MD Electrophysiology Fellow, Geisenger Medical Center, Danville, Pennsylvania, USA
L. Kristin Newby, MD, MHS Associate Professor of Medicine, Division of Cardiovascular Medicine, Duke University School of Medicine, Co-Director, Cardiac Care Unit, Duke University Hospital, Durham, North Carolina, USA
David Newman, MD Associate Professor of Medicine, University of Toronto Faculty of Medicine, Staff Physician, Division of Cardiology, St. Michael’s Hospital, Toronto, Ontario, Canada
Jens Cosedis Nielsen, MD, PhD, DMSc Associate Professor of Cardiology, University of Aarhus Faculty of Health Sciences, Chief Cardiac Electrophysiologist, Department of Cardiology B, Aarhus University Hospital Skejby, Aarhus, Denmark
Jan Nilsson, MD, PhD Professor of Experimental Cardiovascular Research, Department of Clinical Sciences, Lund University Faculty of Medicine, Malmo¨, Sweden
Sigurd Nitter-Hauge, MD, PhD Professor Emeritus, Department of Cardiology, University of Oslo Faculty of Medicine, Head, Medical Department B, Rikshospitalet, Oslo, Norway
xi
Contributors
Keith C. Norris, MD Professor of Medicine, Department of Internal Medicine, Executive VP for Research and Health Affairs, Charles Drew University of Medicine and Science, Los Angeles, California, USA
John B. O’Connell, MD Executive Director, Heart Failure Program, Heart and Vascular Institute, St. Joseph’s Hospital, Atlanta, Georgia, USA
E. Magnus Ohman, MD Professor of Medicine, Duke University School of Medicine, Associate Director, Duke Heart Center–Ambulatory Care, Director, Program for Advanced Coronary Disease, Duke University Medical Center, Durham, North Carolina, USA
Tanvier Omar, MBBCh, FRPath(SA) Lecturer in Anatomical Pathology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Principal Pathologist and Head, Division of Cytopathology, Department of Anatomical Pathology, National Health Laboratory Service, Johannesburg, South Africa
Suzanne Oparil, PhD, MD Professor of Medicine, Physiology, and Biophysics, Director, Vascular Biology and Hypertension Program, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA
Kristina Orth-Gome´r, MD, PhD Professor of Community Medicine, Department of Public Health Sciences, Karolinska Institute, Stockholm, Sweden, Charite´ University Medicine Berlin, Berlin, Germany
Catherine M. Otto, MD J. Ward Kennedy-Hamilton Endowed Professor of Cardiology, Director, Cardiology Fellowship Programs, Department of Medicine, Division of Cardiology, University of Washington School of Medicine, Associate Director, Echocardiography, University of Washington Medical Center, Seattle, Washington, USA
Richard L. Page, MD Professor and Head, Division of Cardiology, Robert A. Bruce Endowed Chair in Cardiovascular Research, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
Joseph E. Parrillo, MD Professor of Medicine, UMDNJ–Robert Wood Johnson Medical School, Chief and Edward D. Viner Chair, Department of Medicine, Director, Cooper Heart Institute, Cooper University Hospital, Camden, New Jersey, USA
xii
Ayan R. Patel, MD Associate Professor of Medicine, Tufts University School of Medicine, Director, Cardiovascular Imaging and Hemodynamic Laboratory, Tufts Medical Center, Boston, Massachusetts, USA
J. Norman Patton, MD Assistant Professor of Medicine, Mayo College of Medicine, Chair, Department of Cardiovascular Disease, Mayo Clinic Jacksonville, Jacksonville, Florida
Walter J. Paulus, MD, PhD, FESC Professor of Cardiac Pathophysiology, Department of Physiology, Faculty of Medicine, Free University, Amsterdam, Associate Director, Cardiovascular Center, VU University Medical Center, Amsterdam, The Netherlands
Naveen Pereira, MD Assistant Professor of Medicine, Mayo Clinic College of Medicine, Consultant, Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
Phillippe Pibarot, DVM, PhD, FACC, FAHA Professor of Medicine, Laval University Faculty of Medicine, Director, Research Group in Valvular Heart Diseases, Quebec Lung and Heart Institute, Quebec City, Quebec, Canada
Eduardo Pimenta, MD Hypertension Unit, Princess Alexandra Hospital, Brisbane, Queensland, Australia
Arnold Pinter, MD, FRCPC Assistant Professor of Medicine, University of Toronto Faculty of Medicine, Cardiac Electrophysiologist, St. Michael’s Hospital, Toronto, Ontario, Canada
Robert E. Poelmann, PhD Professor of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands
Piotr Ponikowski, MD Cardiology Department, Military Hospital, Wroclaw, Poland
Shakeel Ahmed Qureshi, MBChB, FRCP Honorary Senior Lecturer, Guy’s, King’s and St. Thomas’ School of Medicine, University of London, Consultant Paediatric Cardiologist, Evelina Children’s Hospital, Guy’s & St. Thomas Hospital Foundation Trust, London, United Kingdom
Michael Ragosta, MD Professor of Medicine, University of Virginia School of Medicine, Director, Cardiac Catheterization Laboratories, Director, Interventional Cardiology, University of Virginia Health System, Charlottesville, Virginia, USA
P. Syamasundar Rao, MD Professor of Pediatrics and Medicine, University of Texas Houston Medical School, Director, Division of Pediatric Cardiology, Children’s Memorial Hermann Hospital, Houston, Texas, USA
Rajni Rao, MD Asistant Professor of Medicine, University of California, San Francisco, School of Medicine, San Francisco, California, USA
Michael W. Rich, MD Professor of Medicine, Washington University in St. Louis School of Medicine, Director, Cardiac Rapid Evaluation Unit, Barnes-Jewish Hospital, St. Louis, Missouri, USA
Kurt C. Roberts-Thomson, MBBS, PhD, FRACP Electrophysiology Postdoctoral Fellow, School of Medicine, University of Adelaide Faculty of Medicine, Electrophysiology Fellow, Royal Adelaide Hospital, Adelaide, South Australia, Australia
Thompson Robinson, BMedSci, MD, FRCP Professor of Stroke Medicine, University of Leicester College of Medicine, Biological and Psychological Science, Honorary Consultant Physician, Department of Aging and Stroke Medicine, Leicester General Hospital, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom
Dan M. Roden, MD Professor of Medicine and Pharmacology, Director, Oates Institute for Experimental Therapeutics, Assistant Vice-Chancellor for Personalized Medicine, Vanderbilt University School of Medicine, Nashville, Tennesseee, USA
Carlos A. Roldan, MD, FACC, FASE Professor of Medicine, University of New Mexcio School of Medicine, Staff Cardiologist, University of New Mexico Health Sciences Center, Director, Echocardiography Laboratory, Raymond G. Murphy VA Medical Center, Albuquerque, New Mexico, USA
Jolien Roos-Hesselink, MD, PhD Associate Professor, Erasmus University Rotterdam, Cardiologist, Director, Adult Congenital Heart Disease Program, Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands
Prashanthan Sanders, MBBS(Hons), PhD, FRACP, FESC Knapman-NHF Chair of Cardiology Research, University of Adelaide, Director of Cardiac Electrophysiology, Royal Adelaide Hospital, Adelaide, South Australia
Nadir Saoudi, MD, PhD Professor and Chief, Cardiology Service, Princess Grace Hospital Center, Monaco (Principality)
Professor of Physiology, Justus-Liebig University Giessen, Giessen, Director Emeritus, Division of Thoracic and Cardiovascular Surgery, Max Planck Institute, Bad Neuheim, Germany
Heinz-Peter Schultheiss, MD Clinical Director, Department of Cardiology and Pneumology, Medical Clinic II, Charite´ University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany
Heribert Schunkert, MD Professor of Medicine, Faculty of Medicine, University of Lu¨beck, Head of Cardiology, Clinic for Internal Medicine II, SchleswigHolstein University Hospital, Lu¨beck, Germany
Prediman K. Shah, MD Professor of Medicine, David Geffen School of Medicine at UCLA, Director, Division of Cardiology, and Oppenheimer Atherosclerosis Research Center, Shapell and Webb Family Endowed Chair in Cardiology, Cedars-Sinai Heart Institute, Ceadrs-Sinai Medical Center, Los Angeles, California, USA
Joseph Shalhoub, BSc(Hons), MBBS (Hons), AICSM, MRCS(Eng) Clinical Research Fellow and Honorary Clinical Lecturer, Department of Vascular Surgery, Imperial College London School of Medicine, Honorary Registrar in Vascular Surgery, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
Robin D. Shaughnessy, MD Attending Pediatric Cardiologist Doernbecher Children’s Hospital Oregon Health & Science University Portland, Oregon
David M. Shavelle, MD, FACC, FSCAI Assistant Clinical Professor of Medicine, David Geffen School of Medicine at UCLA, Director, Interventional Cardiology Fellowship, Los Angeles County–Harbor UCLA Medical Center, Los Angeles, California, USA
Girish S. Shirali, MBBS Assistant Professor of Pediatric Cardiology and OB/GYN, Medical University of South Carolina College of Medicine, Director, Pediatric Echocardiography, Children’s Heart Program, Charleston, South Carolina, USA
Director, Heart Division, Consultant Cardiac Surgeon, Department of Cardiac Surgery, Royal Brompton and Harefield NHS Trust, London, United Kingdom
Alfonso Siani, MD Head, Unit of Epidemiology and Population Genetics, Institute of Food Sciences, CNR, Avellino, Italy
Domenic Sica, MD Professor of Medicine and Pharmacology, Virginia Commonwealth University School of Medicine, Chairman, Clinical Pharmacology and Hypertension, Virginia Commonwealth University Health System, Richmond, Virginia, USA
Agneta Siebahn, MD, PhD Professor of Coagulation Sciences, Department of Medical Sciences, Uppsala University Faculty of Medicine, Head, Coagulation Laboratory and UCR Laboratory, Department of Clinical Chemistry, Uppsala Clinical Research Centre, Uppsala University Hospital, Uppsala, Sweden
Henrik Sillesen, MD, DMSc Associate Professor of Medicine, University of Copenhagen Faculty of Health Sciences, Chief of Vascular Surgery, Department of Cardiology, Rigshospitalet, Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
David K. Singh, MD Chief Cardiology Fellow, Cedars-Sinai Medical Center, Los Angeles, California, USA
Gautam K. Singh, MD, MRCP, FACC Associate Professor of Pediatrics, Division of Cardiology, Washington University in St. Louis School of Medicine, Attending Pediatric Cardiologist, Director of Noninvasive Imaging Research, CoDirector, Echocardiography Laboratory, St. Louis Children’s Hospital, St. Louis, Missouri, USA
Allan C. Skanes, MD Associate Professor of Medicine, Division of Cardiology, Schulich School of Medicine & Dentistry, University of Western Ontario, Cardiologist, University Hospital, London Health Sciences Centre, London, Ontario, Canada
Otto A. Smiseth, MD, PhD Professor of Medicine, Department of Cardiology, University of Oslo Faculty of Medicine, Head, Division of Cardiovascular and Respiratory Medicine and Surgery, Rikshospitalet, Oslo University Hospital, Oslo, Norway
Frank C. Smith, MD Clinical Professor of Pediatrics, SUNY Upstate Medical University College of Medicine, Syracuse, New York, USA
Sidney C. Smith, Jr., MD Professor of Medicine, University of North Carolina at Chapel Hill School of Medicine, Director, Center for Cardiovascular Science and Medicine, Chapel Hill, North Carolina, USA
Alina Solomon, MD Researcher, Department of Neurology, Faculty of Medicine, University of Kuopio, Kuopio, Finland, Aging Research Center, Karolinska Institute, Stockholm, Sweden
Contributors
Wolfgang Schaper, MD, PhD
Darryl F. Shore, MD, FRCS
James R. Sowers, MD Professor of Medicine, Pharmacology, and Physiology, University of Missouri– Columbia School of Medicine, Columbia, Missouri, USA
George S. Stergiou, MD Associate Professor of Medicine, University of Athens School of Medicine, Hypertension Center, Third Department of Medicine, University of Athens Sotiria Hospital, Athens, Greece
Martin K. Stiles, MBcHB, PhD, FRACP Postdoctoral Fellow, University of Adelaide, Electrophysiology Fellow, Royal Adelaide Hospital, Adelaide, South Australia, Australia
Joshua M. Stolker, MD Resident, Department of Cardiology, MidAmerica Heart Institute, Saint Luke’s Hospital, Kansas City, Missouri, USA
Saverio Stranges, MD, PhD Associate Professor of Cardiovascular Epidemiology, Clinical Sciences Research Institute, University of Warwick Medical School, Coventry, United Kingdom
Mary Ellen Sweeney, MD Associate Professor of Medicine, Endocrinology, Diabetes and Lipid Metabolism, Emory University School of Medicine, Director, Lipid and Hypertension Clinics, Atlanta VA Medical Center, Atlanta, Georgia, USA
W.H. Wilson Tang, MD Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Staff Cardiologist and Director of Research, Section of Heart Failure and Cardiac Transplantation Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio, USA
Allen Taylor, MD Professor of Medicine, Uniformed Services University of the Health Sciences F. Edward He´bert School of Medicine, Chief of Cardiology, Walter Reed Army Medical Center, Washington, DC, USA
xiii
Christian Juhl Terkelsen, MD, PhD
Contributors
Department of Cardiology B, Aarhus University Hospital Skejby, Aarhus, Denmark
Udho Thadani, MD Professor Emeritus of Medicine, University of Oklahoma College of Medicine, Consultant Cardiologist, Oklahoma City VA Medical Center, Oklahoma City, Oklahoma, USA
Pierre Theodore, MD Van Auken Endowed Chair in Thoracic Oncology, Assistant Professor of Surgery, University of California, San Francisco, School of Medicine, Thoracic Oncology Program, UCSF Comprehensive Cancer Center, Medical Center Heart and Lung Transplantation Program, UCSF Medical Center, San Francisco, California, USA
John Thomson, BM, BS, MD, FRCP Senior Lecturer, School of Medicine, University of Leeds, Consultant Paediatric Cardiologist, Leeds General Infirmary, Leeds, United Kingdom
Dennis A. Tighe, MD Professor of Medicine, University of Massachusetts Medical School, Director, Ambulatory Cardiology, Associate Director, Non-invasive Cardiology, UMass Memorial Medical Center, Worcester, Massachusetts, USA
Christophe Tron, MD Head of ICU, Department of Cardiology, Charles Nicolle Hospital, Rouen, France
Hung Fat Tse, MBBS, MD, PhD William M.W. Mong Professor in Cardiology, Academic Chief, Li Ka Shing Faculty of Medicine, University of Hong Kong, Consultant Cardiologist, Queen Mary Hospital, Hong Kong, China
Anuradha Tunuguntla, MD Fellow in Cardiology, Louisiana State University School of Medicine/Health Sciences Center, Shreveport, Louisiana, USA
Hideki Uemura, MD, FRCS Consultant Cardiac Surgeon, Brompton Hospital, London, United Kingdom
Hirotsugu Ueshima, MD Professor, Department of Health Science, Shiga University of Medical Science, Otsu, Shiga, Japan
Peter van der Meer, MD, PhD Fellow in Cardiology, Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands
xiv
Frank Van Praet, MD Staff Surgeon, Department of Cardiovascular and Thoracic Surgery, Onze Lieve Vrouw (OLV) Hospital, Aalst, Belgium
Dirk J. van Veldhuisen, MD, PhD Professor of Cardiology, University of Groningen Faculty of Medical Sciences, Chief, Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands
Hugo Vanerman, MD Head, Department of Cardiovascular and Thoracic Surgery, Onze Lieve Vrouw (OLV) Hospital, Aalst, Belgium
Victoria L. Vetter, MD Professor of Pediatrics, University of Pennsylvania School of Medicine, Director of Electrophysiology, Medical Director, Youth Heart Watch (an affiliate of Project ADAM), The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Ronald G. Victor, MD Professor of Internal Medicine, University of Texas Southwestern Medical School, Norman and Audrey Kaplan Chair in Hypertension, Dallas Heart Ball Chair in Hypertension and Heart Disease, Director, Florence A. and Houston J. Doswell Center for the Development of New Approaches in the Treatment of Hypertension, Chief, Hypertension Division, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Renu Virmani, MD Medical Director, CV Path, International Registry of Pathology, Gaithersburg, Maryland, USA
Norbert F. Voelkel, MD Professor of Medicine, E. Raymond Fenton, M.D., Chair in Pulmonary Disease, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Director, Victoria W. Johnson Center for Obstructive Lung Disease Research, VCU Health System, Richmond, Virginia, USA
Wanpen Vongpatanasin, MD Associate Professor, Department of Internal Medicine, Division of Hypertension, University of Texas Southwestern Medical School, Dallas, Texas, USA
Anton Vonk-Noordegraaf, MD, PhD Associate Professor of Medicine, Department of Pulmonology, Faculty of Medicine, Vrije Universiteit, Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
J. Deane Waldman, MD, MBA Professor of Pediatrics and Pathology, University of New Mexico School of Medicine, Professor of Healthcare Strategy, Robert O. Anderson Graduate Schools of Management, University of New Mexico, Albuquerque, New Mexico, USA
Bruce D. Walker, MBBS, PhD Cardiologist, St. Vincent’s Hospital, Darlinghurst, New South Wales, Australia
Lars Wallentin, MD, PhD Professor of Cardiology, Department of Medical Sciences, Uppsala University Faculty of Medicine, Consultant, Department of Cardiology, Co-Director, Uppsala Clinical Research Center, Uppsala University Hospital, Uppsala, Sweden
David D. Waters, MD Emeritus Professor, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, California, USA
Gary Webb, MDCM Professor of Medicine, University of Pennsylvania School of Medicine, Director, Philadelphia Adult Congenital Heart Center, Hospital of the University of Pennsylvania and The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Gerdi Weidner, PhD Professor of Biology, San Francisco State University, Tiburon, California, USA, Professor of Psychology, Johannes Gutenberg University, Mainz, Germany
Peter Wenaweser, MD Assistant Professor of Cardiology, Faculty of Medicine, University of Bern, Attending Physician, Interventional Cardiology, Swiss Cardiovascular Center, Bern University Hospital, Bern, Switzerland
Jorge Wernly, MD W. Sterling Edwards Professor of Surgery, University of New Mexico School of Medicine, Chief, Division of Cardiothoracic Surgery, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
William B. White, MD, FACP, FAHA Professor of Medicine, University of Connecticut School of Medicine, Chief, Division of Hypertension and Clinical Pharmacology, Calhoun Cardiology Center, Lead Physician, Hypertension and Vascular Diseases Associates, Medical Director, Clinical Trials Unit, University of Connecticut Health Center/John Dempsey Hospital, Farmington, Connecticut, USA
William Williams, BSc, MDCM
Stephan Windecker, MD Professor of Medicine, Faculty of Medicine, University of Bern, Director, Invasive Cardiology, Bern University Hospital, Bern, Switzerland
Kai C. Wollert Professor of Medicine–Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
Mark A. Wood, MD Professor of Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
Fred M. Wu, MD Instructor in Pediatrics, Harvard Medical School, Assistant in Cardiology, Children’s Hospital Boston, Brigham and Women’s Hospital, Boston, Massachusetts, USA
Raymond Yee, MD Professor of Medicine, Division of Cardiology, Schulich School of Medicine & Dentistry, University of Western Ontario, Cardiologist, University Hospital, London Health Sciences Centre, London, Ontario, Canada
Glenn D. Young, MBBS, FRACP Senior Lecturer, School of Medicine, University of Adelaide Faculty of Medicine, Cardiac Electrophysiologist, Royal Adelaide Hospital, Adelaide, South Australia, Australia
James B. Young, MD Executive Dean and Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Chairman, Endocrinology and Metabolism Institute, Cleveland Clinic, Celeveland, Ohio, USA
Jonathan G. Zaroff, MD Adjunct Investigator, Kaiser Northern California Division of Research, Oakland, Staff Cardiologist, Kaiser San Francisco Medical Center, San Francisco, California, USA
Kenton J. Zehr, MD Professor of Surgery and Chief, Division of Cardiac Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
Contributors
Co-Chair, Undergraduate Cardiology Teaching, University of Ottawa, Staff Cardiologist, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
Michael R. Zile, MD Professor of Cardiology, Medical University of South Carolina College of Medicine, Charleston, South Carolina, USA
Alan Zajarias, MD Assistant Professor of Medicine, Cardiovascular Division, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
xv
Preface The primary goals of Cardiology were to (1) provide a global perspective on cardiovascular disease, rather than one focused almost exclusively on the USA; (2) provide a clinical focus with practical advice on prevention, diagnosis and treatment of heart disease supported by an expert’s summary of relevant scientific advances; (3) take advantage of advances in publishing technology to provide high-quality color illustrations and a web site for downloading the figures; (4) tightly organize the book for minimal redundancy, and employ color coding to aid navigation; and (5) create case-based special problems to cover issues that fall through cracks of most textbooks. We hoped to provide practicing cardiologists, cardiology trainees, and other physicians with an up-to-date clinical reference they could use in their everyday practice and an instructional resource they could use for teaching. That we largely succeeded is evidenced by the very positive reviews the first edition received; accolades such as Medical Book of the Year for 2002 by the British Medical Association; enough demand for a full-translation Spanish edition; and worldwide sales that considerably exceeded the publisher’s expectations. This success led to a second edition and now a third edition.
For this new edition, Michael Gatzoulis has joined the Section Editors. He is a recognized expert in congenital heart disease. A few chapters have been eliminated or merged into others as a result of changes in our understanding of certain diseases. Several new chapters have been added in areas where knowledge is rapidly expanding. In addition, many of the Special Problems have been eliminated or updated, or are new. Finally, all chapters have been extensively revised and the references updated. The Third Edition now includes access to a dedicated Expert Consult website, where the entire contents of the book and index can be searched and perused independently. We believe the changes outlined above have strengthened this successful textbook and have added to the quality, practical utility, and easy navigability of the first edition. Michael H. Crawford, MD John P. DiMarco, MD, PhD Walter J. Paulus, MD, PhD 2009
xvii
SECTION 1
ATHEROSCLEROSIS AND ITS PREVENTION
SECTION
1
CHAPTER
1
chapter
Pathogenesis of Atherosclerosis Go¨ran K. Hansson and Jan Nilsson
Definition n
ATHEROSCLEROSIS AND ITS PREVENTION: Pathogenesis of Atherosclerosis
1
Atherosclerosis is a focal disease of the inner layer of large and medium-sized arteries.
Key Features n
Atherosclerosis is an inflammatory and fibrotic disease of the arterial intima.
n
The basic lesion of atherosclerosis is a raised, focal, fibrofatty plaque or atheroma.
n
Atheromas contain a core of lipid, largely cholesterol, surrounded by a fibrous cap.
n
The development of atherosclerotic lesions is aggravated by risk factors including hypercholesterolemia, hypertension, smoking, and diabetes.
n
Inflow and accumulation of low-density lipoprotein and monocyte-derived macrophages in the arterial intima result in a fatty streak.
n
Cytokines and growth factors released from inflammatory cells promote the development of a fibrofatty plaque, which contains a cap of smooth muscle cells and collagen.
n
Clinical syndromes are usually caused by plaque activation.
n
This process appears to be precipitated by inflammatory activation and protease secretion in the plaque, which leads to fissuring and endothelial defects that elicit thrombosis.
n
The role of specific antigens, cytokines, and growth factors remains controversial, as does the possible role of microorganisms.
Clinical Implications n
Atherosclerosis is the underlying cause of approximately 90% of all myocardial infarction and a large proportion of strokes and ischemic gangrenes.
n
Atherosclerotic lesions can cause ischemic symptoms, such as angina pectoris, but do not usually lead to ischemic necrosis of the end organs unless thrombi form on their surfaces.
n
In addition to management of classic cardiovascular risk factors, treatment of atherosclerosis in patients with established coronary heart disease should focus on plaque stabilization.
n
Atherosclerosis is an inflammatory and fibrotic disease of the arterial intima.
n
The basic lesion of atherosclerosis is a raised, focal, fibrofatty plaque or atheroma.
n
Atheromas contain a core of lipid, largely cholesterol, surrounded by a fibrous cap.
Atherosclerosis is the most common cause of death and serious morbidity in the Western world. The World Health Organization has predicted that in the near future, it will also become the number one cause of mortality in the entire world.1 Atherosclerosis is a disease of elastic arteries (i.e., aorta, carotid, and iliac arteries) and large and medium-sized muscular arteries (i.e., coronary and popliteal arteries), whereas smaller arteries rarely become affected. It is part of a family of arterial disorders characterized by thickening and loss of elasticity of the vascular wall. The common term used for these diseases is arteriosclerosis, which literally means “hardening of the arteries.” The other diseases of this group include arteriolosclerosis, which is marked by proliferation and hyaline thickening of the walls of small arteries and arterioles, and Mo¨nckeberg’s medial calcific sclerosis, which is characterized by calcification of the media of muscular arteries. Atherosclerosis is by far the most common and important form of arteriosclerosis, and the terms are sometimes used synonymously. The disease process of atherosclerosis is primarily restricted to the intimal layer of the artery wall, which becomes infiltrated by lipids and inflammatory cells and develops various degrees of fibrosis. This observation has led to the belief that atherosclerosis is caused, at least in part, by activation of vascular repair responses. Arterial trauma initiates a healing reaction that involves phenotypic modulation of medial smooth muscle cells into fibroblast-like repair cells that migrate into the intima, where they proliferate and produce extracellular matrix. The accumulation of lipoprotein-derived lipids, including oxidatively and enzymatically modified components of low-density lipoprotein (LDL), is believed to damage the artery, to induce local inflammation, and to activate the repair process.2 This leads to formation of intimal lesions that may progress into atheroma. Although the atherosclerotic process is so strikingly located in the intima, other layers of the artery wall are not unaffected by the disease. The media behind plaques frequently shows atrophy, with loss of smooth muscle cells. This may be caused by a decreased supply of nutrients to the medial cells and by the fact that many of the medial smooth muscle cells have migrated into the intima. As a result of the medial atrophy, the artery dilates. However, even before this final phase, remodeling of the media occurs, tending to enlarge the vessel to accommodate the plaque and thus to preserve the dimensions of the lumen (Fig. 1.1).3 As a result, the artery may appear quite normal at an angiographic evaluation even though it is severely affected by atherosclerosis. This represents a serious problem in angiographic
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Figure 1.1 Remodeling of an atherosclerotic artery. During the initial stages of plaque growth, the artery may compensate for the increased intimal thickness by remodeling of the extracellular matrix in the media and the adventitia, leading to a more oval shape of the vessel.
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evaluation of atherosclerosis. In general, it can be assumed that once a plaque becomes visible at angiography, it is not a new plaque but rather the “tip of an iceberg.” Novel methods that visualize actual plaques rather than the lumen are being developed and are being used in clinical research. They include ultrasound imaging (particularly intravascular ultrasonography), computed tomography, and magnetic resonance imaging. By tagging of molecules that accumulate in lesions or certain types or areas of lesions, such structures can be visualized (e.g., by positron emission tomography or magnetic resonance imaging). For future studies, such molecular imaging is a promising approach. Atherosclerosis does not affect arteries uniformly; it is a focal disease. This is highlighted by the term plaque, which was used by the first pathologists who at autopsy described dotted lesions covering the aortic surface. The focal nature of the disease is in apparent contrast to the fact that most risk factors for development of atherosclerosis, such as hyperlipidemia, hypertension, smoking, and diabetes, are systemic and are likely to affect all parts of the arterial system similarly. This clearly shows that the systemic risk factors must act in concert with local factors. One such factor is the local shear stress exerted by the blood flow. Atherosclerotic plaques do not develop randomly in the arterial system. They are preferentially located close to branching sites in areas of low shear stress, where the time of interaction between blood-borne particles (such as LDL) and the lumen surface is increased. This is associated with increased transendothelial passage of lipoproteins and, when hyperlipidemia is present, increased accumulation of lipid in the subendothelial matrix.2 For reasons that remain to be fully understood, low shear stress is also associated with a local activation of proinflammatory genes that further contributes to the risk for lesion development at these sites.4 More recently, attention has focused on the role of microorganisms in atherosclerosis. Several epidemiologic studies have demonstrated an association between Chlamydia pneumoniae infection and cardiovascular disease.5Chlamydia, cytomegalovirus, and other pathogens have been found in vascular specimens removed at surgery, but it remains unclear whether they contribute to disease development or are “passengers” trapped in the lesions. Cell culture studies
support a pathogenic role for some of these pathogens. However, the observation from several randomized clinical trials that long-term treatment with antibiotics does not reduce coronary event rates has questioned the validity of the concept that bacterial pathogens contribute to atherosclerosis.6 It has become increasingly evident that the clinical symptoms of atherosclerosis are related not so much to plaque development and growth but rather to the degeneration and rupture of established plaques. Plaque growth by lipid accumulation and fibrosis rarely gives rise to lesions large enough to significantly limit blood flow (i.e., more than 75% lumen reduction). Even so, when plaques occur in the coronary arteries, the slow growth of a plaque gives ample time for small collateral vessels to develop. In the case of acute myocardial infarction and unstable angina, they can almost invariably be attributed to thrombus formation on ruptured lesions. Also, the rapid plaque growth that can sometimes be observed on sequential angiographic evaluations is probably caused by plaque rupture followed by fissure healing and encapsulation of the thrombus and other blood cells. Accordingly, it is likely that the treatment of atherosclerosis in patients with established coronary heart disease should primarily focus on achieving plaque stabilization. Experience from intervention trials using lipid-lowering agents (statins) also suggests that plaque stabilization may be a major factor responsible for the reduction in cardiovascular events. In this chapter, we first provide a brief overview of the anatomy of the normal arterial wall, the substrate for the disease. The cellular components of the artery as well as the inflammatory cells that infiltrate the arterial intima during atherosclerosis are discussed. The different histopathologic stages of atherosclerosis are described, and we finally discuss the pathogenesis of the disease and some of its complications. More detailed insights into the epidemiology of atherosclerosis and the biology of risk factors for the disease are provided in other sections of this volume.
ANATOMY AND CELL BIOLOGY OF THE ARTERIAL WALL Histologic Organization The normal artery has a very simple anatomy. It consists of three layers: the tunica intima, which forms a barrier between the artery wall and the circulating blood; the thick muscle layer, the tunica media; and a connective tissue layer, the tunica adventitia, which fuses with connective tissue of the surrounding organs (Fig. 1.2). The tunica media is the largest layer of the artery wall. It is composed of one single cell type, the vascular smooth muscle cell, which provides the bulk of the cell mass of the artery and also produces the extracellular matrix components of the media. The smooth muscle cells are elongated, spindleshaped cells that adhere to each other through junctional complexes. The cells are organized into circular layers that surround the arterial lumen in concentric circles. They produce large amounts of elastic fibers, which form lamellae between the layers of muscle cells. The media therefore has a multilayered organization: two elastic lamellae surround a layer of smooth muscle cells and form a lamellar unit. In elastic arteries such as the aorta, 20 to 50 such lamellar units build up the tunica media. In the smaller muscular
Figure 1.2 Histologic organization of the normal artery wall. This schematic drawing shows a cross section through the wall of a medium-sized muscular artery.
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Connective tissue
“Modified” smooth muscle cell
ATHEROSCLEROSIS AND ITS PREVENTION: Pathogenesis of Atherosclerosis
Endothelium Tunica intima
Internal elastic lamina Elastic lamellae
Smooth muscle
Tunica media
External elastic lamina Connective tissue
Neutrophil
Blood vessel (vas vasorum)
Nerve
Tunica adventitia
Macrophage
arteries, the organization is less developed, although layers of smooth muscle and elastic fibers can be discerned. The outermost elastic lamellae form a thick elastic membrane, the lamina elastica externa, which demarcates the border between the media and the adventitia. Similarly, the innermost elastic lamella, the lamina elastica interna, is thickened and constitutes the border between media and intima. The adventitia is a connective tissue structure that continues into the surrounding connective tissue stroma. Its inner part is fibrous and dominated by collagen and elastin, but this gradually gives way to loose connective tissue with increasing distance from the media. In addition to fibers, the adventitia contains fibroblasts, mast cells, adipocytes, and sympathetic nerve endings. It also carries blood and lymph vessels that penetrate into the outer third of the media. In the normal artery, the inner part of the media and the entire intima are avascular. However, during pathologic conditions such as atherosclerosis, angiogenic factors stimulate neovascularization that extends as far as the intima. The intima consists of a continuous, single-cell layer, the endothelium, and its basement membrane and a connective tissue layer with occasional primitive mesenchymal cells. In the newborn, this layer extends for only a few micrometers. However, it undergoes a progressive intimal thickening during life and can be several hundred micrometers thick in the adult aorta. This is caused by a continued accumulation of connective tissue fibers, proteoglycans, and mesenchymal cells. The mesenchymal cells appear to be “modified” smooth muscle cells that have lost contractile capacity and function as fibroblasts (i.e., by producing connective tissue elements). “Cushions” of increased intimal size and arterial disorganization are found at branching points in the arterial tree. Here, the endothelium exhibits increased permeability and has a higher proliferation rate. The intima is thickened, the lamellar organization of the media is disturbed, and the smooth muscle cells proliferate at an increased rate. These
sites are hot spots for cell division and tissue renewal and might contain vascular stem cells.7 It is also possible, however, that they represent a tissue response to increased hemodynamic strain because they are often found at sites of disturbed flow. It is striking that the anatomic distribution of atherosclerotic lesions overlaps with that of intimal cushions. It remains unclear whether the cushions are substrata for lesion formation or whether the same factors (e.g., hemodynamic strain) that induce cushion formation also promote atherosclerosis.8
CELLS OF THE ARTERY WALL Endothelial Cells The endothelial cell is a thin, elongated epithelial cell that is specialized to constitute a barrier and to control the bloodartery permeability. Its cytoplasm is filled with pinocytotic vesicles, which may form chains that penetrate through the cell, whereas the borders between adjacent endothelial cells are developed into junctional complexes with specialized structures that increase mechanical strength and control macromolecular permeability. Endothelial cells of arteries and veins, and those of most capillaries, form a continuous monolayer of polygonal cells that are tightly fitted to each other through such junctions. They develop embryonally from hemangiopoietic stem cells, which form blood islands as well as primitive endothelial sacks and tubes. The primitive endothelium penetrates all organs of the embryo, forming a continuous vasculature and recruiting local mesenchymal cells to develop into smooth muscle cells that surround the endothelial tubes. In adults, endothelial cells may also originate from bone marrow–derived stem cells, so-called endothelial progenitor cells. Whether treatment with such endothelial progenitor cells may improve myocardial function after an infarct is presently the subject of intense investigations.
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The endothelium has three important functions: to determine blood-tissue permeability, to control vascular tone, and to regulate the properties of the vascular surface with regard to hemostasis and inflammation (Table 1.1). Transendothelial permeability is delicately controlled and depends on the size and physicochemical properties of the molecules. Small uncharged gaseous molecules such as oxygen diffuse without much restriction across the endothelium, moving along a concentration gradient from blood to the extravascular space. Many other small molecules, including glucose, also exhibit little restriction against free diffusion across the endothelium. In arteries and veins, the supply of oxygen and nutrients largely occurs through transendothelial diffusion. Macromolecules, in contrast, penetrate the endothelium only to a limited extent, depending on their size. Thus, small proteins can pass through the interendothelial clefts, whereas large proteins and particles can reach the subendothelial space only through endocytotic vesicles. As discussed later, lipoproteins are among the particles that penetrate the endothelium in this way; they play a pivotal role in the initiation of atherosclerosis. Vascular tone is determined by the degree of contraction of the smooth muscle cell population of the artery. However, the endothelium controls smooth muscle contractility by releasing paracrine vasoactive mediators (see Table 1.1). Nitric oxide is an inorganic gas that is produced from L-arginine by an endothelial enzyme, nitric oxide synthase. This production occurs constitutively but is increased when the intracellular calcium level is raised in the endothelial cell as a result of the action of acetylcholine, bradykinin, and some other circulating mediators. Nitric oxide diffuses through the endothelial plasma membrane, passes the extracellular space, and activates an enzymatic cascade in the smooth muscle cell. This leads to smooth muscle relaxation and
FUNCTIONS OF THE VASCULAR ENDOTHELIUM Permeability regulator (filter function)
Regulator of vascular tone (regulation of smooth muscle contractility)
Regulator of hemostasis and inflammation
Large molecules
Vesicular transport Passage through intercellular junctions
Small molecules
Vesicles, junctions, and through the cytoplasm
Smooth muscle relaxation
Nitric oxide, others
Smooth muscle contraction
Endothelin, angiotensin II
Platelet adhesion and activation
von Willebrand factor, P-selectin, E-selectin, platelet-activating factor, PGI2 Thrombomodulin, heparan sulfate, others t-PA, u-PA, PAI-1
Coagulation
Fibrinolysis
PAI-1, plasminogen activator inhibitor; t-PA, tissue plasminogen activator; u-PA, urokinase-type plasminogen activator.
6
Table 1.1 Functions of the vascular endothelium.
reduced vascular tone. Other vasoactive endothelial factors counterbalance this effect. They include the vasoconstrictive peptide endothelin 1, which is expressed as a large preproendothelin polypeptide by the endothelial cell and proteolytically processed to generate active endothelin-1 during endothelial activation. Like endothelin-1, angiotensin-II also acts to contract smooth muscle cells. It is present as a circulating proform, angiotensinogen, which is processed to angiotensin II by enzymes expressed by endothelial cells. The endothelium exhibits active functions that are related to hemostasis, inflammation, and vascular tone (see Table 1.1). The endothelial surface contains a set of factors that regulate platelet adhesion, coagulation, and fibrinolysis. They include von Willebrand factor (a component of the coagulation factor VIII complex), surface molecules that are involved in platelet adhesion, coagulation-regulating factors such as thrombomodulin, and fibrinolysis-regulating factors such as plasminogen activators (tissue and urokinase type) and their inhibitor (plasminogen activator inhibitor 1). Several of these factors are stored in specialized intracellular organelles, Weibel-Palade bodies, that empty their content to the endothelial cell surface when the cell is activated by thrombin or some other mediators. Similarly, endothelial cells control the inflammatory properties of the vascular surface by expressing leukocyte adhesion molecules, such as E-selectin and the intercellular adhesion molecule-1; chemokines that promote the recruitment of leukocytes, such as monocyte chemotactic protein-1 and interleukin-8; and cytokines that can activate immune cells, such as interleukin-1. Prostacyclin (PGI2) is a bioactive lipid produced by the endothelium. It is a powerful inhibitor of platelet aggregation and also promotes vascular relaxation. Counterbalancing its effect, thromboxane A2 (TXA2) produced by platelets stimulates platelet aggregation. The balance between PGI2 and TXA2 determines whether platelet microthrombi are permitted to form on the endothelium. Under normal conditions, PGI2 dominates and prevents thrombus formation. Aspirin inhibits TXA2 formation to a greater extent than PGI2 formation and therefore prevents thrombosis, whereas cyclooxygenase-2 inhibitors (coxibs) reduce PGI2 production, which may lead to thrombosis.
Smooth Muscle Cells The smooth muscle cell is by far the most prevalent cell type in the artery, where it constitutes more than 95% of all cells. Smooth muscle cells contain myosin and actin filaments but have a less advanced contractile apparatus than the striated muscle cells of the heart and skeletal muscle. The vascular smooth muscle cell is particularly primitive and combines a capacity to change its tone with a fibroblast-like role as producer of the large extracellular matrix of the vessel wall. Smooth muscle cells are recruited from the local mesenchyme during embryonal development. This is probably initiated by a molecular signal from the embryonal endothelium, which induces mesenchymal cells to form a circular layer around the endothelial tube. In the adult artery, almost all smooth muscle cells are present in the medial layer. They are fitted to each other by junctional complexes that include tight and gap junctions. This not only increases the tensile strength of the smooth muscle layer but also permits rapid transfer of signaling molecules between
Infiltrating Leukocytes and Other Nonvascular Cells Macrophages form a small but significant component of the cell population in the normal artery. They are derived from blood monocytes, enter by interacting with leukocyte adhesion molecules on the endothelium (probably both the luminal endothelium and that of the vasa vasorum), and settle in the intima and the adventitia. Lymphocytes are also found in the artery, although not as frequently as macrophages. T cells are present in the intima and the adventitia, whereas B cells are largely confined to the adventitia. Periarterial lymph nodes are normally present along the aorta and its major branches. They permit immune activation by circulating antigens that penetrate into the arterial wall, from which they are transported to the local lymph nodes by lymph vessels of the arterial wall.
Mast cells, which are derived from hematopoietic stem cells and present throughout the connective tissue, are also found in the arterial wall, particularly in the adventitia. Adipocytes, finally, are common in the adventitia and a major cell type in the loose connective tissue that surrounds the artery. They are derived from local fibroblasts, and their size and number obviously depend on the nutritional state.
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cells throughout the arterial smooth muscle population. The contractile apparatus of smooth muscle cells is dominated by actin filaments that are mainly composed of a unique actin isoform, a-smooth muscle cell actin. Although the contractile filaments are associated with each other and form specialized structures termed dense bodies, they are not at all as well developed as in striated muscle, and no sarcomeres can be discerned. This reduces the contractile capacity of the smooth muscle cell compared with the striated one. In most of the arterial tree, the contractile repertoire of the smooth muscle cell is limited to changes in vascular tone. However, this not only permits fluctuations in blood pressure but also regulates perfusion of different organs and tissues. Smooth muscle tone is regulated by several mechanisms. Local regulation by the endothelium is of key importance, as mentioned before. In addition, metabolites produced by the surrounding tissue, autonomous nerve control from sympathetic nerve endings, and circulating mediators control smooth muscle tone. Together, all of these stimuli orchestrate a fine-tuned regulation of vascular tone, blood pressure, and local perfusion. The matrix produced by the smooth muscle is composed of two major types of fiber, elastic and collagen fibers, together with a ground substance containing a loose proteoglycan network. The elastic fibers are particularly important for the mechanical properties of the vessel media, whereas collagen is a major secretory product of smooth muscle cells in the intima. Smooth muscle cells as well as endothelial cells are normally quiescent cells that do not divide. However, vascular injury elicits a proliferative response in which medial smooth muscle cells divide, migrate into the intima, and then divide repeatedly to form an intimal thickening. This process, which resembles the restenosis observed after angioplasty and vascular surgery, is controlled by growth factors.9 Thus, the first round of replication in the media is initiated by the basic isoform of fibroblast growth factor, which is released from extracellular stores in the tissue. The subsequent migration and continued proliferation depend on stimulation by the platelet-derived growth factor (PDGF), which is released from adherent, activated platelets on the vascular surface, from infiltrating monocytes, and, at certain stages, from vascular endothelial and smooth muscle cells themselves. It has also been proposed that some intimal smooth muscle cells are derived from bone marrow–derived stem cells.7
HISTOPATHOLOGY OF ATHEROSCLEROSIS On the basis of morphologic studies performed by pathologists during many years, three types of atherosclerotic plaque have been described: n fatty streaks; n fibrous plaques; and n complicated lesions. Fatty streaks consist of intimal accumulations of macrophages filled with numerous lipid droplets (foam cells). The lipid droplets consist of cholesterol esters derived from oxidized or aggregated LDL that is taken up by a specific family of scavenger receptors. On gross examination, they are visible as yellow streaks that follow the direction of the blood flow. Fatty streaks do not affect the blood flow. In fibrous plaques, lipids are present both in macrophage foam cells and in the extracellular matrix. The intima is thickened because of accumulation of smooth muscle cells and extracellular matrix. Lipids and macrophages are usually most frequent in the core region, which also contains T lymphocytes and occasional B cells and mast cells. Smooth muscle cells and the extracellular matrix are more abundant in the subendothelial region, often forming a fibrous cap covering the lipid and inflammatory cells in the deeper part of the plaque (Fig. 1.3). In coronary arteries, fibrous plaques are often eccentric, covering only a part of the vessel. Even if fibrous plaques grow to significantly reduce the lumen of the vessel, they are not believed to be a major cause of clinical symptoms as long as they remain intact. However, fibrous plaques are heterogeneous in their nature, mainly depending on the balance between the amount of lipids and inflammatory cells on one hand and the amount of fibrous tissue on the other. Plaques with a thin fibrous cap and a large core of lipids and inflammatory cells have a high risk of rupture and are sometimes referred to as thin cap atheromas or vulnerable plaques. This risk does not appear to be dependent on the size of the plaque. Complicated lesions are plaques that in addition to lipids, inflammatory cells, and fibrous tissue also contain a hematoma or hemorrhage and thrombotic deposits. Complicated lesions predominantly develop as a result of a rupture of a fibrous plaque. Another possible cause may be bleeding from capillaries entering the plaque from the adventitial vasa vasorum. Bleeding from intraplaque capillaries may cause rapid plaque growth, and much of the cholesterol in such lesions is derived from erythrocyte membranes rather than lipoproteins. Fissures, erosions, and ulcerations in the fibrous cap and luminal surface are other frequent characteristics. The morbidity and mortality from coronary atherosclerosis derive mainly from these lesions; it is estimated that of all acute thrombotic events, about two thirds are caused by
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A
B /
Figure 1.3 Early stages of plaque growth in apoE mice. A, Early stage of a fibrous plaque consisting of a cap of smooth muscle cells and collagen covering a core of lipid-rich macrophages. B, A more advanced plaque with massive accumulation of macrophages (brown) in the core of the lesion.
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plaque ruptures, whereas one third are due to thrombus formation on an eroded endothelial surface with an intact fibrous cap. At older ages, these lesions often contain calcium deposits. The pathophysiologic relevance of these calcium deposits is not clear, but they may make the plaques more brittle and likely to rupture in response to tensile stress. Again, it may be useful to look on these different types of lesion from the perspective of healing reactions in response to injury. From this point of view, intimal lipid accumulation appears to play a key role as a cause of the vascular injury. The fact that macrophages are initially recruited to the intima suggests the presence of minor injuries caused by toxic effects of lipid accumulations in the extracellular matrix. The removal of extracellular lipids through macrophage uptake represents an effective early defense mechanism in response to this injury. The failure of this defense would then lead to formation of fibrous plaques. If macrophages were unable to remove toxic lipid products, resulting tissue injury would activate a repair process involving recruitment of smooth muscle cells from the media. A successful repair process would keep the intimal layer intact. However, if the repair process fails to fulfill its function, the fibrous component of the plaque will become too weak to resist the tensile forces of the blood flow and rupture. On the basis of their morphologic characteristics as well as experience from different animal models of atherosclerosis, it has been assumed that the three plaque types represent different stages of atherosclerosis and develop in a chronologic order from fatty streaks into fibrous plaques and finally into complicated lesions. However, as our knowledge about the atherosclerotic process has increased, it has become clear that this view does not sufficiently describe the complex nature of the disease. Only a certain population of fatty streaks appears to be at risk of progressing into more advanced lesions. The rapid changes in plaque characteristics
in response to rupture have important clinical implications that need to be taken into account. A new classification has been proposed by the American Heart Association Committee on Vascular Lesions, categorizing the process of lesion progression into eight different phases (Fig. 1.4).10 Although the terminology initially appears complicated, it has the advantage of integrating morphologic changes and clinical consequences in a way that is meaningful for both investigators and clinicians. It also takes into account the role of what
LESION MORPHOLOGY OF THE PROGRESSION OF CORONARY ATHEROSCLEROSIS Macrophages- Macrophages-SMC SMC lipid droplets extrac lipid lipid droplets
N
I
III
II
1-slow progression
Confl extra- Collag & SMC Collag & SMC Collagen layer lipid cellular lipid cap lipid core
IV
Va
Vb
- Mural - Occlusion - Reocclusion
Vc
VI
3-intermediate progression
2-rapid progression – disruption & thrombosis
Figure 1.4 Lesion morphology of the progression of coronary atherosclerosis according to the histopathologic findings. Collag, collagen; Confl, confluent; Extrac, extracellular; N, normal; SMC, smooth muscle cells.
visualize by angiography (see Fig. 1.1). Although type IV lesions are generally clinically silent, their recognition by intravascular ultrasonography, magnetic resonance imaging, or radiolabeled ligands with high affinity for vascular lesions will become important as they have the potential to rapidly develop symptom-producing ruptures. Thrombus formation on ruptured type IV lesions is the most likely explanation when occlusions or significant stenoses develop in a section of a coronary artery that on recent angiographic evaluation has appeared normal. Type V lesions are characterized by an increase in the fibrous tissue that covers the lipid core in type IV lesions. This fibrosis is caused by smooth muscle cells that proliferate and secrete extracellular matrix proteins such as collagen and proteoglycans. Animal experiments suggest that these smooth muscle cells are recruited from the media, where some cells undergo a phenotypic modulation into fibroblast-like repair cells. In contrast to the contractile smooth muscle cells, these “synthetic” smooth muscle cells contain abundant rough endoplasmic reticulum but no filament bundles. The human arterial intima, in contrast to that of most animals, normally contains some smooth muscle cells. It remains to be finally determined whether the cells that form the fibrous tissue in type V lesions in humans originate from the media or from preexisting intimal cells. Collagen often becomes the predominant feature of type V lesions and may account for most of the volume of the plaque. The ingrowth of capillaries is also more prominent than in type IV lesions. Type V lesions are often too large for the artery to compensate by remodeling, resulting in a narrowing of the lumen. The contour of these narrowings remains smooth, but they are usually detectable by angiography. Although type V lesions have more fibrous tissue than type IV, most ruptures still take place in this lesion type. Rupture-prone type V lesions typically have a thin layer of fibrous tissue at the border region between the plaque and the surrounding normal intima. This region is characterized by increased smooth muscle cell death and degradation of extracellular matrix by infiltrating inflammatory cells. Because type V lesions often invade the lumen and disturb the laminar blood flow, they are also more exposed to tensile forces. Type VI lesions are plaques that contain thrombotic deposits or hemorrhage. The major cause of development of type VI lesions is plaque rupture, and fissures, erosions, and ulcerations of the subendothelial fibrous tissue are frequently observed. It is also possible that development of type VI lesions may be a result of bleeding from the capillaries that reaches into the plaque from the vasa vasorum. The occurrence of clinical events, such as acute myocardial infarction and unstable angina, is with few exceptions dependent on a type VI lesion. However, development of type VI lesions can also take place in the absence of clinical symptoms. Autopsy studies in subjects who had coronary atherosclerosis but who died of noncardiac causes showed presence of recent intraplaque thrombus in 16% of those with hypertension and diabetes and in 8% of those without these factors. In another study of a population aged 30 to 59 years, 38% of those with advanced lesions in the aorta had thrombi on the surface of the lesions. Much of the thrombus that forms on top of a
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are considered physiologic changes in the vascular wall, such as adaptive intimal thickening. Human arteries normally have both thin and thick segments. These differences are already present at birth and reflect physiologic variations in shear and tensile forces. The thicker intima segments are found near branches and are called adaptive intimal thickening. They are self-limited in growth and never obstruct the blood flow. In cross section, an adaptive thickening is seen as an eccentric, crescentshaped increase of the outer wall of the bifurcation. The adaptive intimal thickening consists of a subendothelial layer of proteoglycan-rich extracellular matrix containing sparse smooth muscle cells covering a deeper layer of tissue with abundant elastic fibers, collagen, and smooth muscle cells. These intimal thickenings result from normal physiologic adaptation and are not regarded as part of the atherosclerotic process. However, at the same time, intimal adaptive thickenings appear to be particularly susceptible to the development of atherosclerotic lesions. The type I lesion is the earliest lesion and is characterized by minor lipid depositions and sparse macrophage foam cells. In the coronary arteries, type I lesions are usually colocalized with adaptive intimal thickenings, suggesting that the same shear stress factors that give rise to these changes also are involved in the formation of atherosclerotic plaques. Immediately after birth, 45% of infants have type I lesions. They become less frequent during the first years of childhood but begin to increase again around the age of 10 years. In type II lesions, macrophage foam cells are more numerous and organized in what is classically recognized as fatty streaks. Type II lesions also contain occasional T cells, mast cells, and lipid-filled smooth muscle cells. They are usually present at certain lesion-prone locations, and segments with adaptive intimal thickening are at greatest risk in this respect. The type III lesion is the first stage to be recognized by classic pathology as an atherosclerotic plaque or atheroma. The most important distinction versus type II lesions is the presence of small extracellular lipid deposits. This lipid accumulates in the deepest regions of the lesion below the macrophages and the T cells. The lipid deposits expand the extracellular matrix compartment and disrupt the cellular organization of the intima. The presence of type III lesions is believed to be predictive of future clinical disease. In type IV lesions, the amount of extracellular lipid has increased to form a continuous cell-free pool of cholesterol deposits. The lipid may be derived both from degenerating foam cells and from direct deposition of lipoprotein lipids. According to the old classification, the disease has now reached the stage of an advanced lesion. The lipid core is surrounded by inflammatory cells and covered by a thin layer of smooth muscle cells and connective tissue. Capillaries, originating from the adventitial vasa vasorum, start to grow into the deeper parts of the plaque. In accordance with the earlier lesions, type IV lesions initially develop at the same sites as adaptive intimal thickenings. Type IV lesions are generally crescent shaped and increase the thickness of the artery wall opposite the flow divider of a bifurcation. At this stage, the artery remodels to maintain its original lumen volume. The outer contour of the vessel becomes oval, and as a consequence, these lesions are difficult to
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ruptured plaque is likely to be removed by the fibrinolytic system, but some of the material can also be incorporated into the plaque, which reseals. This process is responsible for most cases of rapid plaque progression that can be seen with angiography. The thrombotic material gradually becomes colonized by smooth muscle cells, which convert it back to fibrous tissue. As a result of this healing process, the lesion returns to a type V morphology. Type VII and type VIII lesions are advanced plaques that have no or only minor amounts of lipids but contain masses of calcium deposits (type VII lesions) or predominantly consist of collagen (type VIII lesions). These lesions are believed to represent the end stage of the disease. Calcification is an age-related phenomenon and is widely present in the coronary arteries of subjects older than 70 years. Because calcification takes place in preexisting tissue, it does not generally contribute to plaque growth. The clinical importance of plaque calcification is unclear, but it is likely to make lesions less elastic and more sensitive to tensile forces. Type VIII lesions are more stable than type V and VI lesions. From a clinical point of view, much would be gained if type V and VI lesions could be converted into type VIII lesions. Lipidlowering intervention trials using angiographic endpoints have shown that the beneficial effect on cardiovascular events is much greater than can be expected from the modest effect on plaque size. This observation suggests that the effect of lipid-lowering treatment is plaque stabilization rather than plaque regression. This notion is also supported by studies demonstrating that statins decrease plaque lipids and inflammation and increase the plaque collagen content.11
PATHOGENESIS OF ATHEROSCLEROSIS Historical Background
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The mechanisms by which atherosclerotic lesions form and expand have puzzled scientists for 150 years. The brilliant German pathologist Rudolf Virchow proposed in 1856 that atherosclerosis is caused when plasma components (including lipids) elicit an inflammatory response in the arterial wall. Another pathologist, von Rokitansky, suggested that the atherosclerotic lesion is formed by organization of thrombi on the surface of the arteries. In the first years of the last century, a major piece was added to the puzzle when Anitschkov in St. Petersburg observed the large lipid deposits in atherosclerotic plaques, speculated that cholesterol might cause atherosclerosis, and tested this idea by feeding rabbits cholesterol. This led to atherosclerotic lesions similar to those in humans. A few years later, two other Russian investigators, Starokadomskij and Sobolev, showed that mechanical injury to the aorta leads to intimal lesions resembling atherosclerosis. This fitted in with Virchow’s hypothesis because injury would increase the infiltration of plasma components into the artery. In the 1950s, Florey and coworkers tied some of these observations together by showing that a de-endothelializing injury increases the accumulation of lipids and macrophages in the artery.12 With the advent of molecular medicine, it became possible to formulate more specific hypotheses for the pathogenesis of atherosclerosis. Ross and colleagues13 in 1974 proposed that arterial injury causes local release of PDGF from
adherent platelets or other cells. This would initiate a proliferative response in the smooth muscle population that could lead to atherosclerosis. An alternative hypothesis advocated by Benditt14 stated that atherosclerosis is due to uncontrolled smooth muscle cell proliferation similar to that in a benign tumor. The discovery by Brown and Goldstein15 of LDL receptors and the mechanisms of cholesterol metabolism permitted testing of the “cholesterol hypothesis” with efficient pharmacologic and genetic tools. It clearly showed, in humans as well as in experimental models, a direct correlation between serum cholesterol (in particular LDL-cholesterol) and the extent of atherosclerosis. With these findings, it became obvious that any hypothesis concerning the pathogenesis of atherosclerosis must attempt to explain the role of cholesterol in this disease. New genetic disease models based on disturbances in lipid metabolism in gene knockout mice have permitted a detailed dissection of pathogenetic steps and have advanced our understanding of atherosclerosis significantly during the last 10 years.16
ATHEROSCLEROSIS: A CURRENT HYPOTHESIS Studies of human lesions have identified molecules and cells that participate in the disease process. The recent development of genetic mouse models has made it possible to test the role of such specific factors in the formation and progression of atherosclerotic lesions. However, certain factors that may be of great importance in atherogenesis (e.g., several growth factors and adhesion molecules) cannot be studied by this approach because defects in the genes that encode these factors are not compatible with life. New technical achievements in knockout technology permit the induction of gene defects at a certain time point or in a certain tissue; the use of such methods has improved our understanding even further. A unifying hypothesis can now be proposed on the basis of these studies.2 It is presented here and outlined in Figure 1.5.
Low-Density Lipoprotein Accumulation and Modification The first detectable changes in an experimental animal subjected to proatherogenic stimuli, such as hypercholesterolemia, are an appearance of blood-derived lipids in the subendothelial intima and the expression of leukocyte adhesion molecules on the endothelial surface. When LDL levels rise in plasma, increasing amounts pass across the endothelium and into the intima. This process is enhanced at sites of increased transendothelial permeability, which are found at branches of the arterial tree. The elimination of LDL from the intima is limited because of the lack of a microvasculature in this region. The capacity to eliminate LDL is therefore quickly exceeded, and LDL is trapped in the extracellular matrix. Proteoglycans of the matrix have an affinity for LDL, which leads to binding of LDL to the matrix and the buildup of an LDL pool.17 In the intima, LDL undergoes a series of modifications that include aggregation, oxidation, and degradation of LDL components. They can be explained by an oxidative attack on the LDL particle, possibly by oxygen radicals generated
HYPOTHESIS FOR THE INDUCTION OF ATHEROSCLEROSIS
LDL
T
C
CC C'
LDL retention
LDL oxidation
ScR expression
Chemoattraction
Foam cell Cytokines SMC
Figure 1.5 Hypothesis for the induction of atherosclerosis. Lowdensity lipoprotein (LDL) enters the arterial intima through an intact endothelium. In hypercholesterolemia, the influx of LDL exceeds the eliminating capacity, and an extracellular pool of LDL is formed. This is enhanced by association of LDL with proteoglycans of the extracellular matrix. Intimal LDL is oxidized through the action of free oxygen radicals formed by enzymatic or nonenzymatic reactions. This generates proinflammatory lipids that induce endothelial expression of the adhesion molecule vascular cell adhesion molecule 1, activate complement (C0 ), and stimulate chemokine (CC) secretion. All of these factors cause adhesion and entry of mononuclear leukocytes, particularly monocytes (MC) and T lymphocytes (T). Monocytes differentiate into macrophages, a process that is promoted by local macrophage colony-stimulating factor secretion in the forming lesion. Macrophages up-regulate scavenger receptors (ScR), which internalize oxidized LDL and transform into foam cells. Macrophage uptake of oxidized LDL also leads to presentation of fragments of it to antigen-specific T cells. This induces an autoimmune reaction that leads to production of proinflammatory cytokines. Such cytokines include interferon-g, tumor necrosis factor-a, and interleukin-1, which act on endothelial cells to stimulate expression of adhesion molecules and procoagulant activity; on macrophages to activate proteases, endocytosis, nitric oxide, and cytokines; and on smooth muscle cells (SMCs) to induce nitric oxide production and to inhibit growth, collagen, and actin expression.
in tissue macrophages.18 However, it is unclear why the antioxidants that protect LDL from oxidation in the blood cannot prevent the same process in the intima. Oxidation of LDL is described in more detail in other sections of this volume.
Recruitment of Inflammatory Cells Oxidation of LDL leads to the release of modified lipids such as lysophosphatidylcholine. Several of these lipid species can act as signaling molecules that activate endothelial and smooth muscle cells.19,20 This leads to expression of the leukocyte adhesion molecule vascular cell adhesion molecule-1 (VCAM-1), which is a receptor for monocytes and T lymphocytes.21 Such cells express a “counterreceptor,” very late activation antigen-4, which can ligate VCAM-1 as well as certain matrix molecules on the vascular surface. In concert with other adhesion molecule interactions, VCAM-1 ligation
Foam Cell Formation The macrophage plays a pivotal role in the forming atherosclerotic lesion. By virtue of its capacity to internalize oxidized lipoproteins, it accumulates cholesterol and transforms into a lipid-laden foam cell, which is the prototypic cell of atherosclerosis. Brown and Goldstein, who received the Nobel Prize for their discoveries concerning lipoprotein receptors and cholesterol metabolism, observed that macrophages do not take up significant amounts of normal, native LDL. However, they can internalize huge amounts of oxidized LDL through a set of scavenger receptors.15,27 These cell surface receptors recognize “macromolecular patterns” containing clustered negative charges; such patterns are present on oxidized LDL but also on bacterial endotoxins and several other macromolecules.28 Such ligands are bound to scavenger receptors, internalized, and degraded in the lysosomes. Cholesterol esters that are present in oxidized LDL are hydrolyzed, and free cholesterol escapes into the cytoplasm. It is re-esterified by cytosolic enzymes, and a pool of cholesterol esters start to form intracellular droplets in the macrophage. With continued uptake of oxidized LDL, such lipid droplets pile up in the cytoplasm until the macrophage is transformed into a lipid-laden foam cell. The fatty streak is essentially an accumulation of foam cells together with some T cells and extracellular cholesterol (largely lipoproteins) under an intact endothelium. The scavenger receptor family, which includes the receptors SR-A, SR-B1, MARCO, CD36, and others, might have developed during evolution to protect us from endotoxinemia rather than to handle oxidized LDL,29 and the number of scavenger receptors on the surface of the macrophage is
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MC
leads to sticking of monocytes and T cells on the endothelial surface at sites of lipid accumulation and modification. Chemokines (i.e., chemotactic cytokines) are produced by macrophages, endothelial cells, and smooth muscle cells.22 Their induction appears to be related to lipid accumulation and oxidation,23 although the precise mechanisms are not fully clarified. In addition, aggregates of oxidized cholesterol induce complement activation, which also generates chemotactic signals.24 Both these stimuli can promote the migration of mononuclear cells from the endothelial surface, through intercellular clefts of the endothelial layer, and into the subendothelial intima. It is possible that other stimuli apart from lipids activate the endothelium and initiate leukocyte recruitment to the intima. In particular, heat shock proteins expressed during cell injury have been shown to activate the endothelium and to promote entry of monocytes and T cells.25 Interestingly, immunization with such heat shock proteins substantially aggravates atherosclerosis. Once present in the intima, monocytes differentiate into macrophages. This process is promoted by the cytokine monocyte colony-stimulating factor (M-CSF), which is produced by activated vascular cells. Because the monocyte is a relatively inert proform of the active macrophage, the differentiation process is of critical importance for pathology. This is illustrated by the observation that M-CSF–deficient mice do not develop atherosclerosis even if they are exposed to hypercholesterolemia or bred with atherosclerosis-prone mice.26
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not controlled by the intracellular cholesterol content. Therefore, the macrophage will continue to internalize oxidized LDL until its cytoplasm is overloaded with cholesterol ester. Scavenger receptors are regulated, however, by cytokines of the immune system and by metabolic factors other than cholesterol. In general, inflammatory cytokines tend to reduce receptor levels, whereas those cytokines that stimulate macrophage growth and differentiation up-regulate them. This focuses our attention on the inflammatory and immune aspects of the fatty streak. The Toll-like receptors (TLRs) are another family of pattern recognition receptors involved in atherosclerosis. The TLRs are an important part of the innate immune system and mediate a rapid inflammatory response to a number of different structures exclusively expressed by viral and bacterial pathogens. These receptors are abundantly expressed in human atherosclerotic lesions.30 Hypercholesterolemic mice lacking the TLR signal protein MyD88 develop less atherosclerosis, suggesting that hypercholesterolemia results in formation of endogenous ligands that react with TLRs and contribute to the formation of atherosclerotic plaques.31
IMMUNE INTERACTIONS IN THE FORMING LESION Antigens and Immune Activation
12
T cells, like macrophages, enter the arterial intima after binding to an activated endothelium. Almost all the T cells are of the memory-effector type (i.e., they have been primed by a previous encounter with their respective antigen in lymphoid organs).32 Once in the forming lesion, the T cells can be reactivated, provided their cognate antigens are present. In addition, there is a need for antigen-presenting cells because T cells, in contrast to B cells, cannot recognize free, soluble antigens. Instead, they require antigen to be “presented” in fragmented form and bound to major histocompatibility complex (MHC) molecules. In the plaque, antigen presentation appears to occur largely after uptake of antigen by macrophages, which present antigen fragments bound to MHC class II molecules (in humans, HLA-DR, DQ, and DP). Such antigen-MHC complexes are recognized by CD4þ T cells, which are the predominating T-cell type in the plaque. Recognition leads to activation, which is a chain reaction of intracellular signals. It causes production of autocrine growth factors, DNA synthesis, T-cell division, secretion of cytokines, and, in some cases, development of cytotoxic properties. As discussed later, the cytokines serve to transduce antigen recognition into effector mechanisms. Isolation and cloning of T cells from human plaques have revealed that a significant proportion of them recognize components of oxidized LDL.33 Therefore, LDL can be viewed as an endogenous particle that is transformed into an autoantigen by oxidation. Antibodies to oxidized LDL are present in high titers in patients with atherosclerosis as well as in experimental models of the disease. However, it remains unclear whether antibody titers actually predict extent of disease progression.34 In addition to oxidized LDL, several other candidate antigens have been proposed for atherosclerosis.35 They are listed in Table 1.2. Several of them, including heat shock protein 60, Chlamydia pneumoniae proteins, and oxidized
CANDIDATE ANTIGENS IN ATHEROSCLEROSIS Immune Responses Detected
Antigen
Type
Oxidized LDL
Autoantigen
Local and systemic Cell-mediated and humoral
Heat shock protein 60
Autoantigen, crossreacts with microbial antigens
Local and systemic Cell-mediated and humoral
Chlamydia pneumoniae
Microbial
Systemic Cell-mediated and humoral
Cytomegalovirus
Viral
Systemic Cell-mediated and humoral
Herpes simplex type I
Viral
Systemic Cell-mediated and humoral
Table 1.2 Candidate antigens in atherosclerosis.
LDL, not only function as T cell–dependent antigens but also act directly on macrophages to promote inflammation. This dual action of “atheroantigens” may be important for the progression of the disease.
Immune Cytokines and Effector Mechanisms T-cell cytokines produced after activation include proinflammatory cytokines that activate macrophages, endothelial cells, and smooth muscle cells but also cytokines that can inhibit inflammation and promote fibrosis. Different T-cell subtypes produce discrete sets of cytokines, which leads to different functional responses (Table 1.3). In the human plaque, most T cells are of the TH1 type, which causes macrophage activation and inflammation.36 Another proinflammatory T-cell subset, TH17, plays a major role in some other inflammatory diseases, but its role in atherosclerosis is still unclear. The most important TH1 cytokine is interferon-g, which has profound vascular activities. It activates endothelial cells to express adhesion molecules and procoagulant activity, inhibits smooth muscle cells from making actins and collagens, and modulates cell division in the vessel wall. In addition, and most important, interferon-g is a major macrophage-activating cytokine. It stimulates the macrophage to increase phagocytosis, to secrete inflammatory cytokines such as tumor necrosis factor-a (TNF-a) and interleukin-1, to release proteolytic enzymes, and to produce large amounts of toxic oxygen and nitric oxide radicals. In addition, TNF-a inhibits lipolytic enzymes, induces procoagulant activity, and changes the balance between fibrinolytic and antifibrinolytic factors on the endothelial surface.22 All of these effects act to promote atherosclerosis, and interferon-g appears to be the major cytokine causing the special form of arteriosclerosis that develops in transplanted organs. The proinflammatory TH1 effector activity is counterbalanced by regulatory T cells. These cells protect against autoimmunity and release anti-inflammatory cytokines such as interleukin-10 and transforming growth factor-b. They can also inhibit the activity of TH1 cells by direct cell-to-cell
SOME CYTOKINES EXPRESSED IN ATHEROSCLEROTIC LESIONS
Proinflammatory cytokines
Interferon-g
T cells (TH1-type CD4þ; CD8þ); NK cells
M activation, inflammation, EC and SMC activation, nitric oxide production, growth inhibition, reduced matrix formation, ScR regulation
IL-2
T cells
T-cell proliferation
IL-4
T cells (TH2)
Allergic responses, B-cell activation, T-cell proliferation
IL-12
M , EC, SMC
Induces TH1 responses
IL-10
M , T cells Treg
TH2 stimulation, TH1 inhibition
TNF-a
M , TH1 cells
Adhesion molecules, growth factors, prostaglandins, nitric oxide, proteases, procoagulant
IL-1
M , EC, SMC
Similar to TNF; promotes T-cell activation
IL-6
M , T cells, EC, SMC
Acute-phase proteins; B-cell activation
Chemokines
MCP-1
M , EC, SMC
Attracts MC and T cells
IL-8
M , T cells, EC, SMC
Attracts granulocytes
Growth factors
PDGF
Platelets, M , EC, SMC
SMC proliferation
bFGF
SMC, EC
SMC and EC proliferation
VEGF
M , SMC
EC proliferation
TGF-b
M , EC, SMC, Treg platelets
Growth regulation; fibrogenic; anti-inflammatory
M-CSF
M , T cells, EC
Stimulates M differentiation and ScR expression
GM-CSF
M , T cells, EC
Differentiation of MC and granulocytes
bFGF, basic fibroblast growth factor; EC, endothelial cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; MC, monocyte; M-CSF, macrophage colony-stimulating factor; MCP-1, monocyte chemoattractant protein 1; M , macrophage; PDGF, platelet-derived growth factor; ScR, scavenger receptor; SMC, smooth muscle cell; TNF, tumor necrosis factor; TGF, transforming growth factor; Treg, regulatory cells; VEGF, vascular endothelial growth factor.
Table 1.3 Some cytokines expressed in atherosclerotic lesions.
contact. Several lines of evidence have shown that regulatory T cells protect against atherosclerosis in hypercholesterolemic animals.37,38 The balance between the different subsets varies between organs, with time during the course of an inflammatory disease, and also with the metabolic state of the host. This appears to depend on the levels of antigen, the conditions under which antigens are presented, and the presence or absence of immune-regulatory cytokines such as interleukin-10 and interleukin-12. The latter has also been detected in atherosclerotic plaques, where it may promote proinflammatory immune responses.39 Although cytokines are soluble, hormone-like substances, some cell surface factors may also be important in cell-cell signaling during atherogenesis. CD40 is a cell surface receptor on macrophages, B cells, and vascular cells. It binds to CD40 ligand, another surface protein that is present on T cells (but under some conditions expressed also by vascular cells). Their interaction leads to immune activation. When it occurs in the forming atherosclerotic lesion, it is an important driving force for disease progression and appears to act in a manner similar to the proinflammatory cytokines.40 CD40 ligand and several other cell surface proteins display structural similarities to TNF-a, hence the name the TNF superfamily. Other family members such as lymphotoxin, OX40 ligand, LIGHT, RANK ligand, and CD137 have also been associated with atherosclerosis on the basis of genetic association, presence in lesions, and functional properties.2,22,41 Certain immune responses may be protective rather than proatherogenic. Thus, immunization with oxidized LDL inhibits atherosclerosis in several animal models.42,43 Similarly,
transfer of B cells from atherosclerotic to disease-prone mice protects them from severe disease.44 This seemingly paradoxical effect may be caused by production of protective antibodies or anti-inflammatory or otherwise vasculoprotective cytokines. Several therapeutic approaches that modulate immune activity have been used successfully to inhibit atherosclerosis in animal models. They include the use of polyclonal immunoglobulins45 and anti-CD40L antibodies,40 immunization with oxidized LDL,46 peptide fragments of apolipoprotein B,47 and anti–MDA-apoB peptide antibodies.48 We are now awaiting clinical studies of these approaches.
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Immuneregulating cytokines
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PROGRESSION FROM FATTY STREAK TO ATHEROSCLEROTIC PLAQUE The fatty streak is of no clinical significance. In fact, many of them disappear spontaneously. However, certain fatty streaks progress into true atherosclerotic, fibrofatty plaques. This characteristically occurs at sites of hemodynamic strain. Smooth muscle cells migrate to the subendothelial space, divide, and synthesize extracellular matrix. The result is a fibrous cap that separates the lipid-filled core of the lesion from the endothelial surface. It consists of fibrocyte-like, elongated smooth muscle cells surrounded by thick layers of their own matrix. The stimuli that induce fibrous cap formation probably act by inducing smooth muscle activation.2 Cell migration and proliferation will ensue, together with the synthesis by the cells of collagen and proteoglycans. In view of the
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focal localization of plaques, it is likely that local factors of the artery wall activate the smooth muscle cells. Most interest has been focused on growth factors, and data from vascular injury models show that basic fibroblast growth factor (bFGF) and PDGF can induce proliferation of quiescent arterial smooth muscle cells in vivo. In addition, PDGF acts as a chemotactic factor for smooth muscle cells. Whereas bFGF is deposited in the arterial extracellular matrix and can be released on injury, PDGF expression by endothelial cells can be up-regulated by flow changes.49 Hematopoietic cells can also release PDGF, and in particular, platelets and macrophages may be important sources of this growth factor. Interestingly, endothelial damage with defects covered by platelet microthrombi is observed in this phase of the disease in experimental models. A plausible scenario for the transition from fatty streak to fibrous plaque is therefore that hemodynamic stress or inflammatory activation causes growth factor release from platelets or macrophages. This stimulates smooth muscle cells to migrate, divide, and form the fibrous cap. The lipid core has been physically separated from the endothelial surface, and the plaque is stabilized. The price for this is obviously an encroachment on the lumen of the artery.
PLAQUE ACTIVATION AND THE PRECIPITATION OF CLINICAL SYNDROMES
14
The progressive reduction in luminal size can lead to clinical syndromes such as effort angina and intermittent claudication, but it is remarkable that even very large plaques may be completely asymptomatic. The development of acute clinical complications usually requires an additional pathogenetic event to occur, which is the formation of a thrombus on the plaque.50 When this takes place, acute coronary syndromes such as myocardial infarction are observed. In other vascular beds, transitory cerebral ischemic attacks, brain infarction, and acute ischemic gangrene are caused by plaque thrombosis. Several lines of research have established the role of thrombosis in the precipitation of acute ischemia. Injection of radioactive fibrinogen into patients with acute coronary syndromes has revealed incorporation into fresh coronary thrombi, and histopathologic analysis of coronary arteries has made it possible to identify mural thrombi on “culprit lesions.” Interestingly, such lesions almost always show evidence of surface damage; approximately 80% of them exhibit small fissures through the endothelium and down into the plaque, whereas the remaining 20% appear to have areas of endothelial desquamation.51,52 Such surface defects lead to exposure of prothrombotic subendothelial material and will rapidly result in thrombosis. The superficial fissures found in most culprit lesions have been taken as evidence of plaque rupture. This term does not imply a crack through the entire endothelial wall; rather, the intimal plaque structure or part of it fissures. A plaque fissure usually extends from the endothelial surface through the fibrous cap and down into the lipid core of the plaque.
Why do plaques rupture? An important clue came from the observation that activated macrophages, T cells, and mast cells abound in the vicinity of the rupture.53,54 This points to an inflammatory mechanism as the inducer of rupture. Such an interpretation is supported by the finding of circulating cytokines and activated T cells in patients with acute coronary syndromes such as unstable angina.55 Subsequent immunohistochemical, biochemical, and cell biological studies have made it possible to propose a scenario for plaque activation and rupture.2,56 According to this hypothesis (Fig. 1.6), inflammatory cells of the plaque are activated by proinflammatory lipids, cytokines, antigens, or microbes. The ensuing immune or inflammatory activation results in macrophage activation. As part of it, the macrophage releases matrix metalloproteinases, which are enzymes that digest the collagen of the fibrous cap. Proinflammatory cytokines present in the inflammatory area prevent rebuilding of the collagen fibers by inhibiting collagen gene expression. Such cytokines (in particular, interferon-g and TNF-a) also inhibit smooth muscle proliferation and actin gene expression, which eliminates the mechanisms for repair of the fibrous cap. Cytotoxic oxygen and nitric oxide radicals released by the macrophages contribute to the process by causing apoptotic cell death. All of these events reduce the tensile strength of the fibrous cap to such an extent that it succumbs to the mechanical stress exerted by the pulsating blood flow. Advanced plaques contain cells that produce prostaglandinlike molecules called leukotrienes.57,58 They are bioactive lipids with proinflammatory and vasoconstrictive effects. Molecular epidemiologic studies identify genes controlling
HYPOTHESIS FOR PLAQUE ACTIVATION
Thrombus
EC
Collagen
Mast cell Smooth muscle cell
T cell
Macrophage
Figure 1.6 Hypothesis for plaque activation. Inflammatory activation in coronary plaques may be induced by lipids, cytokines, antigens, or microorganisms. Activated macrophages release matrix metalloproteinases, which digest collagen fibers of the plaque cap. Activated T cells produce cytokines, which inhibit proliferation and collagen secretion by cap smooth muscle cells. Activated mast cells release proteases such as chymase, which can also degrade cap structures. All of these factors weaken the fibrous cap, which eventually leads to the formation of fissures in the surface of the plaque. Such fissures serve as sites for thrombus formation by exposing subendothelial adhesive and procoagulant structures and also because inflammation can induce tissue factor expression by plaque cells. Thrombi may build up to eventually occlude the lumen; this precipitates myocardial infarction. EC, endothelial cell.
SUMMARY Is atherosclerosis a metabolic, inflammatory, infectious, or hemodynamic disease? In the past, scientists have debated whether atherosclerosis should be considered a disturbance of cholesterol metabolism, an inflammatory and fibrotic disease of the vessel wall, or a dysregulation of hemodynamic homeostasis. As evident from this chapter, all of these factors participate in the formation and activation of atherosclerotic plaques. Without hypercholesterolemia, it is unlikely that LDL would accumulate in the intima. Therefore, the chain of events that leads to atherosclerosis would never start. This view is confirmed by the success of lipid-lowering therapy against cardiovascular disease.
It could equally well be claimed that atherosclerosis would not occur if inflammatory cells did not enter the vessel wall. A large body of evidence shows that the disease can be prevented if leukocyte adhesion or macrophage differentiation cannot take place. Similarly, disease progression is retarded dramatically when immune activation is prevented. The acceleration of disease in hypertension and the success of antihypertensive therapy show that a disturbed blood flow should be considered an important aggravating factor for atherosclerosis. Similarly, hemostatic factors, including those regulating platelet adhesion, humoral coagulation, and fibrinolysis, are involved in plaque activation. Blocking of platelet adhesion is an important therapeutic strategy against complications of angioplasty and vascular surgery and, together with anticoagulant therapy, also in acute coronary syndromes and cerebral and peripheral ischemia. Our limited understanding of the roles of diabetes and smoking in the pathogenesis of atherosclerosis is in striking contrast to our knowledge of the effects of hypercholesterolemia and hypertension. Diabetes may act by perturbing the local carbohydrate metabolism in the vessel wall, but it could also affect the regulation of cellular functions by affecting growth regulation through insulin-like growth factors. Furthermore, hyperglycemia, which is usually present in diabetes, may result in nonenzymatic glycation of extracellular proteins, which is followed by uptake through specific receptors, resulting in both intracellular accumulation and signaling pathways that may affect hemostasis, angiogenesis, and cellular activation. Finally, non–insulin-dependent diabetes mellitus is often part of a metabolic syndrome that also includes hypertriglyceridemia and abdominal obesity. Abnormal triglyceride metabolism, which is part of this syndrome, may modulate vascular gene expression through specific transcriptional mechanisms (in particular through so-called peroxisome proliferator-activated receptors) and also cause release of proinflammatory cytokines from adipose tissue. Intense research into these aspects of diabetes and the metabolic syndrome may lead to new concepts of these risk factors for atherosclerosis within the next few years. Information concerning smoking as a pathogenic factor in atherosclerosis is even more limited than information about diabetes. Epidemiologic studies show that the proatherogenic effect is not due to nicotine. Scientists have therefore proposed that complex biomolecular components of tar and cigarette smoke may damage endothelial cells or activate immune mechanisms. However, no definitive evidence links any of these factors to atherosclerotic disease. It is apparent from this brief summary that several factors are epidemiologically linked to atherosclerosis, and at least three of them—hypercholesterolemia, inflammation, and hypertension—can be placed in a pathogenetic scheme. Our final conclusion must therefore be that atherosclerosis is a true multifactorial disease. The formation, progression, and activation of atherosclerotic plaques require an interaction between metabolic, inflammatory, hemodynamic, and hemostatic factors. All of them may turn out to be important targets for therapy, and all of these pathways are worth exploring in trying to develop new therapies against this major lethal disease of the Western world.
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leukotriene biosynthesis as risk factors for cardiovascular disease,59 and experimental studies show important, proatherogenic effects of leukotrienes on vascular endothelial and smooth muscle cells.60 When blood components are exposed to the subendothelium, platelets are immediately activated. They adhere to the surface and start to aggregate. A set of surface receptors mediate attachment between the platelet and the tissue; they include glycoprotein IIb/IIIa, which binds fibrinogen, and glycoprotein Ib, which binds the von Willebrand factor. Adenosine diphosphate and other factors released by the adhering platelet induce activation of other platelets, and the exposure of platelet membrane structures promotes activation of the humoral coagulation cascade. This is initiated when the protein tissue factor (thromboplastin) is exposed on the surface. It can be induced on macrophages, endothelial cells, and smooth muscle cells by proinflammatory cytokines and the CD40 system. Thus, inflammatory and immune activation promotes thrombosis in two ways: by causing plaque rupture and by inducing tissue factor expression.2,56 In addition to tissue factor, cofactors such as membrane phospholipids and the von Willebrand–factor VIII complex are also important for humoral coagulation. The end result is the formation of a fibrin clot that surrounds and stabilizes the platelet thrombus. With the formation of a solid thrombus, an acute coronary syndrome is often precipitated. However, defense mechanisms intrinsic to the blood and vessel wall may counteract thrombosis and prevent or eliminate complete obstruction. The most important of these defense mechanisms is the fibrinolytic system. It is a proteolytic cascade that is activated by plasminogen activators (tissue plasminogen activator and urokinase-type plasminogen activator), both of which can be expressed by endothelial cells. An inhibitor of fibrinolysis, the plasminogen activator inhibitor 1 (PAI-1), is also expressed by endothelial cells, and the balance between fibrinolysis and antifibrinolysis is therefore pivotal for the control of thrombus formation. By modulating the expression of plasminogen activator and PAI-1 genes, proinflammatory cytokines are important regulatory factors of this balance. Research into the pathogenetic mechanisms that lead from silent atherosclerosis to myocardial infarction have been hampered by lack of suitable models. However, new mouse models may be useful for dissecting the pathogenetic sequence of acute coronary syndromes.61,62
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chapter
Genetics of Atherosclerosis Heribert Schunkert and Jeanette Erdmann
n
Myocardial infarction in a first-degree relative (man < 55 years, woman < 65 years) is an established cardiovascular risk factor.
n
Positive family history increases the risk of myocardial infarction 1.5- to 2.0-fold.
n
Twin and family studies revealed an estimate for heritability (h2) of up to 60% for myocardial infarction.
n
Some features of coronary disease, including calcification, left main disease, and proximal location of lesions, carry a high heritability.
n
In rare cases (10,000 cases and 10,000 controls), no negative study, positive association results in different ethnicities 9p21.3
Unknown
18, 37-44
II. Beyond controversy (at least in one ethnicity) More than two large independent replication studies (>1000 cases and 1000 controls) in the same ethnicity, negative association results in different ethnicities, positive meta-analysis LP(a)
Lipoprotein
45
ApoE4
Lipoprotein handling
46
LPL
Lipoprotein lipase
40
CETP
Lipoprotein handling
47
PCSK9
Lipoprotein handling
48
LDLR
Lipoprotein handling
70
LTA
Inflammation
49
Galectin 2
Inflammation
50
ALOX5AP
Inflammation
51
LTA4H
Inflammation
52
III. Still controversy More than three small independent replication studies (40 inches for men or >35 inches for women 2. triglycerides 150 mg/dL 3. HDL-cholesterol 55 yr (men/women)
All >20 yr (men/women)
People with known cardiovascular risk factors
All with 1þ risk factor, diabetes, or evidence of atherosclerosis
All with diabetes, multiple risk factors, or family history of premature cardiovascular disease
All >35/>45 yr (men/women) with known risk factors or a high risk of diabetes
All >20 yr (men/women)
Ethnic groups Maori, Pacific peoples, and people from the Indian subcontinent
—
—
All >35/>45 yr (men/women)
—
The International and Australian guidelines do not provide any clearly defined guidance on selecting people for risk assessment.
Table 4.4 Recommended guideline criteria for use of cardiovascular risk assessment in individuals without cardiovascular disease.
measurement of all major risk indicators (Table 4.5), because the magnitude of cardiovascular risk is determined by the synergistic effect of the combined risk factors. The assessment of people with diabetes differs between the guidelines. For example, diabetes is not listed in the calculations of the American National Cholesterol Education Program and the Canadian guidelines, as people with diabetes are categorized as coronary heart disease equivalents.33 Most other guidelines consider diabetes a risk factor and include it in the risk assessment. The New Zealand guidelines, for example, make a 5% 5-year cardiovascular risk adjustment to patients with diabetes diagnosed more than 10 years, in addition to the weighting given to diabetes in the Framingham-based risk score.30 Only the UKPDS risk score34 requires measurement of blood glucose concentration for inclusion in the algorithm. Most guidelines now recognize the “metabolic syndrome,” in which clustering of cardiovascular risk indicators is associated with increased risk of a cardiovascular event.35 Three or more of the five risk factors (all continuous variables that have been arbitrarily dichotomized) are required for a diagnosis of metabolic syndrome according to the U.S. National Cholesterol Education Program criteria (Table 4.6). However, identification of metabolic syndrome is not formally incorporated into any of the risk calculators, and currently, none of the guidelines suggest automatic adjustment for the metabolic syndrome in the calculated cardiovascular risk. Its measurement is therefore mainly as a guide to clinicians to intensify attainment of treatment goals or to consider intervention for individuals who would otherwise be assessed to have intermediate risk (most likely the young). In addition, certain emerging risk factors and measures of subclinical atherosclerosis (see Table 4.3) may be used as adjuncts to the major risk factors in assessing risk, although data on their added value in determining the absolute risk of cardiovascular disease are limited. Assessment of these risk indicators should be limited to special circumstances in which the decision to intervene is uncertain on the basis of standard risk factors. Only the U.S. National Cholesterol Education Program guidelines33 advocate vascular imaging or measurement of high-sensitivity C-reactive protein in these cases.
RISK INDICATORS TYPICALLY MEASURED AND RECORDED IN ASSESSING CARDIOVASCULAR RISK Age Gender Ethnicity* Smoking history Lipid profile (note: fasting is unnecessary for total cholesterol or HDL-cholesterol level) Fasting plasma glucose concentration/diabetes Blood pressure Family history of premature cardiovascular disease Body mass index/waist circumference Presence of left ventricular hypertrophy *Not all guidelines take ethnicity into account in assessing risk.
Table 4.5 Risk indicators typically measured and recorded in assessing cardiovascular risk.
CLINICAL IDENTIFICATION OF THE METABOLIC SYNDROME, ACCORDING TO THE NATIONAL CHOLESTEROL EDUCATION PROGRAM Risk Factor
Defining Level
Abdominal obesity Men Women
Waist circumference 102 cm* 88 cm*
Triglycerides
1.7 mmol/L
HDL-cholesterol Men Women
2
Europe
Fatal CVD risk
0.5
New Zealand
Fatal and nonfatal CVD risk
>3
Moderate-Intermediate
1-2
Low 5.3
1.0 1.2 1.5 1.9 2.3 2.8 3.5 > 4.1
Absolute risk
Absolute risk‡
Total CHD‡
Total CHD¶
2% 3% 4% 5% 7% 8% 10% 13% 16% 20% 25% 31% 37% 45% > 53%
2% 2% 3% 4% 5% 6% 7% 9% 13% 16% 20% 25% 30% 35% > 45%
Color key for relative risk Green Below average risk Blue Average risk Yellow Moderately above average risk
Red High risk
* Low absolute risk level = 10-year risk for total CHD endpoints for a person the same age, BP 7% after 2–3 months with optimum titration
No
Continue current therapy
Yes
Increase in total mortality (P < .04)
Add insulin
Add a sulfonylurea or glinide
Add a glitazone
Table 6.6 Glucose lowering and cardiovascular risk in diabetes.
in blood pressure, lipid profiles, and HbA1c. Referral to a nutritionist or, in the case of cardiac patients, participation in a cardiac rehabilitation program should be recommended in all sedentary or overweight patients. The next step in control of hyperglycemia is the addition of medications. Naturally, the lead should come from the patient’s diabetologist or internist (if there is one). The effectiveness of the current therapies rests not only on the intrinsic characteristics of the drugs but on the level of hyperglycemia, the degree of insulin resistance, the duration of diabetes, and other factors. The mainstay of oral therapy is the biguanide metformin. A suggested flow diagram for treatment options appears in Figure 6-2. On the basis of the UKPDS, it would seem that monotherapy with the hepatic insulin sensitizer metformin in the obese patient in whom diet and exercise are failing to maintain control would be the best approach. Metformin has the advantage of a favorable lowering of triglycerides and of causing less weight gain than the sulfonylureas (indeed, many patients may lose a small amount of weight). For the nonobese patient who has type 2 diabetes, sulfonylurea therapy may be appropriate first-line therapy.5 Sulfonylureas act by enhancing insulin secretion and may lower HbA1c by up to 1.5%. The glinides repaglinide and nateglinide are another class of oral hypoglycemic agents that also enhance insulin secretion but bind to a different insulin receptor and have a much shorter circulating half-life. They are given immediately before meals and are ideal in patients with an erratic daily routine. In general, they produce less hypoglycemia. Sulfonylurea or glinide plus metformin combinations may also be used when the
*Goal HbA1c is 180 mg/ dL), intensive insulin therapy should be considered to treat to a goal of 90 to 140 mg/dL with care to avoid hypoglycemia. 3. In non–intensive care patients, glucose levels should be maintained below 180 mg/dL through the use of subcutaneous insulin regimens.
Inpatient Hyperglycemia
66
Inpatient hyperglycemia has gradually come to the forefront as the number of patients with diabetes as a discharge diagnosis has increased dramatically. The treatment of hyperglycemia in the acute care setting has remained haphazard for a number of reasons, the most prominent being the perception that hypoglycemia should be avoided at all costs. Not only are patients with diabetes at risk, but the common phenomenon of stress hyperglycemia is often overlooked in nondiabetic patients admitted to the hospital. A Swedish study showed that 31% of patients admitted for acute myocardial infarction had hyperglycemia at the time of discharge.46 Hyperglycemia contributes to overall morbidity and mortality in the hospitalized patient regardless of the initial diagnosis. A meta-analysis of 15 studies of patients with and without diabetes hospitalized for acute myocardial infarction
Cardiologists treating patients admitted to the hospital, whether as a consultant or the admitting physician, should be cognizant of these glycemia goals. In patients with documented hyperglycemia either with or without a prior diagnosis of diabetes, consultation with an endocrinologist should be considered early in their hospitalization to institute appropriate insulin regimens.
Lipid Management Many data, ranging from early data of the Framingham study53 to more recent data of follow-up studies of men (the Multiple Risk Factor Intervention Trial7) and women (the Nurses’ Health Study8), have demonstrated the predictive power of cholesterol levels, both low-density lipoprotein (LDL) cholesterol (positively) and high-density lipoprotein
Lung, and Blood Institute, which addressed the implications of five major clinical statin trials that had been published since NCEP III. They confirmed the benefit of therapeutic lifestyle intervention and the NCEP III LDL-cholesterol goal of less than 100 mg/dL (2.6 mmol/L) for diabetics and patients and non–HDL-cholesterol goal of less than 130 mg/dL. In addition, they introduced the term very high risk, which identifies patients with CAD who have one or more additional risk factors that confer a very high risk of near future events. For these patients, the suggested treatment goal is less than 70 mg/dL (1.8 mmol/L), even if the baseline LDL level is already below 100 mg/dL (2.6 mmol/L). For moderately high risk patients (2þ risk factors and a 10-year risk of 10% to 20%), the recommended LDL-cholesterol goal is less than 100 mg/dL (2.6 mmol/L) but with the therapeutic option of less than 70 mg/dL. It is also suggested that when a patient at high or very high risk also has a high triglyceride level or low HDL-cholesterol concentration that consideration be given to the addition of a fibric acid or niacin (Table 6.7). The ADA1 also recommends an LDL-cholesterol goal of less than 100 mg/dL (2.6 mmol/L) and further recommends lowering of triglycerides to less than 150 mg/dL (1.7 mmol/ L) and raising of HDL-cholesterol to above 45 mg/dL (1.15 mmol/L) in men and above 55 mg/dL (1.40 mmol/L) in women with diabetes. The addition of HDL-cholesterol– raising and triglyceride-lowering strategies to the LDLcholesterol recommendation is due in part to results obtained from studies with fibric acid derivatives, such as the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT).62 In addition, the American Heart Association has also made recommendations for women.63 With respect to primary prevention in diabetics, the evidence for lipid-lowering therapy comes from two major trials. The Heart Protection Study included a subset of 5963 patients with diabetes who were randomized to simvastatin or placebo.63 Simvastatin treatment was associated with a 27% reduction in CAD events after 5 years, and the benefit was independent of the degree of LDL lowering. In the Collaborative Atorvastatin Diabetes Study (CARDS), 2838 patients with type 2 diabetes were randomized to atorvastatin or placebo.64 CVD events were reduced by 36% and overall death rate by 27% in the treatment group. On the basis of these studies, all patients with type 2 diabetes should be considered for statin treatment. The first study to report on secondary prevention was the Scandinavian Simvastatin Survival Study (4S),65 which was also the first of the new generation of trials that used statins. This trial involved 4444 men and women who had stable angina or previous myocardial infarction and moderately high cholesterol levels (213 to 309 mg/dL [5.5-8.0 mmol/ L]) and triglyceride levels below 221 mg/dL (2.5 mmol/L). This latter restriction, plus the exclusion of conditions likely to reduce life expectancy, probably explains why only 202 (4.5%) of the trial population had diabetes, almost certainly type 2 in the majority of cases. Overall, the trial reported three highly significant findings: n a 35% fall in LDL-cholesterol accompanied by a 30% fall in total mortality (the primary outcome); n a 42% fall in CHD mortality; and n a 34% fall in major CHD events.
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ATHEROSCLEROSIS AND ITS PREVENTION: Therapeutic Approaches to the Diabetic Patient
(HDL) cholesterol (negatively), for CVD in type 2 diabetes. Also apparent in diabetes is a greater predictive power of triglycerides,54,55 which probably reflects an association with overproduction and impaired clearance of very-low-density lipoprotein (VLDL) particles and remnants.56 These features are linked to insulin resistance, the key metabolic abnormality seen in type 2 diabetes. Also associated with decreased VLDL catabolism is a reduction in HDL-cholesterol level. However, total cholesterol and LDL-cholesterol concentrations are not usually greatly altered in moderately well controlled type 2 diabetes. Thus, triglyceride levels are characteristically elevated and HDL-cholesterol levels are characteristically depressed, and these findings form the hallmark of traditional diabetic dyslipidemia. Another characteristic lipid abnormality seen in type 2 diabetes and insulin resistance is a shift in density of the LDL particle to the more dense (type B) particle.57 This change is thought to enhance the atherogenicity of LDL34 and is correlated with triglyceride levels and with postmenopausal status in women. It is thus difficult, both statistically and pathophysiologically, to distinguish which of these disturbances (VLDL remnants, triglycerides, HDL-cholesterol, and LDL phenotype B) are the key players. Our knowledge of lipid-CVD relationships in type 1 diabetes is even more limited, although in general terms, similar relationships to the general population appear to be present from the Pittsburgh EDC, DCCT/EDIC, and EURODIAB studies, with, as in type 2 diabetes, a suggestion that triglycerides may play a greater role than in the general population.58,59 Interestingly, in moderately well controlled type 1 diabetes, absolute lipid concentrations are not greatly disturbed. Lipoprotein concentration may therefore account for little of the excess CVD risk seen in type 1 diabetes. This has led to an increased focus on lipoprotein composition, and a number of differences have been identified, including triglyceride enrichment of LDL and HDL particles and disturbed reverse cholesterol transport, LDL oxidation and immune complex formation may be particularly important risk factors.60 Further study is needed to determine whether interventions directed at improving these compositional changes or oxidative properties will result in a reduction in CVD events. Until recently, most of the large lipid intervention trials had either ignored or excluded patients with diabetes. This means that we have not had evidence on which to base cholesterol-lowering (or other lipid modulation) therapy in diabetes, despite the fact that the lipid-CVD connection is just as strong in diabetes as it is in the general population, if not stronger (see earlier).56 Fortunately, a number of trials have recently reported data that involve diabetic subjects; this has helped to address some of these issues, but others are left unanswered. The Third National Cholesterol Education Program (NCEP) Expert Panel16 acknowledged what many practitioners have accepted as standard of care, that diabetes mellitus is considered a CAD risk equivalent (i.e., that patients with diabetes should have the same LDL-cholesterol goals as patients with existing CAD). In 2004, Grundy and colleagues61 published an NCEP report, endorsed by the American College of Cardiology, the American Heart Association, and the National Heart,
67
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GOALS AND INTERVENTION LEVELS FOR LOW-DENSITY LIPOPROTEIN CHOLESTEROL
1
CHAPTER
ATHEROSCLEROSIS AND ITS PREVENTION
6
Risk Category
Risk Factors*
LDL-Cholesterol Goal
Initiate TLC
Consider Drug Therapy
Low risk
0-1
3 ULN
"
0.25%
5*
10
20
20
40
22%#
27%#
10
20
40
40
80
27%#
34%#
20
40
80
32%#
41%#
40
80
37%#
48%#
80
160*
42%#
55%#
0.50% 7%"
1% 2%
#
2%
*Not an approved dose. LE" >3 ULN, liver enzyme increase to more than three times the upper limit of normal. HDL, high-density lipoprotein; LDL, low-density lipoprotein. From Roberts W. The rule of 5 and the rule of 7 in lipid-lowering by statin drugs. Am J Cardiol 1997;49:106-107.
Table 8.9 Comparative efficacy of the five currently available statin drugs.
Each doubling of the statin dose results in an additional 5% reduction in total cholesterol and 7% reduction in LDL-cholesterol. This pattern is referred to as the rule of 5 and rule of 7 in lipid lowering by statin drugs.77 At higher doses of rosuvastatin (40 mg), atorvastatin (80 mg), and simvastatin (80 mg), reductions in LDL-cholesterol of up to 60% have been observed.78,79 Reductions in LDL are accompanied by reductions in apolipoproteins B, C-II, C-III, and E. Statins increase HDL-cholesterol levels by 5% to 15% and reduce triglyceride levels by 7% to 37% in patients without hypertriglyceridemia, but responses are variable.6,78,79 Differential effects on HDL-cholesterol have been observed, but it is not known whether these translate to different effects on clinical outcomes. In patients with severe hypertriglyceridemia, the triglyceride-lowering effect of statins is magnified and can be in the range of 50% with a high dose of a potent statin. Comparisons of lipid-lowering effects among the statins are not always standardized because of differences in the populations studied, the doses of drugs used, and variations in the baseline levels of lipids. The beneficial effect of statins on cardiovascular events have been attributed to several mechanisms other than lipid lowering (Table 8.10).80 Statins may prevent thrombosis, inhibit platelet adhesion and activation, and improve the rheologic profile. They have been shown to reverse endothelial dysfunction, most probably through direct effects on endothelial vasoactive factors, endothelin 1, and nitric oxide. Moreover, statins may inhibit the production of inflammatory cytokines involved in monocyte adhesion, chemotaxis, and metalloproteinase secretion. An alternative explanation is that these beneficial effects are a consequence of cholesterol lowering. The statins are generally most effective when they are given in the evening because the rate of endogenous cholesterol synthesis is highest at night. Atorvastatin and pravastatin, however, can be taken any time of day without affecting efficacy. Food has little effect on the absorption of statins, except for pravastatin, which should be taken on an empty stomach, and lovastatin, which is better absorbed when it is taken with meals. Pregnant women should not take statins because of possible teratogenic effects. Women of childbearing age should use reliable methods of contraception if they are prescribed statins. Persons with hepatic disease should avoid statins or be given lower than standard doses.
Complications Clinical trial data and postmarketing surveillance data for statins support an excellent safety record. Adverse effects may range from mild gastrointestinal complaints to rare cases of rhabdomyolysis. Approximately 1% of persons taking HMG-CoA reductase inhibitors experience an elevation in serum hepatic transaminases to more than three times the upper limit of normal. These changes are usually transient, even when the drug is continued, and are rarely associated with clinical consequences. Symptoms of hepatitis may rarely occur and resemble those of an influenza-like syndrome. A clinical indication that such an adverse effect has occurred is that the levels of LDL-cholesterol and HDL-cholesterol may be much lower than expected with treatment. Symptoms tend to resolve, and increases in hepatic enzymes tend to return to normal on removal of the drug. Mild elevations in aminotransferases (less than twice normal) do not usually require cessation of drug therapy. Liver enzymes may rise in the setting of alcohol abuse, and statins should be used with caution in this situation. Liver function tests should be performed before initiation of therapy, at 2 to 12 weeks after the start of therapy, and after increases in dosage. Liver enzymes almost never increase after the first few months of therapy unless the drug dose has been increased or a concomitant condition has arisen. The spectrum of myopathic syndromes that may occur with statin therapy includes myalgia (muscle aches and tenderness), myositis (pain and muscle weakness with malaise or fever and elevated creatine kinase), and rhabdomyolysis (severe myositis that may lead to acute renal failure).81 An increased risk of myopathy is associated with concomitant use of fibrates, nicotinic acid, erythromycin, protease inhibitors, and cyclosporine.82 Simvastatin is more myopathic than other available statins at higher doses, and it is contraindicated at the 40- and 80mg dose in combination with a fibrate. Cerivastatin was withdrawn from the market in August 2001 because of its myotoxicity after 52 deaths from rhabdomyolysis had been recorded worldwide.83 A U.S. Food and Drug Administration review showed that many deaths occurred in patients who received very high doses or who also received gemfibrozil, a combination that had been contraindicated. The rate of fatal rhabdomyolysis associated with
SECTION
MECHANISMS OF ACTION OF STATINS OTHER THAN LIPID LOWERING
1
CHAPTER
Antiatherosclerotic Properties of Statins
8
Endothelial Dilatation
LDL Oxidation Resistance
VSMC Proliferation
VSMC Apoptosis
Lovastatin
"
"
#
"
Pravastatin
"
"
Neutral
Neutral
Simvastatin
", neutral
"
#
"
Fluvastatin Atorvastatin
NA
NA
#
"
NA
#
"
Anti-inflammatory Properties of Statins Mononuclear Cell Functions Statin
Endothelial Adhesion
Proinflammatory Cytokine Production
Chemotaxis
Metalloproteinase Secretion
TNF-a
IL-1b
IL-6
IL-8
MCP-1
Lovastatin
#
#
NA
"
"
NA
"
",¯
Pravastatin
NA
NA
Neutral
#, neutral
Neutral
#
Neutral
Neutral
Simvastatin
#
NA
#
"
"
NA
"
"
Fluvastatin
NA
NA
#
NA
NA
NA
NA
NA
Atorvastatin
#
#
NA
"
"
NA
"
"
Antithrombotic Properties of Statins Fibrinolysis Statin
TF
TFPI
Platelet Aggregation
Fibrinogen
Plasma Viscosity
PAI-1
Lp(a)
Lovastatin
NA
NA
"
", neutral
#, neutral
#, Neutral
"
Pravastatin
Neutral
Neutral
#
#, neutral
#
#
"
Simvastatin
#
"
Neutral
Neutral
Neutral
"
"
Fluvastatin
#
"
NA
Neutral
NA
NA
"
Atorvastatin
NA
NA
NA
"
NA
NA
"
ATHEROSCLEROSIS AND ITS PREVENTION: Cholesterol-Lowering Therapy
Statin
" increase; # decrease; IL, interleukin; LDL, low-density lipoprotein; Lp(a), lipoprotein(a); MCP-1, monocyte chemoattractant protein 1; NA, not available; PAI-1, plasminogen activator inhibitor 1; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TNF-a, tumor necrosis factor a; VSMC, vascular smooth muscle cell. From Rosenson R. Non–lipid-lowering effects of statins on atherosclerosis. Curr Cardiol Rep 1999;1:225-232. # Current Science Inc.
Table 8.10 Mechanisms of action of statins other than lipid lowering.
cerivastatin therapy was 10 to 50 times higher than the rates associated with the other statins, which reaffirms that current statin therapy is very safe.84
Indications The HMG-CoA reductase inhibitors are indicated to treat several types of hyperlipidemia, including types IIa, IIb, and III (dysbetalipoproteinemia), in conjunction with a lifestyle program. They are the agents of choice in patients with heterozygous familial hypercholesterolemia and other forms of primary hypercholesterolemia, such as familial combined hyperlipidemia and polygenic hypercholesterolemia. Statins are effective therapy in patients with mild to moderate hypercholesterolemia who have other risk factors for CVD. They are also indicated in patients with mixed hyperlipidemia, diabetic dyslipidemia, remnant removal disease (familial dysbetalipoproteinemia), and the nephrotic syndrome. The demonstration in recent clinical trials that statins decrease risk irrespective of baseline LDL-cholesterol levels
has made this class of drugs a treatment for elevated risk, not just elevated cholesterol levels. Thus, statins are indicated for patients with atherosclerosis without a contraindication as well as for patients at equivalent risk, such as diabetics. As the safety of long-term statin use becomes better established, and as the cost of statin therapy decreases with increased availability of generic statins, the indications for statin treatment are likely to continue to broaden.
Bile Acid Sequestrants Three bile acid sequestrants, cholestyramine, colestipol, and colesevelam, are available for clinical use. Cholestyramine (4 to 8 g) is mixed with a suspension of juice or water and taken before meals two or three times a day up to a maximum of 24 g. It may also be mixed with pure´ed fruit. Colestipol (5 to 10 mg) may be taken in a similar manner or as a 1-mg tablet. Colesevelam, a polymeric, high-potency, waterabsorbing hydrogel, is formulated as a tablet and so does not need to be mixed with liquid.85 The recommended dosing is
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6 tablets once daily or 3 tablets twice a day (total daily dose, 1.95 g). Bile acid sequestrants are often used as an adjunct to statin therapy or as a second-line agent in individuals who do not tolerate statins. Both cholestyramine and colestipol reduce the absorption of vitamin D and other fat-soluble vitamins. They bind polar compounds such as digoxin, warfarin, thiazide diuretics, beta blockers, thyroid preparations, and statins. Because of this, other medications should be taken at least 1 hour before or 4 hours after the bile acid sequestrants are taken.
Mechanism of Action Normally, almost 98% of bile acids that enter the small intestine are reabsorbed in the ileum and return to the liver through the portal vein to be cleared in their first pass through the liver. They are resecreted into bile to complete the enterohepatic circulation. Resins bind to bile acids in the small intestine and prevent their absorption. Thus, they interrupt the enterohepatic circulation of bile acids, which increases the conversion of cholesterol into bile acids in the liver as a result of loss of feedback inhibition. The hypocholesterolemic effect of resin therapy is due to enhanced LDL receptor activity on the surface of the liver. This leads to increased clearance of LDL from plasma and promotes the clearance of VLDL and VLDL remnants, which decreases the conversion of VLDL to LDL. However, reduced cholesterol content of hepatic cells stimulates a compensatory increase in cholesterol synthesis. This in turn increases the secretion of VLDL into the circulation and explains why resin therapy may be associated with increased concentrations of triglycerides. A marked increase in triglycerides may occur in patients with a tendency toward hypertriglyceridemia; in severe cases, resins should be avoided. Typical responses to monotherapy with bile acid sequestrants are reductions in LDL-cholesterol in the range of 15% to 30%, no change or slight increases in triglycerides (10% to 15%), and increases in HDL-cholesterol of 3% to 5%. The mechanism for the increase in HDL levels is not established.
Complications
106
Bile acid sequestrants are not absorbed systemically; therefore, their side effects are generally limited to the gastrointestinal tract. The advantage of nonabsorption makes bile acid sequestrants a good option for women with moderate hypercholesterolemia who are in their childbearing years. Constipation, fullness, and gas are most frequently associated with use, occurring in 30% of patients. Symptoms are worse at higher doses and can often be avoided by gradually increasing the dose of resin. If constipation persists, it can be treated by increasing the daily intake of water and foods with wheat fiber or by adding psyllium or prune juice to the diet. Dosage reduction may be indicated if symptoms do not resolve. Studies suggest that colesevelam lacks the constipating effect seen with the other bile acid sequestrants; however, it appears to reduce intestinal absorption of beta-carotene.85 As previously mentioned, resins may interfere with the absorption of other drugs, and levels of some medications may need to be monitored. Prothrombin times may be altered in patients receiving anticoagulant therapy.
Indications The primary indication for resin therapy is for use in combination with statin therapy to reduce LDL-cholesterol levels. For example, in one study of 94 hypercholesterolemic men and women, coadministered colesevelam and atorvastatin produced additive LDL-cholesterol reductions comparable to those observed with maximum atorvastatin dosage, and notably, triglyceride levels were not negatively affected by colesevelam alone or in combination.86 Bile acid sequestrants may be first-line therapy in patients with mild hypercholesterolemia who are not able to tolerate statin therapy or for patients who desire a nonsystemic agent, such as women of childbearing potential. They are less effective in the setting of mixed hyperlipidemia.
Fibric Acid Derivatives Several fibrates are available for clinical use, including gemfibrozil, bezafibrate, ciprofibrate, and fenofibrate. Gemfibrozil is widely used in combination with a lifestyle approach to lower levels of triglycerides. It is typically given as one 600mg tablet twice daily, 30 minutes before the morning and evening meals. In contrast, fenofibrate should be given with meals. It is commonly dosed at 160 mg/day in patients with primary hypercholesterolemia or mixed hyperlipidemia and at 54 to 160 mg/day in patients with hypertriglyceridemia. In addition to their primary action of reducing serum triglycerides, fibrates increase serum HDL-cholesterol and, to a lesser extent, lower LDL-cholesterol.
Mechanism of Action Several different mechanisms are postulated for the lipidaltering effects of fibrates. They appear to enhance the oxidation of fatty acids in liver and muscle, increase the activity of lipoprotein lipase, enhance the catabolism of LDL-cholesterol, and reduce the rate of VLDL synthesis. These effects result in reductions in LDL-cholesterol and serum triglyceride levels. The extent of reduction in total and LDL-cholesterol levels in response to fibrate therapy depends on initial levels but is in the range of 5% to 20%. Triglycerides may be lowered by between 20% and 50%. Fibric acid derivatives also raise HDL-cholesterol levels by 10% to 20%, but the precise mechanism for this effect is not completely understood. Concentrations of the major apolipoproteins (A-I and A-II) found in HDL have been shown to increase in response to gemfibrozil treatment. Fibrates have been shown to increase the buoyancy of LDL particles, but the clinical significance of this effect is not established.
Complications The fibrates are generally well tolerated. The major side effects reported with their use are gastrointestinal complaints (nausea, abdominal and epigastric pain). Because fibrates increase biliary cholesterol concentrations, they may be associated with an increased incidence of gallstones. Their use is contraindicated in persons with severe renal or hepatic disease.6 Other adverse effects that have been reported include erectile dysfunction in men using clofibrate, increased serum transaminases, and myositis in patients with impaired renal dysfunction. A reduction in the dose of warfarin by as much as 30% may be necessary because fibrates displace it from albumin-binding sites. As previously mentioned, the use of
statins, particularly simvastatin, in conjunction with fibric acid derivatives may increase the risk of myositis and rhabdomyolysis.
Niacin (Nicotinic Acid) Niacin (nicotinic acid) is a water-soluble B vitamin that has beneficial effects on several lipid parameters when it is given in pharmacologic doses (1 to 6 g/day). It is the most effective agent to increase levels of HDL-cholesterol. Niacin is available in a crystalline form or as timed-release formulations (e.g., Niaspan). The slow-release formulations are associated with a lower incidence of cutaneous flushing and itching, a frequent side effect of niacin, but they may have a greater incidence of hepatotoxicity. Studies indicate that immediate-release, intermediate-release, and extended-release, once-a-day prescription forms of niacin are essentially equivalent in their efficacy in reducing triglycerides and increasing HDL-cholesterol.87 Niacin is taken with a large glass of water at mealtimes while avoiding hot beverages to help avoid flushing. It is suggested that prolonged exposure to the sun be avoided and that sun protection be used in conjunction with niacin.
Mechanism of Action Niacin inhibits the mobilization of free fatty acids from peripheral tissues to the liver, an effect that reduces hepatic synthesis of triglycerides and secretion of VLDL. Reductions in triglycerides observed with niacin are similar to those obtained with fibric acid derivatives (20% to 50%) and partly depend on the formulation (Fig. 8.5). The conversion of VLDL to LDL is also inhibited by niacin, thereby lowering LDL-cholesterol levels by 5% to 25%. The amount of total and LDL-cholesterol lowering depends on initial serum triglyceride levels, with smaller decreases observed for patients with the highest initial levels of triglycerides. Reduction in LDL-cholesterol may also result from increased clearance of VLDL remnants and decreased synthesis of LDL-cholesterol. Levels of HDL-cholesterol may be increased up to 35% with niacin and may be secondary to a decrease in VLDL triglyceride concentrations. In addition, niacin has been shown to lower levels of lipoprotein(a) and may cause a shift in LDL particle size from small, dense particles to the less atherogenic large, buoyant type.
1
CHAPTER
8
HDL-cholesterol with plain nicotinic acid
+30
HDL-cholesterol with timed-release nicotinic acid
Baseline
Change in serum lipoprotein concentrations (%)
Fibrates are clearly indicated in patients with type V hyperlipoproteinemia and triglyceride levels above 1000 mg/dL to prevent acute pancreatitis. They are also used in patients with type IV and IIb mixed hyperlipidemia. Less commonly, they may be given to patients with type IIa hyperlipidemia when other agents are not tolerated. They are also used in patients with hypoalphalipoproteinemia who are at increased risk of CVD because of other lipid abnormalities or concomitant risk factors.
SECTION
LDL-cholesterol with plain and timed-release nicotinic acid
−30 Triglycerides with plain nicotinic acid
0
1000
Triglycerides with timed-release nicotinic acid
2000
3000
Dose of nicotinic acid (mg/day)
Figure 8.5 Effects of plain and timed-release nicotinic acid on serum lipoprotein concentration. HDL, high-density lipoprotein; LDL, low-density lipoprotein. (From Knopp RH. Drug treatment of lipid disorders. N Engl J Med 1999;341:498-511. # Massachusetts Medical Society.)
the initial week of therapy. Tolerance to flushing generally develops after several days. This side effect may also be minimized by gradually increasing the dose of niacin during several weeks to months. Other dermatologic side effects include itching, rash, and acanthosis nigricans. In addition to hepatotoxicity, adverse gastrointestinal effects associated with niacin use are epigastric distress and activation of peptic ulcer disease and chronic bowel disease. Glucose intolerance is reported with niacin; therefore, the drug should be avoided or used with caution in patients with diabetes. In addition, hyperuricemia, cardiac arrhythmias, and toxic amblyopia have been reported with niacin.
ATHEROSCLEROSIS AND ITS PREVENTION: Cholesterol-Lowering Therapy
Indications
EFFECTS OF PLAIN AND TIMED-RELEASE NICOTINIC ACID ON SERUM LIPOPROTEIN CONCENTRATION
Indications Niacin is indicated for patients with mixed lipid disorders, often in conjunction with a statin. It may be used in patients with primary hypercholesterolemia; however, high doses (>3000 mg/ day) are often necessary to achieve a significant LDL-lowering effect. Niacin is also an option in patients with modest elevations in LDL and in those with non-LDL lipid disorders. Although niacin may raise HDL levels in patients with primary hypoalphalipoproteinemia, the clinical significance of raising an isolated low HDL-cholesterol concentration remains unknown. The effect of niacin on cardiovascular events is currently being evaluated in two large randomized clinical trials.
Complications
Cholesterol Absorption Inhibitors
Cutaneous flushing mediated by prostaglandins is a common side effect of niacin that can be prevented by administration of aspirin (325 mg) 30 to 60 minutes before each dose during
A new category of agents, the selective cholesterol absorption inhibitors, directly block the absorption of cholesterol by the small intestine. Ezetimibe is the first such agent to
107
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8
be approved for clinical use. Ezetimibe has shown clinical benefits when it is used as monotherapy and in combination with other lipid-modifying agents.88 The recommended dose of ezetimibe is 10 mg once daily.88
Mechanism of Action The mechanism of action of ezetimibe differs from that of other classes of cholesterol-lowering drugs. Ezetimibe inhibits the intestinal absorption of dietary and biliary cholesterol by impeding the transport of cholesterol across the intestinal wall. This leads to a decrease in the delivery of intestinal cholesterol to the liver and a reduction of hepatic cholesterol stores, resulting in an increase in clearance of cholesterol from the blood.
Complications Clinical trials of ezetimibe (administered as monotherapy or with a statin) showed that ezetimibe was well tolerated. Ezetimibe can be taken with or without food without any impairment in efficacy. No clinically significant gender effects, P450 3A4 drug interactions, or drug-drug interactions have been identified.88
Indications Ezetimibe is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL-cholesterol, and apoB in patients with primary (heterozygous familial and nonfamilial) hypercholesterolemia. Ezetimibe, administered in combination with a statin, is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL-cholesterol, and apoB in patients with primary (heterozygous familial and nonfamilial) hypercholesterolemia.88 Concerns have recently been raised about ezetimibe, both with respect to efficacy and safety. The addition of ezetimibe to simvastatin failed to have a beneficial effect on carotid intima-media thickness change in a clinical trial of patients with familial hypercholesterolemia.89 In another trial,90 cancer and cancer-related mortality were significantly increased in patients in the ezetimibe treatment group.91
Estrogen and Selective Estrogen Receptor Modulators
108
Despite some beneficial effects on lipid levels, combination hormone replacement therapy (i.e., estrogen given in combination with a progestin) does not appear to be a viable option for CVD prevention. Data from the Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II), a randomized, blinded, placebo-controlled clinical trial of estrogen combined with medroxyprogesterone acetate, found that long-term (6.8 years) use of hormone replacement therapy did not reduce the risk of cardiovascular events in postmenopausal women with CHD.92 Furthermore, the Women’s Health Initiative, a randomized trial of conjugated equine estrogen and medroxyprogesterone acetate in 16,000 healthy postmenopausal women, revealed a higher risk of CHD, stroke, pulmonary embolism, and invasive breast cancer in the active treatment group.93 The estrogen-only arm of the trial showed no cardiovascular benefit but an increased risk of stroke.94 Selective estrogen receptor modulators (SERMs) are a potential alternative to estrogen therapy in postmenopausal
women. SERMs bind to estrogen receptors and produce beneficial estrogen-like effects on bone and on lipoprotein metabolism. However, like estrogen, SERMS are associated with increased risk of deep venous thrombosis, and they increase the incidence of hot flushes.95 The Raloxifene Use for the Heart (RUTH) study randomized 10,101 postmenopausal women at high risk for CHD to raloxifene or placebo and observed them for a median of 5.6 years.96 Raloxifene had no significant effect on coronary events, the co-primary endpoint, but invasive breast cancers and vertebral fractures were reduced, at the cost of an increase in venous thromboembolism and fatal stroke.
Indications On the basis of findings from the HERS and the Women’s Health Initiative studies, the initiation or continuation of hormone therapy for the purpose of prevention of CHD is not recommended, despite its beneficial effects on lipids.97 Based on the results of the RUTH study, raloxifene is also not recommended for CHD prevention.
THERAPY FOR REFRACTORY HYPERLIPIDEMIA In patients with refractory hyperlipidemia, LDL plasmapheresis can be an effective therapeutic modality. Patients with CHD who have LDL-cholesterol levels above 200 mg/dL (or above 300 mg/dL if there is no CHD) despite maximal lifestyle and drug therapy may be considered candidates for plasmapheresis. Several systems that remove apoB-containing lipoproteins from the blood, including heparin precipitation and models that use immunoabsorption or dextran sulfate cellulose columns, are available. A single treatment may reduce LDL-cholesterol by up to 150 mg/dL and lipoprotein(a) levels by 50%. Side effects associated with therapy include hypotension, nausea and vomiting, and flushing. Major limitations to the use of LDL apheresis include cost and inconvenience. Ex vivo gene therapy has reportedly been successful in a small number of patients with familial hypercholesterolemia.
SUMMARY Therapy for hyperlipidemia has been shown to reduce allcause mortality and major cardiovascular events. It is associated with few adverse effects and is cost-effective. Appropriate management of lipids begins with a clinical assessment to identify any underlying causes of dyslipidemia. Once a diagnosis is established, lifestyle therapy should be prescribed for all patients. Pharmacotherapy is an increasingly important adjunct to dietary approaches to hyperlipidemia for both primary and secondary prevention of cardiovascular events. Statins have been proved to reduce events for high-risk patients even with average or low LDL-cholesterol levels. The initiation of drug therapy and aggressiveness of treatment depend on the presence of CVD or risk factors for CHD. Selection of a specific drug therapy depends on the lipid phenotype and the need to minimize side effects and costs. Underuse of lipid-altering therapy in high-risk patients has been documented worldwide.
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Special Problems in Hyperlipidemia Therapy
a. Child with Hypercholesterolemia
DEFINITION OF PROBLEM Children with two defective genes for the low-density lipoprotein (LDL) receptor develop severe familial hypercholesterolemia with LDL-cholesterol concentrations in plasma between 500 and 1000 mg/dL. In these children, severe arteriosclerotic lesions are evident histologically, causing coronary events in the first decade of life. Raised complex lesions appear in the second and early third decades in children with heterozygous familial hypercholesterolemia; the LDL-cholesterol level is usually between 200 and 300 mg/dL. In very young adults with only moderately elevated LDL-cholesterol (130 to 200 mg/dL) and other risk factors such as smoking and low concentration of high-density lipoprotein (HDL) cholesterol, lesions may be obvious in the late teens and 20s. These pathologic studies have made it clear that risk factors are operative early in life. The severity of the lesions correlates with these risk factors, and these findings raise important questions about the current lack of more systematic programs to evaluate and to prevent vascular disease in children (Figs. 9A.1 and 9A.2). Most of these questions are only being formulated and need more studies to demonstrate benefit. What we do know is that vascular disease begins early in life and is accelerated by the classic risk factors.
CASE PRESENTATION During the preschool physical for a healthy-appearing 12-year-old girl, the pediatrician notes small nodules in her calcaneal tendons consistent with tendon xanthomas. All other physical findings are within normal limits. There is a family history of myocardial infarction in the maternal grandfather at age 48 years and sudden death at age 51 years. He did not smoke cigarettes and was not diabetic. As a result, the pediatrician requests determination of plasma cholesterol and HDL-cholesterol concentrations, which return as 352 mg/dL and 54 mg/dL, respectively. The child, a younger brother, and both parents return after a 12-hour fast for a complete lipoprotein analysis. The father and brother are within normal limits. The mother’s LDL-cholesterol is 290 mg/dL. The patient’s total plasma cholesterol level is now
Warren W. Davis and W. Virgil Brown
344 mg/dL; triglycerides are 90 mg/dL, HDL-cholesterol is 55 mg/dL, and LDL-cholesterol is 271 mg/dL. There is no evidence of endocrine, renal, or liver dysfunction.
DIFFERENTIAL DIAGNOSIS The findings in this child and the family are typical of heterozygous familial hypercholesterolemia. The maternal grandfather almost certainly had elevated LDL-cholesterol in the same range as now seen in the patient and her mother. It is not totally clear as to the impact of other risk factors because the family is not aware of his blood pressure or HDL-cholesterol level. His clinical event at age 48 years is a clear warning to the 37-year-old mother, who was previously unaware of her hypercholesterolemia. It is important to plan dietary change for this family that is effective for both mother and daughter and that respects the lifestyle choices of the father and brother. This requires some thought and planning best done in collaboration with a registered dietitian. The reduction of the daily intake of cholesterol to less than 100 mg and of the saturated fat to less than 7% of calories is feasible. This may require the child to become vegetarian at home, leaving the cholesterol and saturated fat intake for meals outside the home to make socialization easier for this 12-year-old. The mother would need to adopt a similar approach to her daily habits. Because the mother is probably 15 years away from entering a high-risk period for acute coronary events, monitoring the effect of these lifestyle changes on lipoprotein concentrations for several months is useful. Some patients are remarkably dietary responsive; others are resistant. The patient may show a significant fall in LDL-cholesterol of 20% to 40% with dietary change. Children usually are more diet responsive than adults are. The experiment should be done thoroughly before medications are considered because the period of treatment will be long, and the true benefit of any drug regimen should be judged against a background of the most effective diet. Avoidance of other risk is imperative. Cigarette smoking should be avoided absolutely. The body weight should be controlled. An annual physical examination with careful monitoring of blood pressure should be part of the plan.
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PROGRESSION OF ATHEROSCLEROSIS IN YOUNG PATIENTS
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ESTIMATED PREVALENCE OF AHA GRADES IN LAD
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9
Percent of abdominal aorta with intimal lesions
Non−HDLcholesterol
Normal
High
Normal
Low
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Smoking Black male
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–1 20 9 –2 25 4 –2 30 9 –3 4
–1 20 9 –2 25 4 –2 30 9 –3 4
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% surface area
HDLcholesterol
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Percent of right coronary with intimal lesions
Non smoking
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White female % surface area
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A
Black female
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Risk factor
White female
Grade 4–5 lesion
60
Black male
White male 60 50 40 30 20 10 0
Prevalence (%)
ATHEROSCLEROSIS AND ITS PREVENTION
Non−HDLcholesterol
Flat streaking
Raised lesions
Figure 9A.1 Progression of atherosclerosis in young patients. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study demonstrated that young persons in the United States have demonstrable vascular disease that increases with age. Blood vessels analyzed from postmortem specimens provide data on the distribution of fatty streaks as well as raised and more complicated arteriosclerotic lesions. A, The percentage of the aortic surface involved with intimal lesions was seen to increase with each 5-year interval. B, A similar increase was seen in the coronary arteries. (From Strong JP, Malcom GT, McMahan CA, et al. Prevalence and extent of atherosclerosis in adolescents and young adults: implications for prevention from the Pathobiological Determinants of Atherosclerosis in Youth Study. JAMA 1999;281:727-735.)
Figure 9A.2 Estimated prevalence of American Heart Association (AHA) grades in left anterior descending coronary artery (LAD). Estimated prevalence of AHA grades in LAD by high versus normal non HDL-cholesterol concentration (top); low versus normal HDL-cholesterol concentration (middle); smoking versus nonsmoking status (bottom); and 5-year age group, adjusted for race, sex, and other risk factors. (From McGill HC Jr, McMahan CA, Zieske AW, et al. Association of coronary heart disease risk factors with microscopic qualities of coronary atherosclerosis in youth. Circulation 2000;102:374-379.)
The goal for the mother is to reduce her LDL-cholesterol to well below 160 mg/dL if no other risk factors are evident. At the time of her menopause, this goal can be reconsidered with new evidence from clinical trials accruing during this 10- to 15-year period and with consideration of new drugs available at that time. In the interval, statin or bile acid resin therapy would be indicated to achieve and to maintain the LDL-cholesterol goal. The patient’s risk will be affected positively by the dietary change, and if no other risk factors are added, it is unlikely that coronary artery disease will appear for several decades. However, moderate reduction for many years is far better than marked reduction after vascular disease is manifested. The opportunities for definitive treatment will certainly expand during this interval. If the LDL-cholesterol remains above 190 mg/dL on diet, adding small doses of bile acid
drug ezetimibe. In view of the minimal systemic absorption and minimal side effects that have been noted to date, this should be considered because it will provide a 20% further reduction when it is combined with a statin.
SUMMARY This case illustrates the astute pediatrician’s recognizing clues as to the existence of hypercholesterolemia in a family on the basis of both physical findings and family history. The first and most important result is the identification of an adult woman (mother of the patient) who is in clear need of medical management to reduce the risk of cardiovascular disease. Furthermore, the environment is altered, which can possibly alter the child’s long-term risk at relatively little cost. Of most importance to the child is the awareness and development of a sensible lifestyle that involves monitoring for risk factors as she grows into adulthood and, it is hoped, into a long and healthful life with the benefits of current drugs and of future knowledge. For these children with severe hypercholesterolemia, management in a specialized lipid clinic is advised.
b. Transplant Patient
Warren W. Davis and W. Virgil Brown
DEFINITION OF PROBLEM
TYPICAL CASE
The probability of clinical events related to arteriosclerosis is significantly higher in post-transplantation patients compared with those with similar risk factors but no transplanted organs. Although not all reasons for this accelerated vascular disease are known, high blood pressure and diabetes contribute, and many patients undergoing organ transplantation will develop hyperlipidemia. The drugs that are used to suppress the immune system have significant effects on these risk factors, including lipid metabolism, and make management of the hyperlipidemia difficult. Furthermore, the potential for serious drug interactions between the immunosuppressive drugs and the drugs used to lower lipids increases the difficulty. Treatment objectives include prevention of coronary, cerebral, and peripheral arteriosclerosis as well as vascular disease in the transplanted organ. The prolonged survival after organ transplantation in many patients has made this objective of the utmost importance. Furthermore, the vascular changes in the transplanted organ that have been associated with chronic rejection have many of the characteristics of arteriosclerosis, such as lipid deposition and foam cells. Infiltration of the artery wall with T cells and the other manifestations of an inflammatory process, including the release of cytokines, may be part of the rejection process. Significant clinical disease in the transplanted organ can be evident as soon as 1 year after transplantation. Elevated lipoproteins may play a role in this accelerated disease, and lipid-lowering drugs have reduced the incidence of this problem.
A 42-year-old man presents 6 months after renal transplantation. He currently has no evidence of organ rejection, and the renal function is good with a blood urea nitrogen concentration of 18 mg/dL and creatinine concentration of 1.4 mg/dL. He was discovered to have albuminuria in his teens, diagnosed as chronic glomerulonephritis. During the subsequent years, the urinary protein concentration had been measured at 2 to 4 g/day, the serum albumin concentration was between 2.5 and 3.0 g/dL, and the cholesterol and triglyceride levels had remained between 250 and 300 mg/dL. This nephrotic syndrome was treated by diet only. Elevated blood pressure had been controlled by lisinopril. End-stage renal disease required hemodialysis at the age of 39 years. His current medications are lisinopril, 10 mg; azathioprine, 100 mg daily; cyclosporine, 400 mg daily; and prednisone, 10 mg daily. A lipoprotein analysis immediately before the current visit revealed total cholesterol, 280 mg/dL; triglycerides, 325 mg/ dL; high-density lipoprotein (HDL) cholesterol, 31 mg/dL; low-density lipoprotein (LDL) cholesterol, 184 mg/dL; and lipoprotein(a), 78 mg/dL.
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sequestrants (cholestyramine or colestipol) before dinner often provides a 20% reduction or more. Some children are motivated and will sustain this regimen for years. Use of the encapsulated resin (1 g/tablet) may prove easier for many children. Taking three to five of these before the major meal at home is effective. Constipation is minimal at this dose. Because both cholestyramine and colestipol can bind other drugs, preventing their absorption, any needed medications should be taken at least 1 hour before or 4 hours after the resin dose. The use of colesevelam as the bile acid sequestrant may also improve compliance. Statins have been used clinically for more than 20 years, and multiple studies in children indicate that they are safe. They do not affect growth, and adverse effects do not appear any more frequent than in adult populations. Pravastatin has been given the indication for treatment in children by the Food and Drug Administration. Therefore, patients with elevations of LDLcholesterol or with other risk factors, including a family history of very early clinical events, can be treated with pravastatin. For the severely involved child with LDL-cholesterol above 300 mg/dL, other statins or more than one drug may be needed. Cholesterol absorption may be reduced with the
DIFFERENTIAL DIAGNOSIS After full recovery from surgery, all risk factors should be evaluated. This includes measurements of total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and lipoprotein(a). Secondary causes of elevated lipids, such as liver disease, nephrotic syndrome, and hypothyroidism, need to
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be eliminated. Inadequate control of diabetes can also be a factor. The presence of hyperlipidemia related to the renal disease before the transplantation will be common, but genetic causes of lipid elevations may also be operative. The use of cyclosporine or tacrolimus (FK 506) is associated with the significant abnormalities in lipids, including elevated cholesterol and triglycerides. In addition, higher doses of steroids are also a factor in aggravating the elevation of triglycerides and cholesterol. Lipoprotein(a) tends to rise significantly in some patients and may confer additional risk.
TREATMENT OPTIONS Treatment should include evaluation of diet and exercise patterns and prescription of important changes. Loss of excess adipose tissue can have profound effects on triglyceride concentrations and to a lesser extent on LDL-cholesterol. One may also achieve a rise in HDL and a drop in blood pressure. An American Heart Association Step II diet is recommended. Additional saturated fat and cholesterol restriction may be possible with the help of a dietitian. High blood pressure needs to be treated and in this patient may have been aggravated by immunosuppressive therapy. Many patients will still have unacceptable levels of cholesterol and triglycerides after these interventions. The LDLcholesterol goal of less than 130 mg/dL should be set and appropriate drug therapy prescribed after dietary effects have been evaluated for 8 to 12 weeks. Triglycerides should be reduced below 200 mg/dL. If hypercholesterolemia is the main abnormality, treatment with a statin drug can be started. Tacrolimus causes less severe alterations in lipid values than cyclosporine does, and the use of tacrolimus can be considered when lipid changes are prominent. Pravastatin in doses of 20 to 80 mg has a theoretical advantage because its metabolism does not involve the cytochrome P450 system (Fig. 9B.1). Cyclosporine and many other drugs
EFFECT OF PRAVASTATIN ON CHOLESTEROL IN HEART TRANSPLANT PATIENTS
are powerful competitive inhibitors of this system (specifically the 3A4 enzyme) and may cause accumulation of several members of the statin class of drugs. In addition, reduced rejection and improved survival have been demonstrated with pravastatin in heart transplant patients compared with those given no statin therapy (Figs. 9B.2 and 9B.3). Other statins may prove effective but low doses should be used, and careful monitoring of aspartate transaminase and alanine transaminase is recommended to guard against liver and muscle dysfunction. Theoretically, full doses of fluvastatin or rosuvastatin could be used because they are not metabolized by the 3A4 isoenzyme of the P450 system. However, the clearance of rosuvastatin by the liver is inhibited by cyclosporine, which interferes with uptake of this drug from the plasma space. Bile acid
EFFECT OF PRAVASTATIN ON SURVIVAL IN HEART TRANSPLANT PATIENTS 100 Survival (% of patients)
SECTION
90 80 70
P=.025
60 0
2
4
6
8
10
12
Months after transplantation Pravastatin
Control
Figure 9B.2 Effect of pravastatin on survival in heart transplant patients. The pravastatin-treated patients experienced a significant improvement in survival. (From Kobashigawa JA, Kasiske BL. Hyperlipidemia in solid organ transplantation. Transplantation 1997;63:331-338.)
IMPROVEMENT IN SURVIVAL OF PRAVASTATIN-TREATED PATIENTS EFFECT OF INTIMA THICKNESS ON PRAVASTATIN-TREATED PATIENTS 0.7
260
0.6
240
Maximal intimal thickness (mm)
Cholesterol (mg/dL)
280
220 200 180
0.4 0.3
P=0.025
0.2 0.1
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6
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Months after transplantation Pravastatin
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0.5
Control
Figure 9B.1 Effect of pravastatin on cholesterol in heart transplant patients. Heart transplant patients assigned randomly to pravastatin (40 mg/day) maintained much lower mean cholesterol levels than did those treated with placebo during 12 months. (From Kobashigawa JA, Kasiske BL. Hyperlipidemia in solid organ transplantation. Transplantation 1997;63:331-338.)
0 Baseline (pravastatin) Baseline (control) Increase from baseline to 1 year (pravastatin) Increase from baseline to 1 year (control)
Figure 9B.3 Effect of pravastatin on intimal thickness. The major difference in survival of pravastatin-treated patients (see Fig. 9B.2) appeared to be secondary to reduced proliferative change in the intima of their coronary arteries. (From Kobashigawa JA, Kasiske BL. Hyperlipidemia in solid organ transplantation. Transplantation 1997;63:331-338.)
c. Hypercholesterolemia in the Elderly
DEFINITION OF PROBLEM Elevated cholesterol is often found in patients older than 75 years with no history of cardiovascular disease. On occasion, this is due to elevated high-density lipoprotein (HDL) cholesterol, but low-density lipoprotein (LDL) cholesterol above 160 mg/dL (>4.2 mmol/L) is a more common finding. When evaluation of renal, liver, and endocrine status is within normal limits, it might be assumed that this elevated plasma cholesterol is relatively benign because the patient has lived a long life without apparent consequences. However, population studies tell us that myocardial infarction and stroke are most frequent in this age group and that elevated LDL-cholesterol and reduced HDL-cholesterol continue to be risk factors. Expensive hospitalization, disability, and long-term nursing care are the result in many of these patients. We have powerful drugs for reducing cholesterol, and benefit in those older than 70 years has now been proved. The absolute benefit in a population of the elderly is actually greater than in middle-aged patients because the incidence of disease is so great in this age group.
TYPICAL CASE A 78-year-old retired physician is seen as a new patient. He notes remarkably good health over the years, having been hospitalized only once—tonsillectomy at age 11 years. He plays golf at least once weekly, takes care of his small garden without help, and travels frequently with his wife. There have been no symptoms suggesting angina, claudication, or dyspnea on exertion, and his activity level has been relatively stable. His blood pressure was found to be 165/100 mm Hg approximately 5 years ago and has been treated with hydrochlorothiazide. His cholesterol level has always been approximately 250 mg/dL, but the HDL level was 48 to 50 mg/dL (1.2 mmol/L). This was treated with dietary advice, but he has never taken lipid-lowering medications. He reports eating little dairy fat and meat only once daily. This is often fish or chicken with no skin. He has never smoked, and his blood glucose concentration has always been less
SUMMARY
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Transplant patients have higher than expected risk of atherosclerotic events related to abnormalities in HDL-cholesterol, LDL-cholesterol, and triglycerides. Patients with organ transplantation can have prolonged survival if they are properly managed. Benefits are demonstrated in clinical trials, and therefore drug therapy for lipid abnormalities should be undertaken. It is mandatory that appropriate attention be given to drug interactions if significant adverse reactions are to be avoided.
Warren W. Davis and W. Virgil Brown
than 100 mg/dL. His brother, who smoked, died of a myocardial infarction at 68 years. He is unaware of hypercholesterolemia in the family. His two sons, aged 46 and 50 years, are thought to be healthy and with cholesterol concentrations below 200 mg/dL. On physical examination, he weighs 175 pounds (79.5 kg) at 5 feet 11 inches (180 cm). His blood pressure is 155/92 mm Hg. There is a moderate corneal arcus bilaterally. There is a soft bruit over the left subclavian artery. The chest and cardiac examination findings are otherwise normal. The abdominal examination reveals a murmur over the right inguinal area. There are no tendon or cutaneous xanthomas, and the pulses are easily palpable. The ankle-brachial blood pressure ratio is 1.0. The neurologic examination is within normal limits. Laboratory analyses confirm normal renal, liver, and thyroid status. The fasting plasma glucose concentration is 88 mg/dL. A fasting lipoprotein analysis reveals a total cholesterol level of 265 mg/dL (6.88 mmol/L), triglycerides of 280 mg/dL (3.18 mmol/L), HDL-cholesterol of 42 mg/dL (1.1 mmol/L), and calculated LDL-cholesterol of 167 mg/dL (4.34 mmol/L).
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sequestrants or the cholesterol absorption inhibitor ezetimibe can also be combined with a statin to achieve further reduction in LDL-cholesterol. Timing of the dose of bile acid sequestrants is critical to prevent inhibition of absorption of other drugs that are critical in management of the transplant patient. Fibric acid derivatives might also be used when triglyceride levels remain high. Pravastatin or fluvastatin might be combined with these agents in severely hyperlipidemic patients. Education of the patient and monitoring are doubly necessary in these patients because drug combinations may increase the incidence of rhabdomyolysis or liver dysfunction.
DIFFERENTIAL DIAGNOSIS This is an active man continuing to enjoy life and making contributions to his community and family. The bruit suggests but does not prove that some arteriosclerotic lesions already exist. These may be due to stable lesions that will never cause a clinical event; however, unstable plaque in his aorta and coronary or cerebral arteries may lead to a life-damaging or life-destroying episode. The probability of this is increased by his age and his elevated blood pressure as well as by his elevated LDL-cholesterol. The blood pressure may be due in part to his large-vessel disease with some segmental renal compromise. The elevated LDL-cholesterol is probably polygenic in origin because the family history does not suggest a major genetic defect, his diet is consistent with guidelines, and there are no other metabolic abnormalities evident.
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REDUCTIONS IN CORONARY EVENTS IN OLDER ADULTS WITH HYPERCHOLESTEROLEMIA
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0
TC
LDL-C
TG
CHD mortality
All-cause mortality
Nonfatal MI
HDL-C
–10
%Δ
ATHEROSCLEROSIS AND ITS PREVENTION
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–20
–30
–40
Figure 9C.1 Reductions in coronary events in older adults with hypercholesterolemia. The response to statin therapy has been observed to be similar in middle-aged and elderly persons. The Scandinavian Simvastatin Survival Study (4S) found no difference in the sustained response of lipoprotein concentrations to simvastatin in those older than 65 years. CHD, coronary heart disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; TC, total cholesterol; TG, triglycerides. (From Miettinen TA, Pyo¨ra¨la¨ K, Olsson AG, et al. Cholesterollowering therapy in women and elderly patients with myocardial infarction or angina pectoris: findings from the Scandinavian Simvastatin Survival Study [4S]. Circulation 1997;96:4211-4218.)
≥65 years 5 cm), and, in very carefully selected patients, involvement of the aortic arch. When medical treatment fails and complications develop, the course is usually catastrophic. It is paradoxical but not surprising that the indications for operation are those same factors that increase the surgical risk. The prognosis in such cases is dismal even if an emergency operation is performed. Early operative intervention for selected patients at low surgical risk with uncomplicated acute type B dissection may reduce the incidence of late death secondary to rupture of distal false aneurysm and redissection. In some centers, urgent surgery is the treatment of choice for carefully selected patients with acute type B dissections, even if they are uncomplicated. With this approach, current surgical mortality rates of patients with uncomplicated type B dissection have improved significantly during the past 10 years and may now be lower than 10%.12 On the other hand, elderly patients and those with uncomplicated acute type B dissections who have severe pulmonary, cardiac, renal, or central nervous system disease, however, have a better prognosis if they are treated medically. Endovascular repairs have been used in selected patients with acute type B dissection with satisfactory results. Whereas the indications are not yet clear, endovascular repairs are now a new viable treatment option. At this time, indications include patients who develop complications, particularly the elderly, who are not suitable for open repair. Further studies are necessary to compare endovascular stent-graft placement with medical treatment in patients with uncomplicated dissections. Given the relatively low mortality for uncomplicated type B dissections, the benefit of stent-grafting may be difficult to prove. The indication for endografts in chronic dissections is less clear. Given the stiffness and the multiple fenestrations of the chronically dissected septum and the fact that the circulation of distal organs and limbs is frequently dependent on the patency of the false lumen, it seems unlikely that stent-graft insertion could repair the consequences of the dissection.
Surgical Procedure for Type A Dissection Current surgical management for acute type A dissection recommends a local and expeditious operation consisting of a supracoronary graft replacement of the ascending aorta redirecting forward flow into the true lumen and correction of aortic regurgitation. The native aortic valve should be preserved whenever possible. Valve reconstruction can be performed in approximately 75% of patients with acute type A dissection and in 50% of patients with chronic dissection with aortic insufficiency.13 This approach prevents most deaths and is associated with the lowest operative risk. Although it is debatable, this conservative surgical approach should not be used in patients with Marfan’s syndrome, Ehlers-Danlos syndrome, or other connective tissue disorders because of the questions about limited durability of aortic valve reconstruction. The most radical replacement of the ascending aorta and the aortic valve with a composite graft-valve prosthesis and the complex valve-sparing replacement of the aorta with coronary reimplantation are reserved for patients with severe involvement of the sinuses and proximal coronaries. Given the negative impact of a patent false lumen on aortic expansion and late survival, every effort should be made to avoid the persistence of the false lumen. This includes avoidance of aortic clamping, open distal anastomosis, resection of the entry point and adjacent friable aorta, and use of perfusion strategies that direct flow into the true lumen. One of the most important controversies in the surgical treatment of acute dissection with entry sites in the aortic arch is whether the entire arch should be included in the repair (Fig. 12.7). Many authors agree that if the tear can be visualized in the proximal arch through the open aorta, it should be included in the repair (hemiarch repair). On the other hand, if the primary intimal tear cannot be exposed and resected safely (e.g., type A dissection with a tear in the distal aortic arch or the descending thoracic aorta), it should not be included in the resection because the operative risk for a complete arch replacement is extremely high. Early and late survivals are not affected adversely with this approach, but the subsequent reoperation rate is higher. The exception to this recommendation is selected low-risk younger patients, in whom it may be prudent to use profound hypothermic circulatory arrest and to include the aortic arch in the repair. The risk of the arch operation in this situation approaches 10% to 15%. If the arch has ruptured, concomitant arch replacement is mandatory, but the operative risk is substantially higher (25% to 50%).
Surgical Procedure for Type B Dissection The repair involves resection of the intimal tear and placement of an interposition graft to obliterate the distal false lumen by approximating the layers of the aortic wall. Distal perfusion should be maintained during the procedure to prevent spinal cord and visceral ischemia. The risk of paraplegia is greater in patients with acute dissection than with atherosclerotic aneurysm, probably because there is no collateral flow. Visceral malperfusion usually improves with restoration of flow into the true lumen. Major aortic branches involved by the dissection may need to be stented or directly revascularized to restore flow. In other cases, as a last resort, a distal fenestration procedure between the true and false
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12
B
Figure 12.7 Surgical repair of dissection of the aortic arch. A, Chronic dissection of the aortic arch 6 months after ascending aortic repair of a type A dissection. The true lumen is completely detached from the adventitia. A large intimal tear is clearly seen. B, Dissection extending distally into the brachiocephalic vessels. (Courtesy of Dr. Loren Ketai, University of New Mexico, Albuquerque.)
lumens can be performed percutaneously in an attempt to improve perfusion of organs or limbs that communicated only with the false lumen.
Endovascular Stent-Graft Techniques A primary goal of the procedure is the exclusion of the primary tear to redirect blood flow into the true lumen. This may increase the likelihood of false lumen thrombosis and may eliminate the risk for late aneurysmal dilatation. In addition, the implantation of endovascular stent-grafts inside of the true lumen permits the internal coverage of friable, enlarging, or even ruptured areas of the aorta, decreasing the risk of acute rupture. A limitation of this technique is the need to anchor the graft in a relatively normal segment of the aorta both proximally and distally. Critical aortic branches originating from the anchoring segments may be occluded. Additional revascularization procedures to ensure flow to these vessels are necessary in one third of the patients. The most common of these is a left carotid–subclavian bypass when the origin of the subclavian is covered by the stent-graft. Selected cases of retrograde dissection from a distal tear around the arch into the ascending aorta have been treated successfully by limited endograft coverage of the entry point. Endovascular stent-grafts have also been used for the treatment of acute dissection involving the arch in combination with open revascularization of the neck vessels before graft deployment. The use of uncovered stents in branch vessels and the creation of controlled re-entry tears in dissection flaps with use of balloon catheters can improve visceral malperfusion syndromes secondary to acute dissections.14
Surgical Results The current operative mortality rate for patients with acute type A dissection remains between 10% and 25%13; for uncomplicated acute type B dissection, it is 13% 12%.14 Selected centers have reported even lower operative mortality for uncomplicated cases.12 The mortality rate has been much higher (25% to 60%) for type B patients with
complications. Most deaths that occur shortly after operations for acute dissection are secondary to hemorrhage, heart failure, brain damage, or respiratory failure.7,11 Independent determinants of operative risk for type A dissections are age older than 70 years, shock at presentation, neurologic deficits, tamponade, myocardial ischemia or infarction, renal failure, and renal or visceral ischemia. Concomitant total arch replacement or coronary artery bypass is a risk factor for early death. For type B dissections, the determinants of risk include an older age, rupture, renal or visceral ischemia, and infarction. The incidence and types of postoperative complications appear to be similar for both type A and type B dissections. The most significant exception to this is the development of new paraplegia after repair of descending thoracic aortic dissection; this is quite rare after type A dissection but can occur in approximately 4% of patients after type B dissection repair.
Results of Endovascular Grafting for Type B Dissection Despite the improvements in device technology and growing clinical experience, the use of stent-grafts for the treatment of aortic dissection is still in a developmental phase.15 Several single-center reports have demonstrated that endovascular repair is technically successful in most cases and that procedure-related risks appear to compare favorably with those of surgery, particularly in patients with complications.14 A recently published meta-analysis16 of 39 studies that included 609 patients showed that overall mortality was 5.3% and major complications occurred in 14% of the patients (21% for acute and 9% for chronic dissection). The incidence of neurologic complications was low (3%); however, in contrast to open repair, stroke was twice more common than paraplegia. Despite those encouraging early results, some concern exists about mid- and long-term outcomes. Thrombosis of the false lumen in the stented segment was achieved in more than 80% of the cases, but occlusion of the false lumen in the distal thoracic and abdominal aorta was observed in only 10%. Late complications occurred in
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a third of the patients, including endoleaks, device migration, and distal aortic enlargement, with a 10% risk of aortic rupture at 2 years. In addition, retrograde type A dissection developed in 4% of the patients.16 Strict follow-up with aortic imaging is necessary to detect and to manage these complications.
Long-term Management All patients who survive acute dissection should be followed up medically for life. The late mortality rate related to aortic complications accounts for one third of late deaths. In many postoperative patients and almost all medically treated patients, the false channel persists, leading to the development of complications and death.17 Progressive expansion of the dissected segment of the aorta is common and occurs in 25% to 40% of patients. Effective control of blood pressure and dP/dt should be continued after the initial episode, even if the patient is normotensive. Maximal blood pressure response to exercise should be assessed with treadmill testing. In one study, aneurysms developed in 45% of patients without good blood pressure control, compared with only 17% of patients with satisfactory control. The ideal drug should have a negative inotropic as well as a hypotensive effect (e.g., beta blockers).18 Pure vasodilator drugs such as hydralazine and minoxidil increase dP/dt and should be used only in the presence of adequate beta-blocker therapy. Calcium channel blockers and angiotensin-converting enzyme inhibitors are potentially beneficial for the longterm management of aortic dissection (as a supplement to the traditional beta-blocker agents). Accurate information of the extent of the dissection at the time of discharge is mandatory for proper follow-up. The aortic size and the status of the false lumen should be monitored periodically. Aortic imaging should be performed on a regular basis to evaluate the involved and uninvolved aorta after treatment and to detect extension of the dissection or enlargement of distal false aneurysms before rupture can occur.7 Recommendations for follow-up after discharge of patients with aortic dissection include regular examinations and chest radiography every 3 months during the first year and every 6 months thereafter. Aortic imaging should initially be performed at 3 months and then at 6 months. For patients with significantly dilated aortas, the intervals should remain at 3 months. If the aorta is not significantly dilated and no clinical or anatomic changes develop between imaging studies, the initial studies can be done at 6-month intervals. Studies can be performed annually after that period; it is probably not safe to exceed 1 year between examinations. Early recognition of aortic disease permits both prevention of aortic rupture and timely reoperation. Unfortunately, late death from aortic rupture can be reduced but not completely eliminated with this policy.17
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The risk of death during the initial phase of acute dissection is very high. It is generally believed that approximately 10% to 15% of patients die suddenly in the first 15 minutes. Approximately 50% of patients are alive 48 hours later,
and only 10% of patients are alive after 3 months. These statistics, however, ignore the clear difference in prognosis between acute dissections involving the ascending aorta and those involving only the descending aorta. Without treatment, only 8% of patients with ascending dissection survive for more than a month, whereas almost 75% may survive after dissection of the descending thoracic aorta.
Long-term Prognosis after Treatment The prognosis of patients with acute aortic dissection in general has improved significantly as a result of earlier and more accurate diagnosis, more effective medical therapy, better surgical techniques, and improved perioperative management. During the past 2 decades, the annual mortality rate for aortic dissection in the United States has declined steadily by more than 50%. There is scant information about the long-term survival of acute type A dissection treated medically. As mentioned before, a clear difference in early prognosis exists between patients with acute dissections that involve the ascending aorta and those that involve only the descending thoracic aorta. In a series of medically treated patients, only 43% of patients with type A dissection were alive 1 month after the dissection, compared with 91% of patients with type B dissection. Interestingly, for survivors of the acute episode, the difference in prognosis disappears after the first month. The 5-year survival rate for patients who survived an acute dissection followed by medical treatment alone was not different between type A and type B dissections. Several factors adversely affect the long-term prognosis of medically treated patients; these include age, presence of serious early complications before therapy was instituted, and large diameter of the descending aorta (>5 cm). Even though patients who survive the acute dissection continue to be at a significantly greater risk of death than the general population, their long-term survival after surgical treatment shows a relatively satisfactory prognosis. Published results for long-term survival after repair of acute dissection are between 70% and 85% at 5 years and between 54% and 66% at 10 years.17 The actuarial survival rate of patients with acute type A dissection showed a slightly (yet significantly) lower life expectancy at 10 years than that of the general U.S. population, matched for age and sex. For patients with acute type B dissection, the actuarial survival rate was 48% at 5 years and 29% at 10 years, not significantly different from that of a matched population. A report focusing on the long-term outcome of all types of dissections showed that 18% of late deaths were caused by rupture of another region of the aorta, 38% were cardiovascular in nature, and 28% were sudden and not defined. Even considering that many patients had cardiovascular disease, some (if not many) of these sudden deaths may have been due to aortic rupture. These results underscore the importance of indefinite clinical follow-up. The surgical nature of the late sequelae suggests that surveillance should ideally be performed by the surgeon (who is the one who must decide when to reoperate).7 Reoperations are common in patients with treated aortic dissections. In the Stanford experience, the incidence of reoperation was 13% 4% at 5 years and 23% 6% at 10 years (linearized rate, 3.1% per patient-year). The type
of dissection has no significant influence on the probability of reoperation, which is more likely in younger patients and in those with Marfan’s syndrome (31% versus 8%).17
The term intramural hematoma (IMH) was introduced to describe a localized aortic dissection without intimal disruption. It is thought to begin with the rupture of the vasa vasorum of the aortic wall. This results in a collection of blood oriented circumferentially around the lumen of the aorta. In the early stages, the blood extravasated in the media or in the subadventitial space does not communicate with the aortic lumen; therefore, it does not show enhancement with the administration of contrast material, nor does it show blood flow into the space on TEE.2 The absence of an intimal tear has been confirmed in several surgical and autopsy cases. Even though IMH can develop in any location of the aorta, two thirds of the patients have involvement of the descending aorta. Echocardiographic findings that are suggestive of the diagnosis of IMH include the following (Fig. 12.8): n the typical reflection pattern of loculated blood with formation of a thrombus between the adventitia and the media;
n n
eccentric aortic lumen; displaced intimal calcium; and areas of echolucency within the aortic wall.
Because the echocardiographic criteria for IMH may not be confirmatory, a second imaging modality is frequently necessary after TEE to secure its diagnosis. On CT images, the IMH is recognized as a nonenhancing circular or crescent-shaped thickening of the aortic wall without evidence of an intimal flap. A fresh hematoma is evidenced by a high-density signal compared with that of the aortic layers (Fig. 12.9). Thrombosis is identified by a multilayered pattern.8 On MRI, acute IMH is demonstrated as a circular or crescent-shaped thickening of the aortic wall without evidence of a classic intimal flap and absence of blood flow in the false lumen. Fresh bleeding is isodense on T1weighted images but has a high signal intensity on T2-weighted images. Subacute IMH, on the other hand, has a high signal intensity on both T1- and T2-weighted images because of the formation of methemoglobin. Spontaneous IMH affects patients with long-standing hypertension. They present with severe chest or back pain similar to that of aortic dissection, but the signs and symptoms of arterial branch involvement are lacking. Aortic regurgitation can occur in some cases of ascending aortic IMH. Pericardial and pleural effusions are common and
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n
E L
H A P E
C Figure 12.8 Intramural hematoma. A, Cross-sectional transesophageal echocardiogram of the descending thoracic aorta showing a large intramural hematoma (bottom). B, Gross surgical specimen of the excised section of aorta. C, Histologic section of the affected aortic wall with a Verhoeff–van Gieson stain for elastin showing penetration of the luminal plaque through the elastic media, with the resultant hematoma separating the elastic layers. A, adventitia; E, elastin fibers; H, hematoma; L, lumen; P, plaque.
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dilate. Patients with annuloaortic ectasia frequently have enlarged mitral valves, which may or may not be abnormal. Annuloaortic ectasia is often associated with Marfan’s syndrome and other connective tissue disorders. It is also common in patients with bicuspid aortic valve. Dilatation of the aortic root due to annuloaortic ectasia frequently leads to aortic valve insufficiency, acute aortic dissection, or a combination of these problems.
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Arteriosclerotic or Degenerative Aneurysms
Figure 12.9 Transverse CT image at the level of the pulmonary trunk. The arrow marks a discrete localized wall thickening of high density. This is considered strong evidence of fresh hematoma.
represent impending external rupture. Spontaneous progression of IMH to classic dissection may occur regardless of the location of the hematoma and characterizes IMH as a precursor of dissection. From collective experience, it appears that IMH of the ascending aorta has a worse prognosis with medical treatment than with early surgery.2 These patients should be managed like those with classic ascending aortic dissection. Patients with descending aortic IMH can probably initially be treated medically. However, several series have also demonstrated the potential for poor outcome in patients with descending aortic IMH treated medically. Thus, followup imaging to rule out progression should be carried out in 2 to 4 days. If the findings demonstrate progression, surgery should be performed preemptively to prevent rupture. If patients tolerate medical management without deterioration, they may continue to be treated conservatively. Several patients have shown involution of the lesions over time. These recommendations should be adjusted to the individual condition of the patient. IMH is a lesion of the elderly, frequently with major associated comorbidities. Many patients may not be appropriate candidates for the aggressive surgical approach described.
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Arteriosclerosis or nonspecific degenerative disease is the most common cause of descending thoracic and thoracoabdominal aneurysms. More than half of the aneurysms reported in surgical series are in this category. Although atheromatous changes have long been recognized in these aneurysms, the causative role of atherosclerosis in their development is not clearly established. Several deficiencies of collagen, elastin, and smooth cells have been described in these aneurysms.
Chronic Aortic Dissection When the false lumen persists after an acute aortic dissection, the thin outer wall has a strong tendency to enlarge gradually. Chronic aortic dissection with a persistent false channel is the second most common cause for the development of chronic thoracic aneurysms. They have a propensity to enlarge and rupture.
Chronic Traumatic Aortic Transection Untreated, acute traumatic transection leads to the extravasation of blood into the periaortic area. If the patient survives, the periaortic hematoma remains in communication with the aorta and forms a false aneurysm that is contained only by the aortic adventitia or mediastinal tissues. The false aneurysm has a tendency to enlarge and rupture. Less than 10% of descending aortic aneurysms have a traumatic origin.
Aortitis Infection is an uncommon cause of thoracic aortic aneurysm and represents a small percentage of cases in modern series. Granulomatous aortitis is an uncommon condition in which the microscopic appearance suggests an infectious etiology, but bacteriologic studies are negative. Granulomatous aortitis may produce simultaneous aortic and pulmonary aneurysms. Secondary syphilis was a common cause of ascending aortic aneurysm in the past. It causes the destruction of the elastic fibers in the aortic media, leading to progressive expansion and rupture.
ANATOMY AND PATHOLOGY Annuloaortic Ectasia
PATHOPHYSIOLOGY
Annuloaortic ectasia is a disease of the fibrous component of the aortic annulus in which the annulus is primarily enlarged. In its progression, the dilatation includes the sinuses of Valsalva and the proximal part of the ascending aorta. Because the dilatation occurs almost exclusively on the right side of the aortic root, which is not muscular, the noncoronary sinus is the first one to become dilated. As the process advances, the right and left aortic sinuses also
Aneurysm formation is a progressive and self-perpetuating phenomenon due to Laplace’s law. As the radius increases, wall stress increases exponentially, leading to further expansion. Aortic dilatation is frequently associated with deposition of laminated thrombus along the walls of the aneurysm. Thrombus formation does not protect against expansion and potential rupture. Eventually, most aneurysms will rupture. The natural history may depend in part on the etiology
Clinical Presentations Many patients are asymptomatic at the time of presentation; the diagnosis is often made during evaluation for other medical conditions, such as aortic regurgitation, hypertension, or atypical chest pain. When symptoms are present, they are often of recent onset and coincide with a change in the rate of expansion of the aneurysm. In other cases, pain may be chronic and of several months’ duration. Location of the pain may be precordial in the case of ascending aorta, or it may radiate to the neck and jaw when arch involvement exists. Aneurysms of the descending thoracic aorta tend to produce back pain. Of great clinical significance is the fact that in most of the patients who present with sudden rupture, the diagnosis of aneurysm was not known before the development of the complication. A constellation of symptoms may result from the aneurysm’s compressing adjacent structures. This may include superior vena cava obstruction, stretching of the left
recurring laryngeal or phrenic nerve, airway compression, dysphagia, and hemoptysis. Evidence of atherosclerotic disease is frequently present in patients with thoracic aortic aneurysms. This includes coronary artery disease, peripheral vascular disease, and cerebral vascular disease. About 10% of the patients have an associated aortic abdominal aneurysm.
DIAGNOSTIC TECHNIQUES The plain chest radiograph can readily identify dilatation and aneurysms because of the natural contrast between the thoracic aorta and the surrounding lung. Conventional CT scanning can identify aneurysms well but provides only axial images and requires contrast material. Three-dimensional reconstructions permit an excellent evaluation of the size and extent of the aneurysm. MRI is a useful technique because it can identify and characterize aortic aneurysms and assess their physiologic consequences. The ability to image the entire aorta in sagittal planes allows assessment of the location and extent of aneurysms. The use of oblique planes permits accurate measurements of aneurysm diameter and the relation of the aneurysm to branch vessels. In addition, coronal plane images can identify ascending aortic aneurysms, and with spin-echo or phase mapping techniques, associated aortic regurgitation and hemopericardium can be assessed. Echocardiography is used to further define the morphologic character of the aorta as well as to evaluate cardiac function. Transthoracic echocardiography can visualize the proximal ascending aorta adequately, permitting the diagnosis of annuloaortic ectasia or postaortic stenosis dilatation. It can also identify thoracic aortic aneurysms, but only MRI and intravascular ultrasonography can also interrogate the abdominal aorta. Aortic angiography, until recently the gold standard, is not generally necessary.
MANAGEMENT The size of the aorta remains the most important factor in the decision-making process to recommend treatment for asymptomatic aortic aneurysms. Because of the significant operative risks associated with the repair, operation is not advised for an asymptomatic patient before the aorta reaches a size associated with a risk of rupture that is greater than the surgical risk. The decision to operate is not simple, and there is a great deal of discussion about the current recommendations for elective resection of aortic aneurysms.20,21 Most recommendations are based on absolute measurements of the aorta that ignore the relationship between aortic size, age, and body surface area. Furthermore, these recommendations are based on the observation that the mean diameter of the aorta at the time of the development of dissection or rupture is around 6 cm for the ascending aorta and 7 cm for the descending aorta. If operation is delayed until this point, it means that half of the patients would have experienced a complication by the time that treatment is recommended. This policy, which may have been justified in an era when the surgical morbidity and mortality were relatively high, is undoubtedly too conservative. Nomograms that permit accurate assessment of the degree of aortic dilatation in relation to the expected size of the
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of the aneurysm. In patients whose aneurysm is related to a previous dissection, the prognosis is worse than for the degenerative ones. Hypertension is an important factor in the development of dilatation.19 Aneurysms of the ascending aorta are frequently associated with aortic valve regurgitation. Aortic regurgitation results from the dilatation of the sinotubular junction. This causes passive stretching of the otherwise normal leaflets, which are pulled away by the displacement of the commissures. Dilatation of the aorta at the level of the sinotubular junction is the most common cause of isolated aortic valvular regurgitation, frequently in the presence of a normal valve and, in many instances, a normal-sized annulus. In typical ascending aortic aneurysms, the aortic annulus often dilates much less than the sinuses and the sinotubular junction. As described before, this is not the case, however, in annuloaortic ectasia, in which annular dilatation is the first pathologic development, followed later by the dilatation of the sinotubular junction. Progressive dilatation and increase in the wall tension of the aneurysm can lead to the development of acute dissection. The relationship between aortic size and risk of dissection is better described in Marfan’s syndrome than in other pathologic processes. However, several findings suggest that the risk of complications is also related to the size of the aorta in other diseases. For instance, in most aortic dissection series, the diameter of the aortic root at the time of presentation is clearly enlarged in the majority of patients, suggesting the presence of preexisting abnormal dilatation. The incidence of postoperative dissection after aortic valve replacement is also significantly higher if the aorta is 5 cm or larger at the time of the operation. In all contemporary natural history studies, the probability of rupture increases significantly beyond an aortic diameter of 6 cm, and the risk increases as the aneurysm increases even further.16 After size, other risk factors associated with aneurysm growth identified by multivariate regression analysis include chronic dissection, Marfan’s syndrome, aneurysm location, age, smoking, hypertension, and sex. Descending thoracoabdominal aneurysms expand faster than ascending or aortic arch aneurysms do. The presence of chronic obstructive pulmonary disease is also a powerful predictor of rupture,20 independent of smoking.
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aorta based on body surface area, age, and sex have been developed. Decisions should be based on the determination of aortic diameter to expected diameter ratios for each individual patient. Current guidelines for elective aortic replacement in patients at low surgical risk recommend operation when the aortic ratio is 1.3 or greater. For higher risk patients, surgery is recommended for a ratio of 1.5 or greater for ascending aortic lesions and 2.0 or greater for descending aortic lesions. For patients who are under observation, operative repair is recommended if the aneurysm expands by more than 0.3 cm per year. Mandatory indications for replacement of the aorta include development of symptoms, acute dissection, intramural hematoma, and rupture. Severe atherosclerosis with mobile plaque is also an emerging indication for operation.
Techniques of Operation Several operative techniques are available for surgical treatment of a dilated ascending aorta. They include the separate replacement of the aortic valve and ascending aorta, a valvesparing root replacement procedure, and the traditional composite root replacement with a valved conduit. Options for a valved conduit replacement include a synthetic graft, a homograft, and a pulmonary autograft. Choosing of the technique appropriate for the individual patient and the specific pathologic process requires careful consideration of several important factors. Among these factors are n age and expected survival; n underlying pathologic changes; n anatomic condition of the aortic valve, sinuses, and sinotubular junction; n risk of anticoagulation; and n presence of active infection. The goals of surgical treatment for descending aortic aneurysm are to resect the diseased segment and to reestablish continuity with an in situ graft. The procedure varies, depending on the location and size of the aneurysm. On occasion, in long aneurysms involving several aortic segments, the operation is staged. Temporary cross-clamping of the aorta produces an increase in cardiac afterload and temporary ischemia of visceral organs, including the spinal cord. Numerous methods have been recommended to minimize the consequences of aortic cross-clamping during the repair. Temporary shunts, partial or total cardiopulmonary bypass, and hypothermic circulatory arrest are recommended for different situations. The choice depends largely on the surgeon’s preference. Interruption of critical intercostal vessels is avoided as much as possible. Techniques for the placement of endovascular stentgrafts have recently been developed. This procedure offers a promising alternative for the treatment of patients with aneurysms. The need for a 2-cm neck proximal and distal to permit a stable seal remains a major limitation to its use, as does the necessity for a large introducer sheath, usually inserted through a femoral cutdown. Initially reserved for patients at very high risk who were not considered candidates for conventional surgical repair, endovascular stentgrafts are proving to be an effective means of treatment in a significant number of patients with favorable anatomic features.22
PROGNOSIS Appropriate choice of surgical procedure for the aortic root and the ascending aorta yields excellent immediate and long-term results. Hospital mortality after elective operation ranges between 4% and 12%, whereas the mortality of emergency operation is still very high. Late survival after operation is approximately 65% at 5 years and 55% at 7 years. The occurrence of dissection severely affects longterm prognosis. Expected mortality for patients undergoing elective resection of descending thoracic aneurysms is higher, in the range of 5% to 15%. Morbidity includes the risk of paraplegia, renal dysfunction, low cardiac output, and bleeding. The incidence of paraplegia for elective procedures ranges between 0% and 20% and averages 4%. The operative morbidity and mortality for emergency procedures are increased several-fold over that for elective repair. Late survival after operation is 70% at 5 years and 40% at 10 years. Interestingly, endovascular stent-grafts have been associated with a low incidence of development of paraplegia, even when all the intercostal vessels between T8 and L1 have been covered. Paraplegia has occurred only when an abdominal aortic aneurysm repair was performed simultaneously with the thoracic endografting.22
PENETRATING AORTIC ULCERS The penetrating aortic ulcer, a unique pathologic event with special prognostic and therapeutic implications, is quite different from the simple superficial ulceration of an arteriosclerotic lesion. Penetrating aortic ulcers are atheromatous plaques that ulcerate and disrupt the internal elastic lamina, burrowing deeply into the aortic media and beyond. Microscopic findings demonstrate intimal degeneration and cholesterol infiltration mimicking clefts that penetrate through the media. Depending on the depth of penetration, blood is found at varying levels of the aortic wall.21 Depending on the degree of local inflammation and fibrosis, the plaque may precipitate a localized hematoma within the aortic wall. The hematoma may break through into the adventitia to form a pseudoaneurysm or may rupture freely into the mediastinum. Penetrating ulcers are frequently misdiagnosed as dissection because they are much less common than classic dissection.23 The clinical presentation is similar to that of classic aortic dissection. However, the symptoms and signs secondary to peripheral arterial compromise, which are so typical of dissection, are lacking. Accurate recognition and differentiation of penetrating ulcers from classic aortic dissection are critical for optimal management because their prognosis may be more serious than with classic dissection. The mean age at presentation is significantly older than that of patients with type A or type B dissection. Close to half the patients have a concomitant abdominal aortic aneurysm.23 The incidence of acute rupture at the time of presentation of the penetrating aortic ulcer has been reported to be higher than that of type A or type B dissection. The diagnosis of penetrating aortic ulcer can be made by most imaging techniques with the demonstration of a contrast material–filled outpouching in the aorta in the absence
SMA
Figure 12.10 MRI clearly demonstrating a penetrating ulcer (arrow) and diffuse atherosclerotic disease. The celiac axis (C) and the superior mesenteric artery (SMA) are seen. Both are severely atherosclerotic.
of a dissection flap or false lumen. TEE demonstrates a crater-like ulcer with jagged edges in the presence of extensive aortic atheroma but in the absence of an intimal flap or false lumen. On CT scans, the diagnosis is confirmed with the demonstration of an outpouching of the aorta in the absence of a dissection flap or false lumen. On MRI, penetrating ulcer is identified by visualization of a distinct ulcer crater in the absence of a dissection (Fig. 12.10). On angiography, penetrating ulcers are recognized as a characteristic localized contrast-filled outpouching. Cobblestoning in the region of the ulcer signifies the presence of severe atherosclerosis. Complicated penetrating ulcers can be accompanied by localized intramural hematoma surrounding hemorrhage and pleural effusion.24 Regardless of the location of a penetrating aortic ulcer, patients should undergo immediate medical treatment to control pain and to prevent rupture. Persistent pain, hemodynamic instability, and radiographic expansion are indications for surgical treatment. On the basis of several reports that have shown that penetrating aortic ulcers of the ascending aorta are prone to rupture, patients with ascending
SUMMARY Aortic dissection is a catastrophic event, and urgent diagnosis and aggressive medical treatment are vital. Regardless of the location of the initial tear, surgical intervention is mandatory when the ascending aorta is involved. Descending aortic dissections are initially managed medically, but operative repair is indicated as complications develop. Long-term medical management with periodic imaging evaluation of all patients is of paramount importance because of the high incidence of late complications from the dissection. Potential improvements in overall survival of patients in the future will most probably be obtained by earlier and more accurate diagnosis, earlier initiation of pharmacologic management, and, when indicated, more expeditious operation.
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C
penetrating aortic ulcer should undergo immediate operation.24 Uncomplicated ulcers in the descending aorta may initially be managed medically with a high index of suspicion for potential expansion or rupture. Surgical treatment becomes necessary in the case of clinical or radiologic deterioration. Patients who tolerate medical management without clinical signs of expansion should undergo follow-up imaging studies at 3 to 5 days to confirm the safety of this approach. Although the preferred operation is resection and graft interposition of the affected area of the aorta, there are special situations in which patch repair and external wrapping of the aorta can be lifesaving in patients who are moribund. Endovascular stent-grafts play a significant role in the treatment of these challenging patients and are gradually becoming the first approach to treatment. Endovascular stent-grafting is a less invasive alternative to conventional operations. Unfortunately, in many cases, the severity of the atherosclerotic disease and the size of the aorta limit its application. Penetrating aortic ulcer can be a life-threatening condition that may not be recognized unless the treating physician is aware of this entity.2 In one series, 40% of patients with penetrating aortic ulcer of the descending aorta suffered rupture during observation in the intensive care unit while being treated for what was thought to be type B dissection. Medically treated patients should be followed up indefinitely with periodic imaging studies. Surgical results depend on several factors, such as age, diffuse aortic atherosclerotic involvement, associated medical conditions, and the frequently nonelective nature of the operation. Best results are seen in nondelayed operations in hemodynamically stable patients. Emergency operation for rupture is associated with a very high morbidity and mortality. As is the case with repair of aneurysm disease, operations in the aortic arch and descending thoracic aorta carry a higher mortality than those in the ascending aorta.
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Abdominal Aortic Aneurysms Joseph Shalhoub and Ian J. Franklin
Definition n
Abdominal aortic aneurysm (AAA) is defined as dilatation of the abdominal aorta to more than 3 cm in diameter.
n
These can be infrarenal, juxtarenal, or suprarenal, according to the relationship to the renal arteries.
Key Features n
AAA is common; 5% of men older than 65 years have a degree of aortic dilatation.
n
AAA is a common cause of sudden death, annually more than 100 per million in Western countries.
n
Most AAAs are asymptomatic until they rupture.
n
Ruptured AAA has a high mortality; most patients die before reaching the hospital. Emergency surgery saves around 60% of those who survive to the operating theater.
n
AAA size remains the best indicator of risk of rupture.
Therapy n
There is no proven survival advantage in intervening for AAAs of less than 5.5 cm in diameter; surveillance by ultrasonography is safe.
n
There are two treatments of aortic aneurysm: open surgical repair and endovascular repair. Open surgical repair was once considered the “gold standard” treatment of AAAs and is a relatively safe and durable procedure.
n
Endovascular repair is now supported by a strong body of evidence, with a lower morbidity and a faster return to work compared with open surgery, particularly in fit patients. However, follow-up is required, and there is a significant reintervention rate to maintain stent-graft function.
n
There is currently no proven pharmacotherapy to limit aneurysm development, but greater understanding of the pathogenesis of AAA may allow the introduction of drugs to limit aneurysm growth.
The first successful repair of an abdominal aortic aneurysm was performed by Pierre Dubost in Paris on March 29, 1951. He used a cadaveric homograft, and the patient, then aged 51 years, survived another 8 years before dying suddenly at home, probably of a heart attack. Until the early 20th century, syphilis was the most common cause of aortic aneurysms, mainly affecting the aortic arch. Of the first 10 abdominal aortic aneurysm repairs performed by Eastcott in London in 1954-1955, four were tuberculous or syphilitic. Such thoracic aneurysms are now rare, and the most common in current clinical practice are aneurysms of the infrarenal abdominal aorta (Fig. 13.1). This, along with evidence we present later, shows that there has been an etiologic
and diagnostic shift in the story of aortic aneurysms in general. There is no clear-cut definition of abdominal aortic aneurysm. Various attempts have been made to relate aortic diameter to height, sex, weight, and the diameter of the suprarenal aorta; but for most practical purposes, the infrarenal aorta is considered aneurysmal when the diameter exceeds 3 cm, implying a 50% increase. This chapter uses the term aneurysm to mean abdominal aortic aneurysm (AAA) unless otherwise stated. Aneurysm is a disease of later life, with the incidence rising progressively with age. Men are eight times more likely to develop an aneurysm than are women. Around 5% of men older than 65 years have an aneurysm, and as more people live longer, the incidence is rising. In one study, aneurysms were detected in 11.4% of men 60 years of age and older undergoing abdominal ultrasound examination for reasons other than a suspected aneurysm.1 Autopsy-based studies indicate that the incidence of ruptured aneurysm is 8.4 per 100,000 of the population for men and 3.0 per 100,000 for women.2 Around 7500 deaths per year in the United Kingdom are caused by ruptured AAA, similar to the number dying of upper gastrointestinal tract malignant disease. Although aneurysms are less common in women, female gender confers a threefold increased risk of aneurysm rupture.3
ANATOMY AND PATHOLOGY Normal aortic wall comprises tunica intima, media, and adventitia. In health, the intima and adventitia are thin, and the tensile strength of the wall is derived from the media. The tunica media consists of vascular smooth muscle cells in a well-organized matrix of concentric lamellae. The smooth muscle cells provide tensile strength and secrete the bulk of the matrix proteins. The two main extracellular proteins are elastin and collagen. Elastin is extensile and can extend to double its resting length yet return to its normal size. This property allows the aorta to expand during systole, thus storing the energy of the cardiac impulse and driving the blood into the tissues as the aorta contracts during diastole. Fibrillar collagen (types I and III) is the main provider of tensile strength in the aortic wall. Collagen is inelastic, but in the aorta, it is wound in a coiled form that allows expansion without altering the length of each fiber. As the aorta is distended, the initial load is taken by elastin. As further expansion occurs, the coiled collagen fibers become taut, and further expansion is prevented.4
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PATHOPHYSIOLOGY Mechanical Considerations
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Blood Pressure
Figure 13.1 In thin individuals, an aortic aneurysm may be seen as a pulsating swelling in the upper abdomen. (Courtesy of Mr. S. Ray.)
On histologic examination, there are striking differences between normal and aneurysmal aorta. Aneurysm wall is usually thicker, but the structure is disorganized and weaker. AAA wall frequently has atherosclerotic lesions on the luminal surface. The normal lamellar structure of the tunica media is disrupted, and the media is thin with marked loss of smooth muscle cells. Elastin is conspicuous by its absence, but there is a relative increase in collagen. The adventitia is thick and inflamed, with infiltrating lymphocytes and macrophages especially around the vasa vasorum. In the past, aortic aneurysms were considered to be a complication of atherosclerosis, and most aneurysms that were not obviously inflammatory or infective were referred to, almost without question, as atherosclerotic aneurysms. It is now evident that earlier models of aneurysm development were overly simplistic and that aneurysms do not simply result from an artery wall somehow weakened by atheroma. Three crucial processes have emerged as being central to the vascular remodeling that results in aortic aneurysms. These are n inflammation; n loss of vascular smooth muscle; and n excessive proteolysis. The pathogenesis of AAAs involves progressive cycles of proteolysis and inflammation, the product of proteolysis driving subsequent inflammation. Little is yet known about the initiating events, and uncertainty of a “chicken and egg” nature exists over which is the primary abnormality. Chronic inflammation in the aneurysm wall leads to an imbalance of proteolytic enzyme activity, causing degradation of the matrix proteins.3 The inflammation also causes depletion of smooth muscle cells.5 These changes result in weakening, dilatation, and eventually rupture of the aorta. There are large gaps in this model. The influence of genetic factors is far from clear. The mechanisms by which risk factors (such as male sex, smoking, hypertension, and atherosclerosis) contribute to aneurysm development have not been firmly established. The trigger for aneurysm formation might even be infective, and several organisms have been implicated, most prominently Chlamydia pneumoniae (see later). Nonetheless, the interactions between inflammatory pathways, smooth muscle cell function, and extracellular matrix turnover are being discovered, revealing potential strategies for drugs designed to prevent aneurysm growth.
Several mechanical factors are pertinent to aortic aneurysms. Blood pressure exerts an effect on the incidence, the rate of dilatation, and the risk of rupture. Hypertension, both systolic and diastolic, is a weak risk factor for aneurysm formation. The incidence of AAA in patients with uncomplicated hypertension has been reported to be as low as 3%, rising to 18% in patients with coexisting advanced vascular disease.6,7 Modulation of blood pressure may influence dilatation. A randomized controlled trial of b-adrenergic blockade in Marfan’s syndrome conducted with 70 patients during 10 years demonstrated that propranolol protects against development of aneurysms of the aortic root, a characteristic complication of the condition.8 The rate of aortic dilatation was around one quarter that in the untreated control patients. This was associated with a reduction in systolic and diastolic blood pressure, and the rate of rise of pressure during systole was also diminished. In one nonrandomized study of 121 infrarenal AAAs, those patients with large aneurysms (5 cm) receiving beta blockers had a significantly reduced mean expansion rate compared with those without b-adrenergic blockade.9 Whereas hypertension is only a weak factor for aneurysm incidence, mean blood pressure is significantly and independently associated with increased risk of aneurysm rupture.3 It is therefore likely that control of blood pressure is important in reducing rupture rates of aortic aneurysms. It is intuitive that elevated blood pressure increases the strain on the aorta, but studies in experimentally induced aneurysms in rats suggest that hypertension also exacerbates inflammation in the aneurysm wall, indicating that hemodynamic load may affect aneurysm development in more than one way.
Aortic Shape As the shape and diameter of the aorta change with aneurysm formation, the stresses within the vessel wall alter. A consequence of Laplace’s law is that for a given intraluminal pressure, the tension in the wall is proportional to the diameter. Thus, as an aneurysm dilates, the tension in the wall increases, leading to further expansion and ultimately rupture. The wall thickening seen as the aneurysm dilates may be a compensatory mechanism to withstand increasing strain because Laplace’s law predicts that the tension in the vessel wall is inversely proportional to the wall thickness. The change in shape toward that of a sphere may also confer some protection against rupture because the tension in the wall of a sphere is half that of a cylinder of the same radius, pressure, and wall thickness.4 Hemodynamic factors have been postulated to account for the localization of the majority of aortic aneurysms to the infrarenal aorta. The pulse pressure increases as the pressure wave progresses distally from the aortic root, although the mean arterial pressure does not increase. The aortic bifurcation has been reported to be a source of pressure wave reflections, but direct measurements of intraluminal pressure have failed to detect regions of unexpectedly high pressure.10
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Atherosclerotic plaque
Inflammation Inflammatory and Atherosclerotic Aneurysms: Two Ends of the Same Spectrum? Surgeons commonly speak of aortic aneurysms as being of one of two types: atherosclerotic or inflammatory. Inflammatory aneurysms are easily recognized by their thick white wall, densely adherent to surrounding structures. Dissection is more difficult, increasing the risk of inadvertent damage to surrounding structures, such as the ureters and duodenum. Fortunately, such aneurysms are less common than the “ordinary” atherosclerotic variety. However, there is now a substantial body of evidence to suggest that inflammation plays a key part in the formation of so-called atherosclerotic aneurysms, even that inflammatory aneurysms may simply represent one end of a broad spectrum (see also Chapter 1).
Characteristics of the Inflammatory Infiltrate in Abdominal Aortic Aneurysm The clear distinction observed macroscopically between inflammatory and ordinary aneurysms is not apparent under the microscope. The typical histologic appearance of an AAA is shown in Figure 13.2. When analyzed histologically, more than 80% of aneurysms exhibit a variable degree of inflammation.11 Heavily inflamed aneurysms are more likely to be symptomatic,12 and there is a positive correlation between degree of inflammation and aneurysm diameter.13 Whereas inflammatory changes can be detected in aortas affected by stenosing arterial disease, the nature of the infiltrate seen in aortic aneurysms is different. The appearances are those of a chronic inflammatory response with a high proportion of lymphocytes and macrophages but few neutrophils. In contrast to occlusive atherosclerotic disease, which is mainly a disorder of the tunica intima, the infiltrate is concentrated in the outer layers of the vessel wall, in the adventitia and media. The infiltrate frequently surrounds vasa vasorum.
Immunoglobulins and Complement Elevated immunoglobulin content (IgG) is a feature of tissues affected by an autoimmune process, including disorders such as rheumatoid arthritis and glomerulonephritis. IgG secretion and complement activation are associated with tissue destruction. Increased concentrations of all four subclasses of IgG together with complement degradation products are present, suggesting that the complement cascade is activated in aneurysm wall.14
Inflammatory Mediators, Cytokines, and Prostaglandin E2 Numerous studies have confirmed high cytokine levels in aneurysm wall. Compared with normal or occlusive aorta, elevated amounts have been detected of tumor necrosis factor a, interleukin (IL)–lb, IL-6, IL-8, monocyte chemoattractant protein 1, and interferon g.15 These cytokines
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Tunica media
Tunica adventitia Vasa vasorum
Inflammatory infiltrate
Figure 13.2 Histologic section through the wall of a typical abdominal aortic aneurysm. There is an atherosclerotic plaque on the luminal surface. The tunica media, which in normal aorta comprises a thick layer of smooth muscle and elastin, is thin and exhibits marked loss of smooth muscle cells. The tunica adventitia is thick, disorganized, and inflamed. The inflammatory infiltrate is particularly prominent around the vasa vasorum.
have the ability to promote production of proteolytic enzymes by macrophages and to induce apoptosis in vascular smooth muscle,16 processes strongly implicated in aneurysm development. Aneurysm biopsy specimens in explant culture produce large quantities of prostaglandin E2 (PGE2) compared with normal aorta, which produces very little.17 PGE2 is synthesized by the enzyme cyclooxygenase (COX), of which there are two isoenzymes, COX-1 and COX-2. COX-2 has been identified and localized to macrophages in the inflammatory infiltrate in AAA wall by immunohistochemistry and in situ hybridization.17 Because the action of matrix metalloproteinases has been shown to be PGE2 dependent, these findings raise the possibility that PGE2 is an important mediator of aneurysm formation and that its synthesis results from COX-2 expression in adventitial macrophages. Moreover, PGE2 appears to depress replication of aortic smooth muscle cells,18 which could account for the loss of smooth muscle seen in the tunica media of AAAs. All explant models of aortic aneurysm have limitations. Human explant specimens represent only late-stage disease, and animal models may differ greatly from the human condition. The inflammatory processes seen in AAA are not confined to the aortic wall. Aortic aneurysms are associated with increased levels of several circulating cytokines.19 There is some evidence that the concentration of interferon g is
ATHEROSCLEROSIS AND ITS PREVENTION: NONCARDIAC VASCULAR DISEASES: Abdominal Aortic Aneurysms
Despite wide-ranging investigations into the physical aspects of aneurysm development, few useful facts have found their way into practical management of aneurysm patients. These are that hypertension should be controlled and that aneurysm diameter is the best indicator of risk of rupture. Other risk factors affecting aneurysm formation, growth, and rupture are discussed later.
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linked to aneurysm growth rate.20 Aneurysms also seem to be an important source of circulating IL-6, and the IL-6 genotype is prognostic of cardiovascular mortality,21 an important finding indicating that aneurysms may affect pathologic processes distant from the aorta.
Is Infection of the Vessel Wall the Cause of the Inflammation? It has been recognized for centuries that syphilis causes aneurysms of the aortic arch. Tuberculosis is known to cause inflammatory aneurysms of the abdominal aorta.22 The notion that stenosing atherosclerotic disease might be caused by infection was first proposed by Sir William Osler in 1908.23 This concept received little attention until 1988, when a Finnish study demonstrated that acute myocardial infarction was associated with raised antibodies to part of the newly identified organism Chlamydia pneumoniae. In the subsequent decade, more than 1000 papers have been published exploring the possible role of this organism in the pathogenesis of vascular disease. C. pneumoniae has now been identified in every large artery in the body, including coronary, carotid, iliac, and lower limb arteries. C. pneumoniae has been identified in the walls of aortic aneurysms; the incidence varies according to the technique used24 and ranges between 0% and 100%; most studies find evidence of the presence of C. pneumoniae in around 35% to 45% of cases. The detection of chlamydial DNA by polymerase chain reaction does not demonstrate the presence of active infection. Indeed, viable C. pneumoniae has been cultured only once from vascular tissue, from the coronary artery of one patient. It seems likely that infection of the vessel wall may leave remnants of chlamydial DNA and membrane components long after active infection has terminated. C. pneumoniae infection of endothelial cells induces procoagulant activity25 and stimulates expression of adhesion molecules essential for leukocyte migration, including intercellular adhesion molecule 1 and vascular cell adhesion molecule 1.26 Moreover, chlamydial infections are frequently chronic, and in the case of the closely related organism Chlamydia trachomatis, the tissue damage may be delayed by several years. In an experimental aneurysm model in rabbits, C. pneumoniae appears to contribute to aortic dilatation by specific activation of macrophages.27 Despite extensive literature that C. pneumoniae is associated with atherosclerosis and plausible circumstantial evidence that it could contribute to the inflammation seen in aneurysm formation, there is no proof that the presence of this organism is anything other than coincidental. Interestingly, one group could not find evidence of C. pneumoniae in the majority of analyzed AAA walls; however, all samples showed a strong cross-reaction between chlamydial antibodies and human immunoglobulin.28 This raises the hypothesis that AAA is an autoimmune disease, perhaps triggered by an initial C. pneumoniae infection. Although bacteria have received the most attention in searching for triggers for vascular disease, viruses, especially herpes viruses, have also been implicated. One study reported finding cytomegalovirus DNA in 86% of inflammatory aneurysms, 65% of so-called atherosclerotic aneurysms, and 31% of normal aortas.29 The herpes simplex virus has
also been detected in inflammatory and atherosclerotic aneurysms: 29% of inflammatory aneurysms and 27% of atherosclerotic aneurysms compared with 6% of normal aortas.29 As with C. pneumoniae, the presence of the infectious agent does not constitute proof of a role in the pathogenesis of aneurysms but merely demonstrates an association between the two.
Summary: Inflammation in Abdominal Aortic Aneurysms Studies in humans showing an abundance of inflammatory cells in aneurysm wall, high circulating inflammatory markers, and high localized production of cytokines together with IgG secretion and complement activation suggest that inflammation is intricately involved with aneurysm development. Further corroborative evidence is provided by the experimental aneurysms in animals. The initial stimuli that provoke the reaction are not identified, although infectious agents have been implicated; nor is it clear whether the inflammation is a consequence or a cause of aortic dilatation. Nonetheless, this growing body of evidence points to the concept that the excessive proteolysis seen in aneurysm wall is driven by chronic inflammation.
Proteolysis Structure of Aortic Wall: Elastin and Collagen The transformation of normal aorta into aneurysm involves profound changes in the cellular composition and extracellular matrix of the vessel wall. Lack of elastin is a striking histologic feature of aortic aneurysm wall, and the normal lamellar pattern of concentric rings of smooth muscle and elastin is absent. Loss of elastin appears to be a critical component of aneurysm formation, occurring early in the process. The proportion of elastin in normal aorta progressively decreases from the root to the bifurcation, making the infrarenal segment the most inelastic part and the most vulnerable to further depletion of elastin.30 Elastin is normally a stable component of the extracellular matrix, showing very little turnover in adult aorta or other tissues. Elastin depletion is due to destruction rather than to diminished production. As elastin is destroyed, the hemodynamic load is taken up by the remaining collagen, and whether the aorta goes on to dilate and to rupture depends on the collagen metabolism in the individual concerned. Collagen turnover is greatly increased in aneurysm wall, with large amounts synthesized in the adventitia, leading to the characteristic thick outer layer. The new collagen is not laid down in a lamellar pattern, and although thicker, the wall is less strong than normal aorta.
Matrix Metalloproteinases Matrix metalloproteinases (MMPs) are a family of enzymes responsible for degradation of extracellular matrix components, including elastin and collagen. Studies in experimental aneurysms support the hypothesis that proteolytic activity is important in aneurysm expansion. Perfusion of rat aortas with elastase rapidly generates aneurysmal dilatation. In the same model, treatment with doxycycline, an MMP inhibitor, reduces aneurysm development, and this is associated with depression of MMP-9 activity.31
Summary: Proteolysis in Aortic Aneurysm Wall On histologic examination, elastolysis is one of the earliest observable events in aneurysm genesis. Aneurysm tissue, compared with normal and athero-occlusive aorta, contains high levels of proteases, particularly MMPs, the main source of which is infiltrating macrophages. These enzymes degrade the extracellular components of the aortic wall, in particular elastin and collagen. Inhibition of MMP activity in experimental aneurysms attenuates aneurysm growth. These observations support the concept of excessive proteolytic activity in aortic wall that causes destruction of the extracellular matrix, leading to weakening, dilatation, and eventually rupture of the aorta.
Smooth Muscle Cell Loss In addition to the changes in the extracellular matrix, aortic aneurysms exhibit marked changes in cellular structure of the vessel wall. The infiltration of the aortic wall with inflammatory cells has been discussed. In the normal aorta, the predominant cell type is the vascular smooth muscle cell (SMC), arranged in concentric elastic lamellae in the tunica media. The SMCs both contribute to the tone of the vessel wall and synthesize the bulk of the matrix proteins and are therefore important in maintaining structural integrity. In addition, SMCs influence extracellular matrix turnover by expression of MMPs and tissue inhibitors of metalloproteinases. In the aneurysm wall, therefore, there is an apparent conflict between synthesis of connective tissue proteins by aortic SMCs and matrix degradation by infiltrating inflammatory cells. This suggests that SMC function might be a pivotal factor in the formation of aortic aneurysms. Any diminution in SMC numbers would deplete a population of cells capable of synthesizing components of the vessel wall and could contribute to weakening and dilatation of the aorta. There is a notable reduction in the number of SMCs in the media of aortic aneurysms relative to normal and atherosclerotic aortas as measured by immunohistochemistry for
a–SMC actin and a reduction in SMC density of 74%.37 The decrease in the SMC population of aneurysm wall coincides with chemical and ultrastructural evidence of SMC apoptosis.38 Intact SMCs remaining within the aneurysm wall display loss of cell volume, cytoplasmic contracture, dissolution of cytoskeletal actin fragments, and distortion of intracellular organelles. The nuclei show clumping and fragmentation of chromatin, changes consistent with apoptosis. These morphologic and histochemical findings are supported by molecular studies. The protein p53 has been implicated in the induction of physiologic cell death in a range of tissues including vascular SMCs39 and is used as a marker for apoptosis. By use of a combination of immunohistochemistry and reverse transcriptase–polymerase chain reaction, p53 and p53 mRNA were localized to the cytoplasm and nuclei of SMCs and detected in greater quantities in aneurysm tissue (by nearly fourfold) compared with normal and atherosclerotic occlusive aorta. These findings taken together suggest that the SMC population in aortic aneurysms is depleted by apoptosis and that this process may occur, at least in part, through mechanisms involving increased expression of p53. The stimuli leading to induction of physiologic cell death remain to be defined, although a number of different mechanisms have been proposed. Atherosclerotic lesions produce high concentrations of oxidants such as nitric oxide, oxygen free radicals, and oxidized low-density lipoproteins. These substances have been reported to induce apoptosis of vascular SMCs in vitro.40 The proximity of SMCs in aneurysm wall to intimal plaque may allow diffusion of these oxidants into the media, resulting in cytotoxic effects on SMCs. This concept alone could not account for SMC depletion in aneurysms or one would expect to see aneurysmal dilatation wherever there is atheroma; clearly, this is not the case. The paucity of vasa vasorum in the infrarenal aorta has been implicated in the development of aortic aneurysms.41 Healthy infrarenal aorta has far fewer vasa vasorum than the proximal aorta or other mammalian aorta of similar size, and the cells of the media are more dependent on diffusion from the lumen for delivery of oxygen and nutrients. Development of atherosclerosis and intimal thickening may exacerbate the situation, resulting in a chronic insufficiency of oxygen and nutrients in the aortic media. Both hypoxia and serum deprivation induce apoptosis of vascular SMCs in vitro, so it is reasonable to speculate that the same effects might occur in aneurysm wall. The chronic inflammation seen in the media and adventitia of aneurysms may have deleterious effects on SMCs. Many of the cytokines produced by inflammatory cells, for example, IL-lb, tumor necrosis factor a, and interferon g, are known to induce apoptosis in vascular SMCs in vitro,42 and these mediators are present in high concentrations in aneurysmal wall. PGE2 in particular, originating in adventitial macrophages, is present in very high levels43 and has a concentration-dependent deleterious effect on aortic SMC proliferation.5 PGE2 may also increase SMC apoptosis.5 There are therefore several mechanisms that could account for the diminution of SMCs seen in AAA.
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Several different laboratories using different methodologies have provided convincing evidence that the principal cell type secreting MMPs in AAA wall is the macrophage.32 MMP-2 and MMP-9 in particular have been localized to macrophages at the adventitial-medial junction.33 Numerous studies have demonstrated abnormal proteolytic activity in human aortic aneurysm wall compared with normal or atherosclerotic aorta.34 Aneurysm tissue contains high concentrations of a range of matrix-degrading enzymes, including serine proteases and MMPs. MMPs appear to play the dominant role in disrupting the aortic wall.35 MMPs 2, 3, and 9 have been identified in high amounts. Studies have shown MMP-2 to be the dominant enzyme in small aneurysms (4 to 5.5 cm); MMP-9 predominates for aneurysms in the 5- to 7-cm range.13,36 MMP-9 concentration actually declines in large (>7 cm) aneurysms, implying that as aneurysms enlarge, hemodynamic rather than biochemical factors may dominate the rate of expansion. Distribution of MMP within aneurysm wall is not homogeneous, and it has been suggested that localized pockets of very high MMP-9 activity could predispose toward aneurysm rupture.
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The Role of Risk Factors in Aneurysm Development and Rupture Gender: Abdominal Aortic Aneurysms Are Less Common but More Dangerous in Women Since the publication of the U.K. Small Aneurysm Trial results, it has become necessary to make a distinction between the risk factors predisposing to aneurysm development and those leading to rupture. The trial yielded a cohort of 2257 patients, of whom 103 suffered AAA rupture during the 7-year period of follow-up. This permitted analysis of the factors that influence aneurysm rupture.3 The study confirmed that even quite small aneurysms may rupture, but such events are rare. Five factors, each of which was associated with an increased risk of rupture, were identified: female gender, mean arterial blood pressure, active smoking, reduced FEV1 (forced expiratory volume in 1 second), and aneurysm diameter. Screening studies have shown that the prevalence of AAA is much lower in women than in men.44 Consequently, advocates of screening usually suggest that such programs be aimed at the male population. The striking finding from the U.K. Small Aneurysm Trial was that female sex conferred a threefold greater risk of rupture, even after adjustment for age, initial aneurysm diameter, body mass index, and height. Moreover, the mean AAA diameter preceding rupture was smaller in women (5.0 0.8 cm) than in men (6.0 1.4 cm). This study therefore demonstrated that although aneurysms are less common in women, those female patients who do develop aneurysms are at substantially higher risk of rupture than their male counterparts are. This suggests that the diameter at which repair of an AAA is indicated is smaller in women than in men.
elastin disruption by the nitrite ion49 and potentiation of neutrophil elastase activity.50 Smoking therefore is a risk factor for development and expansion of aortic aneurysms and appears to have effects independent of promoting atherosclerosis, perhaps by potentiating elastin degeneration. Although smoking is associated with increased aneurysm growth rates, it has not yet been demonstrated that stopping smoking slows aneurysm expansion. Most patients find it difficult to stop smoking, and it is problematic to randomize patients to a “stopping smoking” arm of a trial.
Hypertension The role of blood pressure in aneurysm development was discussed earlier (see the section on pathophysiology, mechanical considerations). Hypertension has been shown to be associated with aneurysm rupture,3 an important finding because hypertension is treatable and control of blood pressure may reduce the likelihood of rupture.
Aneurysm Diameter The changes in mechanical stresses that occur in aneurysm wall in the course of dilatation were discussed earlier (see the section on pathophysiology, mechanical considerations). The alterations in tension within an aneurysm wall are predictable according to Laplace’s law and go some way toward explaining the observation in practice that risk of rupture increases as an aneurysm enlarges. Measurement of aneurysm diameter is the best-known indicator of rupture risk but unfortunately has serious limitations. Small aneurysms can and do rupture (especially in women), although the risk is low. The risk escalates sharply for aneurysms of more than 6 cm in diameter.3
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Cigarette smoking is strongly associated with the development of aortic aneurysms6 and appears to be the strongest risk factor after age. In the North American Aneurysm Detection and Management (ADAM) study,45 smoking was the strongest risk factor for aortic aneurysms, with an odds ratio of 5.57. Aneurysm risk increased with the number of years of smoking and decreased with number of years since stopping smoking. Cigarette smoking has been found to be much more common in young patients (3 cm asymptomatic side (measured 10 cm below tibial tuberosity)
1
Pitting edema confined to the symptomatic leg
1
Collateral superficial veins (nonvaricose)
1
Previously documented deep venous thrombosis
1
Alternative diagnosis as likely as or greater than that of deep venous thrombosis
2
*In patients with symptoms in both legs, the more symptomatic leg is used. Pretest probability is calculated as the total score: high 3; moderate, 1 or 2; low 0.
Table 14.4 Wells’ clinical assessment model for the pretest probability of lower extremity deep venous thrombosis.
Figure 14.6 Doppler ultrasound appearance of deep venous thrombosis. The superficial femoral vein is filled with echogenic material representing thrombus, and no flow can be identified in the vein on Doppler evaluation. Flow can be identified in the adjacent artery on color Doppler evaluation (arrows).
department. The clinical limitations of ultrasonography are its poor ability to diagnose isolated calf vein thrombosis and its reduced sensitivity in patients with asymptomatic disease. The variability in the diagnostic accuracy of ultrasonography in detecting calf vein thrombosis may be related to the small size of the thrombus, the experience of the sonographers, and the differences in populations of patients. The usefulness of ultrasonography is also somewhat reduced in patients with significant leg edema or morbid obesity because of the inability of the ultrasound beam to adequately penetrate the tissues and to visualize the veins. Any equivocal findings on ultrasonography should be confirmed with contrast venography. When venography is not available or is contraindicated because of medical reasons (e.g., allergy to the contrast material, renal failure), serial ultrasonography is recommended. This requires the patient to return to the ultrasound department for one or two repeated ultrasound examinations during the next 5 to 10 days. Serial ultrasonography will help detect potential proximal extension of a calf thrombus if one is missed on initial presentation. Proximal extension into the larger veins of the leg may occur in 20% to 30% of patients who present with isolated calf vein thrombosis. Untreated calf vein thrombosis may spontaneously resolve in 20% of cases and is considered to be less significant in terms of the risk of clinically important sequelae.16 Venography is more reliable than ultrasonography in detecting smaller thrombi in the calf veins, but it is an invasive study that requires the injection of iodinated contrast material into a small vein in the foot and visualization of the venous flow by fluoroscopy. An intraluminal filling defect on two or more views is considered diagnostic of acute deep venous thrombosis. Other findings, such as nonfilling of veins and abrupt cutoff of contrast dye, are less reliable as diagnostic criteria. Phlebitis or allergic reactions to the contrast material occur in up to 2% of patients. The examination is uncomfortable for patients and is technically demanding. Many centers do not have the expertise to perform adequate venography. The contrast load is also contraindicated in patients with renal insufficiency or severe congestive heart failure. Magnetic resonance imaging has a limited role for diagnosis of acute deep venous thrombosis but is a valuable tool in detecting cerebral venous thrombosis.17,18 Its ability to differentiate old versus new thrombus on the basis of signal characteristics of the thrombus is also an advantage over ultrasonography. This feature is particularly important for diagnosis of recurrent deep venous thrombosis, which remains difficult to diagnose by ultrasonography and venography. Acute thrombi are usually hypoechoic and expand the caliber of the vessel on ultrasonography. As the thrombus matures, it usually contracts and becomes more echogenic. However, these criteria are difficult to apply in individual patients and are unreliable in diagnosis of recurrent thrombosis, especially in patients without previous studies for comparison. Contrast-enhanced computed tomographic scanning of the lower extremities has been used to detect deep venous thrombosis in combination with scanning of the chest for pulmonary emboli. There are reports exhibiting the high accuracy of this double imaging technique used in patients thought to have acute pulmonary embolism.19,20 However, critics have pointed to the large dose of radiation from this
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these imaging techniques, testing of D-dimer levels in the blood has been established as a reliable test for exclusion of acute deep venous thrombosis in symptomatic patients. Although contrast venography remains the reference standard technique for diagnosis of deep venous thrombosis, the most popular test is venous ultrasonography. The compression technique in combination with real-time B-mode imaging has proved to be sensitive (95%) and highly specific (96%) for diagnosis of symptomatic, proximal deep venous thrombosis.15 This involves the application of direct pressure on the transverse diameter of the vein with the ultrasound transducer. Inability to fully compress the vessel is considered diagnostic for deep venous thrombosis. In many centers, three-point compression at the inguinal region, mid thigh, and popliteal fossa is the standard approach to detect deep venous thrombosis in the leg. Other strategies involve compression along the length of the femoral vein and the popliteal vein, below the calf trifurcation, and into the calf veins. The addition of Doppler or color imaging does not substantially add to the accuracy of compression ultrasonography but is sometimes helpful for identifying the vessel and assessing the amount of residual blood flow (Fig. 14.6). In addition to imaging of the veins, the ultrasound examination is useful for detecting conditions that can mimic deep venous thrombosis, such as ruptured Baker’s cyst or an abscess. The entire examination usually takes no longer than 10 to 15 minutes. The major advantages of ultrasonography are that it does not use ionizing radiation and is noninvasive, readily available, and relatively inexpensive. Portable ultrasound machines are also available for examination in the hospital of patients who are too ill to be transported to the radiology
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approach and the limited accuracy of the venous imaging portion. Venography is considered the current standard for diagnosis of recurrent deep venous thrombosis, but it is limited by availability and the expertise required to perform the test and to interpret the findings. D-dimer testing is a useful tool to exclude acute deep venous thrombosis.21 D-dimer assays were developed about 2 decades ago to measure this degradation product of crosslinked fibrin. D-dimers are generated when a thrombus undergoes physiologic breakdown through the process of fibrinolysis. To date, many different assays have been evaluated for their accuracy in diagnosis of deep venous thrombosis, but not all are clinically useful.21,22 Currently, all D-dimer assays are based on enzyme-linked immunosorbent assay, latex agglutination, or whole blood red cell agglutination techniques. The enzyme-linked immunosorbent assays provide quantitative results and have a sensitivity of more than 95% but a specificity of 30% or less. New-generation quantitative latex agglutination assays have comparable sensitivities and marginally higher specificities. The whole blood red cell agglutination assay has a sensitivity of about 85% and specificity ranging from 30% to 60%.22 Older latex agglutination tests are not useful for diagnosis of deep venous thrombosis because of poor sensitivity and low specificity, but they are reasonable for crude measurements of D-dimer, as in cases of disseminated intravascular coagulopathy. The lack of specificity of D-dimer testing is due to the elevation of D-dimer levels in nonthrombotic situations, such as infection, inflammation, pregnancy, and malignant disease. In general, a positive D-dimer test result is not useful because the test lacks specificity, whereas a negative result helps exclude acute deep venous thrombosis in selected clinical situations. However, the results of D-dimer assays should not be used alone in the assessment of suspected deep venous thrombosis. Because of the lack of specificity of the D-dimer testing, it should be used only in conjunction with another diagnostic test or a validated clinical prediction rule. Management studies have shown that it is safe to withhold anticoagulant therapy in patients with a negative D-dimer assay result in combination with either a normal finding on ultrasound examination or a low probability of deep venous thrombosis.23 The likelihood for development of deep venous thrombosis in such patients during the next 3 months is less than 2%. Therefore, the appropriate use of D-dimer testing can reduce the need for ultrasound examinations to investigate patients with a suspected first episode of deep venous thrombosis. By the combination of clinical assessment with the available technologies, deep venous thrombosis can be reliably diagnosed in almost all patients on initial presentation.24,25 A reasonable diagnostic strategy for suspected lower extremity deep venous thrombosis is shown in Figure 14.7. Although this strategy simplifies the diagnostic process and reduces the cost associated with investigations, it does not replace the physician’s clinical judgment, which should be appropriately exercised in all cases.
Superficial Thrombophlebitis
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Superficial thrombophlebitis is mainly diagnosed on the basis of the clinical examination. A palpable red and tender cord representing the thrombosed vessel is characteristic.
DIAGNOSTIC STRATEGY FOR DEEP VENOUS THROMBOSIS OF THE LOWER EXTREMITIES
Signs or symptoms of suspected DVT
Clinical probability
Low clinical probability
Intermediate or high clinical probability
D-dimer test
Venous ultrasonography
Negative
Positive
Positive
Negative
Exclude DVT
Venous ultrasonography
Diagnose DVT
D-dimer test
Positive*
Negative
Positive
Negative
Diagnose DVT
Exclude DVT
Serial venous ultrasonography†
Exclude DVT
Positive
Negative
Diagnose DVT
Exclude DVT
* Re-evaluate history and review ultrasound examination for features suggestive of old rather than new thrombosis. If ultrasound findings are inconclusive, venography should be considered. † In patients with a high clinical probability or who cannot return for serial ultrasonography, venography is recommended. Venography can also be considered in patients with cardiorespiratory compromise.
Figure 14.7 Diagnostic strategy for deep venous thrombosis (DVT) of the lower extremities.
Confirmation can be obtained with venous ultrasonography. Thrombosis is detected with the same ultrasound criteria as are used for deep venous thrombosis.
Venous Insufficiency The sine qua non of venous insufficiency is incompetent venous valves. In patients with varicose veins, the incompetent valves are in the superficial veins, resulting in reflux and venous stasis of these small vessels. In patients with deep venous thrombosis, damage to the valves may result in the development of postphlebitic syndrome. Doppler ultrasonography is the test of choice to identify the presence and location of refluxing venous segments. Retrograde flow of blood in superficial, communicating,
Veins of the Upper Extremities As it is for lower extremity deep venous thrombosis, venous ultrasonography is the favored initial screening test; contrast venography remains the reference standard for diagnosis of deep venous thrombosis of the upper limbs. However, because the proximal sections of the subclavian and innominate veins are poorly visualized and cannot be compressed under the clavicle, ultrasonography is not as accurate in this setting compared with detection of deep venous thrombosis of the legs.27 In patients with central venous catheters or pacemaker wires, visualization of the entire vein may also be obscured. Large thrombi are usually identified, but small thrombi can be missed (Fig. 14.8). Use of dampening or absence of Doppler signals alone as the criterion for diagnosis of deep venous thrombosis is unreliable because extrinsic
A
venous compression from central masses or strictures can produce the same results. Therefore, contrast venography should be used if the ultrasound findings are equivocal and the clinical features are compatible with upper extremity thrombosis.
Central Veins Inferior Vena Cava Thrombosis Doppler ultrasonography can diagnose venous thrombosis in the inferior vena cava or the iliac veins in the pelvis either directly by visualizing the thrombus or indirectly by detecting dampening of the Doppler spectrum in the common femoral veins in the legs. Visualization of the inferior vena cava and iliac veins is sometimes difficult because of their greater depth and overlying bowel gas, which frequently blocks the ultrasound beam. Obstruction of the hepatic veins or the adjacent inferior vena cava (Budd-Chiari syndrome) can be easily identified by ultrasound examination because the liver frequently serves as a good acoustic window in transmitting the ultrasound beam. Computed tomography and magnetic resonance imaging are other alternative studies that can demonstrate masses and thrombosis that obstruct either the pelvic veins or the inferior vena cava. Contrast agents are required in these tests to help delineate thrombus from surrounding soft tissue structures.
Superior Vena Cava Thrombosis Doppler ultrasonography can be used initially to diagnose superior vena cava obstruction. Central thrombus extending into the subclavian or more distal vessels can be readily detected. However, isolated central thrombi in the superior vena cava and other conditions obstructing central venous return (e.g., masses or fibrosis) are not well visualized by ultrasonography because the bony thorax blocks the ultrasound beam. The normal variations that occur from transmitted pressure changes related to respiration and atrial contractions may be reduced or completely eliminated. In most instances, contrast-enhanced computed tomography is the test of choice in investigating a patient with symptoms of superior vena cava syndrome (Fig. 14.9). This study can detect thrombosis in the central vasculature and may also provide an
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and deep veins can readily be identified, particularly with color Doppler study. Venous reflux of more than 0.5 second is considered abnormal.26 Other studies that aid in the diagnosis of venous insufficiency include photoplethysmography and direct measurements of venous pressure, which is typically elevated in this condition. Photoplethysmography relies on color changes to assess refilling rates of small skin veins after exercise. These rates are substantially reduced in patients who have significant venous insufficiency. Direct venous pressure measurements require the placement of a small needle with a pressure transducer in a vein in the foot.
B Figure 14.8 Thrombus surrounding a central venous catheter. This 29-year-old man with Crohn’s disease presented with arm swelling. A, Echogenic thrombus (arrows) surrounding the catheter in the basilic vein. B, The catheter can be seen to extend more proximally through the subclavian vein into the superior vena cava. No thrombus surrounds the more proximal portion of the catheter (arrows) in the subclavian vein.
Figure 14.9 Obstruction of the superior vena cava caused by mediastinal adenopathy. In this 55-year-old man with lung carcinoma, a lymph node mass (arrows) is obstructing the superior vena cava. Multiple collateral vessels are demonstrated (arrowheads).
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alternative diagnosis for the symptoms of venous congestion (e.g., bronchogenic carcinoma). Magnetic resonance imaging is also being used to evaluate conditions that obstruct the central veins within the thorax. It can demonstrate venous patency as well as identify thrombi, masses, strictures, or fibrosis, which can obstruct the veins. Intravascular contrast agents are useful in differentiating thrombus from other pathologic processes. Magnetic resonance imaging can also be useful in patients who are not able to receive iodinated contrast media because of severe allergic-type reactions or renal insufficiency. However, patients who receive gadolinium-based contrast agents can also have allergic-type reactions, particularly if they have been demonstrated to have a previous allergic reaction to iodinated contrast material. Pacemakers and many types of cerebral aneurysm clips preclude patients from undergoing this test. A reasonable diagnostic imaging strategy for suspected deep venous thrombosis in the upper extremity, neck, or superior vena cava is shown in Figure 14.10.
DIAGNOSTIC STRATEGY FOR DEEP VENOUS THROMBOSIS OF THE UPPER EXTREMITIES OR SUPERIOR VENA CAVA
Signs or symptoms of suspected central venous thrombosis of upper limbs, neck, or chest: New arm swelling New asymmetric facial swelling Upper arm or shoulder pain Pitting edema of the arm Cyanosis of the arm Dilated superficial veins of the chest wall
MANAGEMENT Veins of the Lower Extremities Deep Venous Thrombosis The most effective way of reducing the frequency of venous thrombosis is to use prophylaxis in appropriate clinical situations. Low-, moderate-, and high-risk situations can be identified on the basis of the patient’s inherent risk of venous thromboembolism and the external factors that can heighten the risk of thrombosis (see Tables 14.1 and 14.2). In high-risk situations, up to 50% to 60% of the patients may develop venous thromboembolism, and approximately 2% to 4% of them will experience fatal pulmonary embolism.28 Although prophylaxis is effective in reducing the risk by 50% to 80%, a substantial number of patients with high risk will still develop deep venous thrombosis. The options for prophylaxis are mechanical (e.g., compression stockings, pneumatic compression devices) and pharmacologic (e.g., subcutaneous unfractionated or low-molecular-weight heparin). The decision to use either or both mechanical and chemical prophylaxis should take into consideration the patient’s risk factors for bleeding and the ability of the patient to tolerate lower extremity compression. Table 14.5 outlines the general recommendations for prophylaxis in various medical and surgical settings.28 Prophylaxis should be continued as GENERAL RECOMMENDATIONS FOR PROPHYLAXIS OF DEEP VENOUS THROMBOSIS General medical disorders Low-dose unfractionated heparin or low-molecular-weight heparin Elastic compression stockings may be added to pharmacologic agents Acute spinal cord injury
Ultrasonography
Low-molecular-weight heparin Presence of echogenic material compatible with thrombus
Equivocal results
Absence of echogenic material*
If anticoagulation is contraindicated, intermittent pneumatic compression with elastic compression stockings General surgery Early ambulation
Diagnose upper limb thrombosis
Serial ultrasonography in five or more days
For low- or moderate-risk surgery, low-dose unfractionated heparin or low-molecular-weight heparin For high-risk surgery (e.g., cancer), low-molecular-weight heparin
Contrast venography or computed tomography
For patients with active or a high risk of bleeding, intermittent pneumatic compression Orthopedic surgery
Intraluminal filling defect
No intraluminal filling defect
Diagnose upper limb thrombosis
Exclude upper limb thrombosis
* In patients with no echogenic material visualized on ultrasound examination, venography should be performed if the clinical suspicion is high. Otherwise, serial ultrasonography is a reasonable alternative.
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Figure 14.10 Diagnostic strategy for deep venous thrombosis of the upper extremities or superior vena cava.
For total hip replacement: warfarin, low-molecular-weight heparin, fondaparinux, or adjusted-dose unfractionated heparin For total knee replacement: warfarin, low-molecular-weight heparin, fondaparinux, or intermittent pneumatic compression For hip fracture: warfarin, low-molecular-weight heparin, or fondaparinux Neurosurgery Intermittent pneumatic compression or low-molecular-weight heparin with elastic stockings
Table 14.5 General recommendations for prophylaxis of deep venous thrombosis.
48 hours of starting a heparin or fondaparinux. In North America, the most common agent used is warfarin. Because of the narrow therapeutic window, the anticoagulant response must be measured and monitored on a regular basis to adjust the warfarin dose to maintain therapeutic levels.36 An international normalized ratio of 2.0 to 3.0 is considered the acceptable therapeutic range for oral anticoagulation in deep venous thrombosis. The ratio is calculated on the basis of the measured prothrombin time and the sensitivity of the specific reagent used to measure the prolonged clotting time. This standardization of the prothrombin time measurement allows direct comparisons of results from different laboratories. Low-molecular-weight heparin is now the preferred therapy for initial and long-term treatment of deep venous thrombosis and pulmonary embolism in patients with cancer.37,38 It is more efficacious than the traditional regimen with heparin followed by a coumarin derivative and does not require laboratory monitoring. The optimal duration of anticoagulation after an episode of deep venous thrombosis is dependent on a number of factors. Clinical trials have shown that a minimum of 3 months is required, but longer periods of anticoagulation are recommended for patients with ongoing risk factors, such as active cancer, or who have had previous episodes of thrombosis.39,40 Continuing vitamin K antagonist therapy is highly effective and will reduce the risk of recurrent thrombosis by more than 80%, but this is accompanied by a risk of major bleeding of 1% to 12% per year. Therefore, the decision to continue or to stop anticoagulant therapy should be based on the risk of recurrent thrombosis versus the risk of major, serious bleeding in each individual patient. Preliminary data have suggested that D-dimer levels may be useful in stratifying patients into different risk groups for recurrent thrombosis.41 Some general recommendations for the duration of therapy are outlined in Table 14.6. Second-line therapies for acute treatment of deep venous thrombosis include thrombolytic therapy and inferior vena cava filter placement. Unfortunately, the efficacy and safety of these modalities have not been sufficiently investigated in clinical trials. Catheter-directed or systemic thrombolysis to treat extensive proximal lower extremity deep venous thrombosis has been advocated by some, particularly if the thrombus extends into the iliac veins in the pelvis. Although there is evidence that radiographic thrombus resolution is accelerated by thrombolytic therapy, significant improvement in clinical recovery or a reduction in the risk of postphlebitic syndrome has not been demonstrated.42 Furthermore, the risk of major bleeding, especially intracranial bleeding, is approximately 2% in patients who receive thrombolysis.43 A recent randomized trial comparing unfractionated heparin alone with different thrombolysis regimens showed venographic improvement with thrombolysis but a substantially higher rate of major bleeding and pulmonary embolism.44 Clearly, risk assessment tools are necessary to identify those patients who may benefit from thrombolysis. Limited evidence is available for the use of inferior vena cava filters. A multicenter, randomized clinical trial demonstrated that inferior vena cava filters can reduce the risk of early pulmonary embolism in patients with proximal deep venous thrombosis who were also treated with anticoagulant
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long as the patient remains at risk for thrombosis, and studies suggest that prophylaxis should be extended beyond hospital discharge in certain populations of patients, such as those having hip replacement or cancer surgery. The standard treatment of symptomatic deep venous thrombosis is systemic anticoagulant therapy with a heparin followed by a coumarin derivative.29,30 Many new anticoagulants are being developed, and some have the potential to replace traditional agents.31 In the past decade, the use of low-molecular-weight heparins has largely replaced the traditional standard of unfractionated heparin for the initial treatment of venous thromboembolism, and more recently, a synthetic, indirect activated factor X inhibitor, fondaparinux, was shown to be comparable to heparins for initial treatment.32,33 In comparison with unfractionated heparin, low-molecular-weight heparins and fondaparinux have more predictable anticoagulant effects, require no laboratory monitoring, can be given subcutaneously, and are associated with a lower risk of heparin-induced thrombocytopenia. Large meta-analyses have also shown that unmonitored, weightadjusted subcutaneous low-molecular-weight heparin is safer and more effective than unfractionated heparin administered by continuous infusion guided by laboratory monitoring of the activated partial thromboplastin time.34 Low-molecularweight heparins and fondaparinux also have the advantage of being available on an outpatient basis, thereby improving the patient’s general quality of life and leading to substantial cost savings by reducing hospitalization. Once a diagnosis of deep venous thrombosis has been confirmed, a low-molecular-weight heparin can be started with weight-based dosing. Laboratory monitoring is not required routinely, but it is recommended in patients with renal insufficiency, with morbid obesity, or who are pregnant. The peak anti-Xa levels at 3 to 4 hours after an injection should be measured in these patients because the pharmacokinetics and pharmacodynamics of these drugs have not been well studied in these special populations of patients. Similarly, the distribution and clearance of these drugs may be different in patients who have extensive iliofemoral deep venous thrombosis or who are hemodynamically unstable because of accompanying pulmonary emboli. These patients require hospitalization and are usually treated with unfractionated heparin. Unfractionated heparin should be given as an initial bolus followed by a continuous intravenous infusion. A weight-based or standard nomogram should be used to adjust the dose of unfractionated heparin according to the activated partial thromboplastin time to ensure that therapeutic levels are reached as soon as possible and are maintained.35 Like low-molecular-weight heparins, fondaparinux is given subcutaneously once daily in doses adjusted for the patient’s weight, and it is cleared by the renal route. Unlike the heparins, fondaparinux can cross the placental barrier; it has been used in pregnant women with heparin hypersensitivity, but the safety data are very limited. These parenteral agents should be given for a minimum of 5 days in patients with uncomplicated thrombosis and for 7 days or longer in those who have extensive disease. These agents must also be continued until the anticoagulant level achieved by the coumarin derivative is therapeutic for at least 2 days. Oral anticoagulant therapy with use of a coumarin derivative or vitamin K antagonist is usually given within 24 to
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therapy; but after 2 years, this benefit was lost, and the patients who received a filter were more likely to develop recurrent deep venous thrombosis.45 Furthermore, there was no difference in the long-term mortality between patients with a filter and those without. On the basis of current evidence, the insertion of an inferior vena cava filter should be reserved for settings in which anticoagulation is contraindicated.46,47 One possible approach to provide early protection against pulmonary embolism without increasing the risk of recurrent deep venous thrombosis is to use a temporary or retrievable filter. Further studies are required to evaluate this potential option.
Venous Insufficiency Graduated compression stockings remain the first line of treatment for venous insufficiency. Although frequently useful for reducing swelling and providing pain relief, stockings do not address the underlying problem of valvular insufficiency. Compliance also tends to be poor because of cost, unattractiveness, and difficulty with putting the stockings on. In patients who are not responsive to conservative measures, more invasive treatment methods are available. In patients who have venous insufficiency that is isolated to the superficial system, the injection of sclerosing agents into the involved veins may be beneficial in mild cases. More extensive reflux can be dealt with by stripping, if possible, all of the incompetent veins. Laparoscopic techniques have now been developed as an alternative to open surgical methods in suitable patients.48 These measures to deal with reflux of the superficial veins are not successful if there is also reflux of the deep veins. Simply stripping or sclerosing the refluxing superficial venous segments can exacerbate limb swelling by eliminating collateral pathways. Several surgical techniques are available for reflux of the deep veins, including direct repair of the valves and transposition of venous segments with competent valves. Success rates are disappointing. Patients with skin ulcerations are treated with local wound care. Skin grafting and plastic surgery may be required in severe cases.
Superficial Thrombophlebitis Superficial thrombophlebitis, without accompanying deep venous thrombosis, usually does not require treatment with
systemic anticoagulation. Warm compresses, nonsteroidal anti-inflammatory agents, and leg elevation are usually effective methods of providing symptomatic relief. Patients who do not respond to these conservative measures will usually respond rapidly to a short course of subcutaneous unfractionated or low-molecular-weight heparin therapy.49 Recurrent or refractory cases should prompt the physician to look for an underlying cause, such as malignant disease or inherited thrombophilia.
Veins of the Upper Extremities Deep Venous Thrombosis Very little research has been done to study the optimal treatment for deep venous thrombosis of the upper extremities. For patients with either primary (or effort-related) thrombosis or catheter-related thrombosis of the subclavian or axillary vein, conventional treatment consists of initial therapy with either low-molecular-weight or unfractionated heparin, followed by long-term oral anticoagulant therapy.50 Anticoagulation should be continued for a minimum of 3 months, longer if a catheter remains in place. As it is for lower extremity deep venous thrombosis, the use of thrombolysis or other more aggressive interventions is controversial. Many vascular surgeons consider catheter-directed thrombolysis to be the preferred initial treatment of selected patients with primary upper extremity deep venous thrombosis. The risk of recurrent thrombosis and postphlebitic syndrome may be reduced, but long-term evidence to support this is lacking. Post-lysis venography may allow better visualization of the involved anatomy to test for positional, extrinsic venous compression at the thoracic outlet, thereby facilitating plans for more aggressive intervention, if indicated. Venous angioplasty and subsequent stenting can correct underlying strictures, although surgical decompression has been found to be necessary to maintain long-term venous patency in patients with significant thoracic outlet obstruction. Catheter-related thrombosis should be treated conservatively with anticoagulant therapy. Removal of the catheter is not necessary and has not been shown to improve outcomes. If the catheter is functioning, routine use should continue. If the catheter is blocked, patency sometimes returns after a few days of anticoagulation, and the catheter can
GENERAL RECOMMENDATIONS FOR THE DURATION OF ANTICOAGULATION FOR DEEP VENOUS THROMBOSIS
Patient Characteristics Associated with Thrombotic Event
Risk of Recurrence
Duration of Anticoagulant Therapy
Reversible major risk factor (major surgery, pelvic or leg trauma, major medical illness)
10% per year
Extended or indefinite therapy*
Unprovoked thrombotic event with heterozygous factor V Leiden or prothrombin G20210A mutation Recurrent unprovoked events with or without thrombophilic state identified Unprovoked thrombotic event with antithrombin, protein C, or protein S deficiency; homozygous factor V Leiden; double heterozygosity; antiphospholipid antibody syndrome; advanced malignant disease
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*May consider longer duration of therapy on the basis of the patient’s preference and risk of bleeding.
Table 14.6 General recommendations for the duration of anticoagulation for deep venous thrombosis.
be salvaged for use. Previously, prophylaxis with low-dose warfarin was recommended, but more studies have shown that low-dose anticoagulant prophylaxis with either warfarin or low-molecular-weight heparin is not effective.
Thrombosis of the inferior or superior vena cava requires systemic anticoagulation to prevent clinically significant pulmonary emboli and to relieve venous obstruction. Interventional radiologic techniques can be used to instill thrombolytic agents directly into the thrombi in certain patient subsets. This may result in faster lysis of thrombi and control of local symptoms. In patients who cannot tolerate anticoagulant therapy, placement of a vena caval filter is indicated because of the high incidence of pulmonary embolism.
PROGNOSIS Prognosis depends on the etiology of the venous disease. Overall, anticoagulant therapy is effective in treating uncomplicated deep venous thrombosis of the upper or lower extremities. The most common complications are pulmonary embolism, recurrent deep venous thrombosis, and postphlebitic syndrome. Pulmonary embolism occurs in 40% of patients who present with deep venous thrombosis, but most of these cases are asymptomatic, and treatment does not differ. The risk of recurrent thrombosis after a 3-month course of anticoagulant therapy is approximately 2% to 5% per year in patients with provoked or secondary deep venous thrombosis and 10% to 15% per year in those with idiopathic thrombosis. About 5% of the recurrent thrombotic events are fatal. Postphlebitic syndrome occurs in up to 50% of patients, but the majority of the cases are mild and manageable with conservative treatment. Anticoagulantrelated bleeding must also be considered in patients receiving long-term anticoagulation. The risk of major bleeding is approximately 1% to 3% per year, but it varies considerably, depending on a number of patient-related factors. Approximately 20% of all major bleeding events are fatal. Patients with poor prognosis after an episode of deep venous thrombosis are those with underlying malignant disease or aggressive thrombophilia (e.g., antiphospholipid antibody syndrome). Cancer patients have a substantial risk of recurrent thrombosis despite conventional anticoagulation with heparin and vitamin K antagonist therapy. These patients also have a higher risk of bleeding due to thrombocytopenia, invasive procedures, and other comorbid conditions. Lowmolecular-weight heparins are more effective and probably safer than vitamin K antagonist therapy in patients with cancer. Although extended or indefinite anticoagulant therapy is
SUMMARY Venous thromboembolism is the most common disease affecting the veins. It affects approximately 0.1% of persons per year, and the incidence rises dramatically with increasing age. The basic pathophysiologic process involves perturbation of the hemostatic balance to favor thrombosis. This can result from venous stasis, vessel wall damage or endothelial dysfunction, or hypercoagulability from excessive activation of the coagulation pathway. Although many patients develop deep venous thrombosis in the presence of risk factors, deep venous thrombosis can also occur without obvious provocation. Some of the patients with idiopathic thrombosis have an inherited or acquired thrombophilic condition, whereas the remainder have no identifiable biochemical or genetic abnormality. Many noninvasive methods are now available to diagnose deep venous thrombosis, but contrast venography remains the reference standard. Compression ultrasonography is the initial test of choice in evaluating a patient with suspected deep venous thrombosis of the extremities, but equivocal or conflicting results require further confirmatory testing. The cornerstone of deep venous thrombosis prevention and treatment is systemic anticoagulant therapy, which is highly effective but somewhat burdensome. To reduce the incidence of thrombosis, prophylaxis should be used in appropriate medical and surgical settings. In patients with confirmed deep venous thrombosis, outpatient low-molecular-weight heparin therapy is the initial treatment of choice, but these agents must be given as subcutaneous injections. Long-term therapy with a vitamin K antagonist is needed to prevent recurrent thrombosis, but laboratory monitoring is necessary to ensure adequate anticoagulant levels and to minimize the risk of bleeding. Monotherapy with low-molecular-weight heparin is preferred to vitamin K antagonists in patients with cancer. The long-term prognosis of most patients with venous thrombosis is favorable, provided the diagnosis is accurate and adequate treatment is instituted without significant delay. Serious morbidity and mortality can result from misdiagnosis, delayed treatment, or treatment-related complications.
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Central Veins
generally recommended in patients with metastatic disease, quality of life and life expectancy are important issues to consider in deciding on how long to treat these patients with anticoagulant therapy. Indefinite anticoagulant therapy may also be indicated in some patients with symptomatic antiphospholipid antibody syndrome. Some of these patients are also resistant to conventional anticoagulant therapy, and a combination of antithrombotic and antiplatelet agents may be necessary to prevent recurrent thrombotic events.
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chapter
Surgery for Vascular Disease Henrik Sillesen
Surgery is indicated or necessary only for a minority of patients with manifestations of vascular disease. The majority of patients, even those who are symptomatic, may be managed by lifestyle changes and medical therapy. Therefore, the vascular physician sees many more patients than are eventually treated by either endovascular or open surgery. In the author’s institution, there are almost 6000 outpatient visits for 1100 procedures annually. Surgery for vascular disease is performed to treat symptoms (intermittent claudication, rest pain, ischemic ulcers, abdominal angina), to prevent strokes (carotid disease), to prevent amputation (critical limb ischemia), or to save the life of the patient (to prevent death from ruptured abdominal aortic aneurysm). In asymptomatic patients with atherosclerotic disease, surgery may be performed to prevent stroke (asymptomatic carotid disease) or death from a ruptured abdominal aortic aneurysm or to treat severe hypertension (renal artery disease). In common for all vascular operations are the following facts: n The operation does not cure the underlying disease. n There is considerable comorbidity in the majority of cases. n For many procedures, the rate of complications is considerable. n Many patients are not managed properly with respect to medical therapy and changes in lifestyle.
based in 1991, and resection of abdominal aortic aneurysm was later shown to be beneficial. A number of trials have demonstrated the value of other procedures; however, newer trials have shown that not all procedures benefit patients because of the major comorbidity in some of these patients. More recently, some (including this author) have questioned the validity of older trials comparing best medical treatment with medical treatment plus surgery. The trials showing the benefit of carotid endarterectomy randomized patients 20 years ago (before the use of statins, today’s antihypertensive drugs, and newer antiplatelet agents); thus, “best medical” treatment has developed tremendously since then and most certainly provides much greater prevention compared with medical treatment at that time (see later discussion). Owing to the limitations of a chapter on surgery for vascular disease in a cardiology textbook, this chapter focuses on the main three areas covering more than 90% of surgery for arterial vascular disease: peripheral arterial disease, aortic aneurysms, and carotid disease (Fig. 15.1). Surgical management of mesenteric artery and renovascular disease is also covered. A short section on management of acute deep venous thrombosis is also included.
Surgery for vascular disease has evolved dramatically during the last 25 years. In Denmark, the number of procedures has increased sixfold in this period. Interestingly, endovascular therapy was developed for peripheral arterial disease more than 40 years ago, and today approximately 25% to 50% of procedures employ this technique. In contrast, it was much later that endovascular techniques were undertaken for treatment of coronary artery disease, for which the majority of patients are managed today by percutaneous coronary intervention. There are a number of reasons for this considerable difference. First, the length of the lesions responsible for chronic lower limb ischemia is often 20 to 30 cm in addition to tandem lesions. Second, flow is low in the resting state, which for most patients is the majority of the time. These conditions predispose to treatment failure; even primary failure to pass the lesion with a guide wire is not uncommon. Vascular surgery was among the first surgical specialties to have level I and level II evidence to guide management decisions. Endarterectomy for carotid stenosis became evidence
Peripheral arterial disease, like atherosclerosis in other vascular beds, is a chronic condition that develops during decades. On average, symptoms from the lower limbs develop 5 to 10 years later than from the coronary circulation. Acute ischemia may develop because of thrombosis in a vessel with preexisting atherosclerotic plaques or stenosis, be due to embolism (i.e., from mural thrombus in the heart or an arterial lesion upstream), or be a result of trauma. Peripheral arterial disease is traditionally divided into four stages (Fontaine): n asymptomatic: ankle-brachial index (ABI) 65 mm)
Tachycardia
Low cardiac index (130 ms), cardiac resynchronization therapy has demonstrated significant benefit in reducing both morbidity and mortality in symptomatic patients with an ejection fraction of 35% or less.105 Meanwhile, for end-stage heart failure patients, ventricular assist device support can provide the last-resort option with better survival over medical therapy,106 and it may even have the ability to provide an opportunity for the reversal of ventricular remodeling in some patients.107 Other advanced cardiothoracic surgical options include coronary artery bypass surgery and valvular surgeries, ventricular remodeling surgery, and cardiac transplantation. Last, controversy about the use of long-term anticoagulation in heart failure persists. There are no data from randomized, controlled clinical trials to guide us in this regard. There is still considerable controversy about who should receive anticoagulation in the setting of heart failure. Even aspirin is controversial. A randomized, controlled trial is seemingly unrealistic; the event rate is so low as to mandate a very large sample size with prolonged follow-up. For now, patients with a previously documented systemic embolism, patients with atrial fibrillation, patients with large anterior myocardial infarction and very low ejection fraction, and patients with noncompaction cardiomyopathy should be considered for anticoagulation. A retrospective analysis of the Studies of Left Ventricular Dysfunction
(SOLVD) database indicated that patients receiving either aspirin or warfarin derive an additional survival advantage over patients who are not anticoagulated.108
Patients who have heart failure represent a growing epidemic. Whereas morbidity, mortality, and age-adjusted incidence and prevalence of coronary heart disease are all declining, heart failure and atrial fibrillation are becoming more common.
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SUMMARY
These two conditions are largely diseases of older patients, and we can expect further incremental growth as the population continues to age. Therapy is improving, but there is still much room for the development of innovative technologic and pharmacologic interventions. We are now in an era of consensus guidelines, evidence-based medicine, and cost controls. It is contingent on physicians to keep abreast of developments, particularly with regard to randomized controlled trials, which, in combination with skillful judgment, are most likely to advance the overall best interest of our patients.
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Management of the Patient with Chronic Heart Failure Barry M. Massie
Definition n
Chronic heart failure is a common condition that is responsible for a large number of deaths and considerable morbidity and cost.
Key Features n
Management of the patient with chronic heart failure must be multifaceted, including both pharmacologic therapy and nonpharmacologic approaches, such as dietary and activity counseling, patient and family education, and close follow-up.
n
The goals of pharmacologic therapy are first to prevent heart failure and, once it is present, to improve symptoms, to prevent progression of left ventricular dysfunction, and to prolong survival.
Therapy n
Appropriate use of diuretics is critical to symptom management, but treatment with neurohormonal antagonists, including angiotensin-converting enzyme inhibitors, beta blockers, and spironolactone, is the key to preventing progression and prolonging survival.
n
In patients who are in sinus rhythm, digoxin is primarily used as an adjunct in patients who remain symptomatic despite optimal treatment with diuretics and these neurohormonal antagonists.
n
The roles of implantable cardioverter-defibrillators and cardiac resynchronization with biventricular pacemakers are evolving.
Chronic heart failure (CHF) is a common condition that is growing in both incidence and prevalence.1 The pathophysiology and diagnosis of CHF are covered in Chapters 68, 69, 71, and 73. Despite major advances in the pharmacologic treatment of patients with CHF, mortality rates often exceed 10% per year and range from 20% to 50% in the most severely affected patients.1 CHF also remains a major cause of morbidity and a major user of health care resources, primarily because it is one of the most frequent causes of disability and admission to the hospital in older individuals.1
UNDERLYING ABNORMALITIES Although CHF may be caused by abnormalities of the heart valves, congenital conditions, or excessive systemic metabolic or flow requirements, there is underlying myocardial damage or dysfunction in the large majority of cases. The symptoms and signs of CHF primarily reflect the severity of underlying myocardial dysfunction and the resulting hemodynamic derangements.2 These may result from impaired systolic (contractile) function caused by the loss of myocardium (from
myocardial infarction or progressive cardiomyopathy) or dysfunction of still viable myocardium (ischemia, tachycardia, or exposure to excessive endogenous hormonal stimulation or exogenous toxins). Alternatively or concomitantly, the dysfunction may be primarily diastolic as a result of reduced myocardial compliance or impaired myocardial relaxation, usually due to myocardial fibrosis or hypertrophy.
IDENTIFICATION OF REVERSIBLE CONDITIONS Relatively few of the causes of CHF are reversible or amenable to specific treatment, but these should be assiduously sought and addressed (see Chapters 69 and 81).3-5 The most important of these are valvular abnormalities and myocardial ischemia resulting from coronary artery disease. These conditions can usually be recognized or suspected from the patient’s history and physical examination, with confirmation by echocardiography for valvular abnormalities and stress testing or coronary angiography in the case of myocardial ischemia. Other relatively common reversible conditions (as a result of avoidance, treatment, or spontaneous remission) include alcohol, thyroid dysfunction, myocarditis, tachyarrhythmias, and bradyarrhythmias.
GOALS OF THERAPY In most patients with CHF, there is no specific treatment; nonetheless, a growing number of nonpharmacologic and drug treatments are available that substantially improve symptoms and outcomes. Table 72.1 lists the goals of CHF treatment and some of the approaches that have proved effective in achieving them.
Prevention The importance of measures for the prevention of heart failure has only recently been adequately emphasized. The American College of Cardiology/American Heart Association CHF guidelines adopted a new approach to the classification of heart failure that emphasizes both the evolution and the progression of the disease (Table 72.2).3 Four stages are defined, the first two of which identify patients in whom prevention is the key goal: n Stage A consists of patients who are at high risk for the future development of CHF but have no identifiable structural abnormality of the heart. n Stage B refers to patients who have structural abnormalities that are known to predispose to CHF but have never experienced symptoms of heart failure.
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Goal
Examples
Prevention
Blood pressure control (especially systolic blood pressure) Treatment of dyslipidemia Secondary prevention in postinfarction patients Beta blockers Angiotensin-converting enzyme inhibitors Antithrombotic therapy Treatment of dyslipidemia Treatment of asymptomatic left ventricular dysfunction Angiotensin-converting enzyme inhibitors Beta blockers
Symptom reduction and improved activity tolerance
Exercise training Diuretics Angiotensin-converting enzyme inhibitors Digoxin Beta blockers
Prevent progression (remodeling)
Angiotensin-converting enzyme inhibitors Beta blockers Spironolactone* Angiotensin receptor blockers{ Cardiac resynchronization (biventricular pacing)
Prolong survival
Angiotensin-converting enzyme inhibitors Beta blockers Spironolactone Angiotensin receptor blockers*{ Implantable cardioverterdefibrillators*
Reduce resource use
Disease management Diuretics Angiotensin-converting enzyme inhibitors Beta blockers Digoxin Spironolactone Cardiac resynchronization
*Treatment that has not been definitively demonstrated to accomplish a goal but is likely to do so on the basis of other results and the known mechanisms of action. { For use in patients intolerant of angiotensin-converting enzyme inhibitors.
Table 72.1 Goals of treatment in chronic heart failure.
n n
980
Stage C includes patients with current or prior symptoms of CHF. Stage D identifies patients with end-stage disease who require specialized treatment strategies.
Figure 72.1 schematically indicates the progression of heart failure and the appropriate interventions at each stage.
Key interventions to prevent heart failure in stage A are the rigorous control of hypertension (especially systolic hypertension in older patients),6 lipid-lowering treatment in those at risk for myocardial infarction,7 and use of angiotensin-converting enzyme (ACE) inhibitors in patients at high risk for vascular events.8 The primary preventive measures in stage B are interventions in postinfarction patients to prevent recurrent infarction or left ventricular remodeling or dysfunction (ACE inhibitors, beta blockers, antithrombotic agents, and lipid-decreasing treatments)9-11 and in patients with asymptomatic left ventricular dysfunction of other causes (ACE inhibitors, beta blockers).10,12
Amelioration of Symptoms For patients with clinical CHF, the first objective of treatment is to reduce symptoms and improve quality of life. To a significant degree, the symptoms are caused by volume retention and the underlying hemodynamic abnormalities. Thus, salt restriction, diuretics, and other agents that reduce ventricular filling pressures and improve cardiac output (digoxin, direct-acting vasodilators, and ACE inhibitors) are effective. However, the origin of the most frequent symptoms, exercise intolerance and dyspnea, is complex and multifactorial, reflecting in part abnormalities of skeletal muscle and ventilation.13 Exercise training has emerged as one of the most effective interventions for relief of symptoms.14
Prevent Progression The greatest advance in the management of CHF during the past 2 decades has been the recognition that several medications can prevent progressive left ventricular dysfunction and dilatation, a process often termed remodeling. Although the initial abnormalities in CHF result in hemodynamic dysfunction, the deleterious effects of excessive neurohormonal responses to these derangements are responsible for progression of this syndrome.15,16 Excessive circulating and myocardial concentrations of angiotensin II, aldosterone, catecholamines, endothelin, and proinflammatory cytokines appear to induce or to exacerbate myocyte loss and dysfunction and interstitial fibrosis. This leads to progressive myocardial dilatation, pathologic hypertrophy, and further dysfunction. Inhibitors of the renin-angiotensin-aldosterone system and beta blockers prevent or even reverse this remodeling process, thereby preventing further deterioration of left ventricular function.
Prolong Survival Medications that prevent or slow the progression of left ventricular dysfunction would be expected to prolong survival, and this has proved to be the case with ACE inhibitors,17,18 beta blockers,19-22 and spironolactone.23 However, 40% to 50% of deaths in patients with CHF are sudden, and therefore the goal of prolonging survival entails prevention of sudden death. Although sudden death is often believed to be caused by ventricular fibrillation, there are a number of potential underlying mechanisms in the setting of heart failure, including myocardial infarction and bradyarrhythmias resulting from sinus node or conduction abnormalities and reflex-mediated responses to severe hemodynamic abnormalities.24 Beta blockers, in particular, have reduced the incidence of sudden death by 40% to 50%, probably by affecting each of these mechanisms.25
STAGES OF HEART FAILURE FROM THE AMERICAN COLLEGE OF CARDIOLOGY/AMERICAN HEART ASSOCIATION GUIDELINES Description
Examples
A
Patients at high risk of developing HF because of the presence of conditions that are strongly associated with the development of HF. Such patients have no identified structural or functional abnormalities of the pericardium, myocardium, or cardiac valves and have never shown signs or symptoms of HF
Systemic hypertension; coronary artery disease; diabetes mellitus; history of cardiotoxic drug therapy or alcohol abuse; personal history of rheumatic fever; family history of cardiomyopathy
B
Patients who have developed structural heart disease that is strongly associated with the development of HF but who have never shown signs or symptoms of HF
Left ventricular hypertrophy or fibrosis; left ventricular dilatation or hypocontractility; asymptomatic valvular heart disease; previous myocardial infarction
C
Patients who have current or prior symptoms of HF associated with underlying structural heart disease
Dyspnea or fatigue due to left ventricular systolic dysfunction; asymptomatic patients who are undergoing treatment for prior symptoms of HF
D
Patients with advanced structural heart disease and marked symptoms of HF at rest despite maximal medical therapy and who require specialized interventions
Patients who are frequently hospitalized for HF or cannot be safely discharged from the hospital; patients in the hospital awaiting heart transplantation; patients at home receiving continuous intravenous support for symptom relief or being supported with a mechanical circulatory assist device; patients in a hospice setting for the management of HF
72
Table 72.2 Stages of heart failure from the American College of Cardiology/American Heart Association guidelines.3,4
STAGES IN THE EVOLUTION OF HEART FAILURE AND RECOMMENDED THERAPY BY STAGE
e.g., Patients with • Hypertension • Coronary artery disease • Diabetes mellitus or
e.g., Patients with Structural heart disease
Patients • Using cardiotoxins • with FHx CM
Therapy • Treat hypertension • Encourage smoking cessation • Treat lipid disorders • Encourage regular exercise • Discourage alcohol intake, illicit drug use • ACE inhibition in appropriate patients (see text)
• Previouus MI • LV systolic dysfunction • Asymptomatic valvular disease
Development of symptoms of HF
Therapy • All measures under stage A • ACE inhibition in appropriate patients (see text) • Beta blockers in appropriate patients (see text)
Stage C Structural heart disease with prior or current symptoms of HF
e.g., Patients with • Known structural heart disease • Shortness of breath and fatigue, reduced exercise tolerance
Stage D Refractory HF requiring specialized interventions
e.g., Patients who have marked symptoms at rest despite maximal medical therapy (e.g., those who are recurrently in hospital or cannot be safely discharged from the hospital without specialized interventions)
Refractory symptoms of HF at rest
Therapy • All measures under stage A • Drug for routine use: Diuretics ACE inhibitors Beta blockers Digitalis Dietary salt restriction
Therapy • All measures under stage A, B and C • Mechanical assist devices • Heart transplantation • Continuous (not intermittent) IV inotropic infusions for palliation • Hospice care
Figure 72.1 Stages in the evolution of heart failure and recommended therapy by stage. ACE, angiotensin-converting enzyme; FHx CM, family history of cardiomyopathy; HF, heart failure; IV, intravenous; LV, left ventricular; MI, myocardial infarction. (With permission from Hunt SA. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult. J Am Coll Cardiol 2005;46:e1-e82.)
Although antiarrhythmic drugs have appeared to have more adverse than beneficial effects in this setting, there is growing evidence supporting wider use of implantable cardioverterdefibrillators (see Chapter 66).26 Coronary revascularization and cardiac transplantation are appropriate approaches in selected individuals (see Chapter 75).
HEART FAILURE AND CARDIOMYOPATHY: CONGESTIVE HEART FAILURE: Management of the Patient with Chronic Heart Failure
HF, heart failure.
Stage B Structural heart disease but without symptoms of HF
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Stage
Stage A At high risk for heart failure but without structural heart disease or symptoms of HF
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Reduce Use of Resources A final goal of CHF management is to reduce use of resources. The key to this is the optimal use of effective medications and dietary modification. Any intervention that accomplishes the first three objectives should also prevent admission to the hospital and reduce the cost of managing CHF.
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However, prescription of medications does not appear to be sufficient in many patients. Specific strategies have been designed to prevent heart failure readmissions by use of nurse case managers, heart failure clinics, home visits, and home monitoring.27,28
NONPHARMACOLOGIC INTERVENTIONS Although drug treatment of CHF has advanced markedly during the past 2 decades, nonpharmacologic interventions continue to have an important and sometimes critical role. These are often neglected by physicians because it is thought that patients are unlikely to follow their recommendations, but for many patients, compliance with these approaches is no worse than that with medication use. Table 72.3 lists nonpharmacologic approaches that have an important role in the effective management of patients with CHF.
Dietary Recommendations Sodium and Fluid Restriction As a result of activation of the renin-angiotensin-aldosterone system and changes in glomerular hemodynamics that favor proximal sodium reabsorption, CHF is a salt-retaining state. Therefore, salt restriction is an important component of the management of all symptomatic patients. With the advent of potent diuretics, severe sodium restriction is no longer essential in mild to moderate CHF, but these patients should
NONPHARMACOLOGIC APPROACHES FOR THE MANAGEMENT OF CHRONIC HEART FAILURE Approach
Recommendations
Dietary advice
Sodium restriction of 2.5 g (2.0 g in more severe heart failure) Fluid restriction, primarily for hyponatremia Low-fat diet and calorie restriction when indicated Abstention from alcohol or restriction to one drink per day
Activity and exercise counseling
Encourage regular activity in all patients Exercise training and cardiac rehabilitation in stable, motivated patients
Patient and family education
Explanation of heart failure and its common symptoms Reasons for salt restriction Medications and importance of compliance Need for daily weight measurements Recognition and management of worsening heart failure
Disease management approaches
982
Home visits by nurse or pharmacist Telephone monitoring and counseling by nurse Automated transfer of weight and vital sign data Comprehensive heart failure clinics
Table 72.3 Nonpharmacologic approaches for the management of chronic heart failure.
not use added salt and should avoid excessively salty food, limiting their daily sodium intake to 2 to 2.5 g (about 5 to 6 g of salt). High salt intake in patients taking diuretics increases potassium loss and exacerbates hypokalemia. Only with more severe symptoms and high diuretic requirements does it become essential to restrict daily sodium consumption further, to 1.2 to 1.8 g (3 to 4.5 g of salt). As important as limiting overall salt intake is the need to minimize fluctuations in sodium intake so that the diuretic requirements can be matched to the sodium intake. Fluid restriction is not a necessary component of CHF management, except in the minority of patients with refractory fluid retention, significant hyponatremia, or severely impaired renal function. Hyponatremia is typically a result of excessive activation of the renin-angiotensin and arginine-vasopressin systems, both of which stimulate thirst and the latter of which causes retention of free water. Severe hyponatremia (serum sodium concentration 40%; results pending
Irbesartan
75 mg
150-300 mg
I-Preserve: 3600-patient trial in patients with heart failure and preserved ejection fraction (45%)
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HEART FAILURE AND CARDIOMYOPATHY: CONGESTIVE HEART FAILURE: Management of the Patient with Chronic Heart Failure
There is compelling evidence that inhibition of the reninangiotensin-aldosterone system results in symptomatic and prognostic improvement in patients with CHF and prevents progressive deterioration of left ventricular function in patients with asymptomatic systolic dysfunction.4,5,18,31,39,44 This has been demonstrated both early after large myocardial infarction and in patients with chronically reduced ejection fractions. Three classes of agents are available that inhibit some components of the renin-angiotensin-aldosterone system: ACE inhibitors, ARBs, and aldosterone antagonists. However, the more frequent and severe occurrence of angioedema with vasopeptidase inhibitors without counterbalancing evidence of greater benefit may prevent their approval. Table 72.7 lists the most commonly used inhibitors of the renin-angiotensin-aldosterone system, with their mechanisms of action, doses, and major clinical results in patients with CHF and left ventricular systolic dysfunction. These are discussed in greater detail in the following.
Aldosterone antagonists Spironolactone
25 mg q24h
25 mg q24h
RALES23: "survival, #hospitalizations in severe CHF
Eplerenone
50 mg q24h
50-100 mg q24h
EPHESUS55: 17% reduction in mortality in post–myocardial infarction patients with ejection fraction 40% and heart failure
Table 72.7 Inhibitors of the renin-angiotensin-aldosterone system in chronic heart failure.
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ACE inhibitor unless it is not tolerated or is contraindicated. Although physicians have been very cautious in prescribing these agents, there are few contraindications to their use. These include pregnancy, history of angioedema, known severe bilateral renal artery stenosis, and uncorrected hyperkalemia (potassium concentration >5.5 mmol/L). Although ACE inhibitors may cause significant and sometimes symptomatic hypotension and worsening renal function when they are initiated, even systolic blood pressures below 80 mm Hg (if asymptomatic) and serum creatinine concentrations above 3.0 mmol/L are not absolute contraindications to their use if appropriate caution and monitoring are used. Patients with increased risk of early hypotension, renal dysfunction, or hyperkalemia include those with preceding low blood pressures (systolic 100 mg/day, enalapril >15 mg/day), even in patients with severe CHF. The Assessment of Treatment with Lisinopril and Survival (ATLAS) trial showed a beneficial trend in survival and a significant 25% reduction in the composite of mortality plus admissions to the hospital for heart failure in patients treated with doses of lisinopril close to 30 mg compared with doses of 5 mg.47 Thus, it is recommended that doses for patients be titrated to the target doses used in the major trials, if these are tolerated. Asymptomatic hypotension, increases in serum creatinine concentration that stabilize, and potassium concentrations of 5.0 to 5.4 mmol/L should not be considered contraindications to further up-titration if appropriate caution is used.
Adverse Effects
988
Apart from the adverse effects discussed before, ACE inhibitors are generally safe and well tolerated. The most common side effect is dizziness, which is often unrelated to blood pressure changes and occurs in 5% to 15% of patients. This
often resolves spontaneously or with adjustment in concomitant medication (by avoiding simultaneous administration of several vasodilating or hypotensive agents). A chronic nonproductive cough occurs in 5% to 10% of patients (more frequently in women) and usually requires discontinuation if it recurs after rechallenge. Rashes occur in 1% to 3% of patients (most commonly with captopril), and angioedema occurs in less than 0.3% (more frequently in African Americans).
Angiotensin Receptor Blockers Results of Clinical Trials The rationale for and theoretical limitations to the use of ARBs are discussed earlier and have recently been reviewed.39 These agents have been shown to improve hemodynamic measurements in patients, without or with concomitant ACE inhibitor therapy.56,57 The Evaluation of Losartan in the Elderly (ELITE) trial tested the hypothesis that the ARB losartan would cause less renal dysfunction than the ACE inhibitor captopril. No difference was observed,49 but an unexpectedly lower number of deaths was observed in the losartan group, although the number of events was very small. The much larger ELITE II trial was designed to test the hypothesis that losartan is superior to captopril in prolonging survival in patients with CHF.50 This trial not only did not confirm the earlier result but demonstrated a trend to a greater mortality rate with losartan (hazard ratio, 1.13; CI, 0.9-1.35; P =.16). The occurrence of the secondary endpoint of sudden death plus resuscitated cardiac arrest was also greater with losartan (hazard ratio, 1.25; CI, 0.98-1.60; P =.08). A subsequent post–myocardial infarction trial, the Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan (OPTIMAAL), comparing captopril and losartan, also exhibited a trend toward poorer survival with losartan than with captopril (relative risk, 1.13; 95% CI, 0.99-1.28; P =.07).51 Whether these results are specific to losartan or to the relatively low dose used (50 mg once daily) or reflect a general advantage of ACE inhibitors over ARBs in these patients is uncertain. Trials soon to be completed that are using more potent doses of candesartan and valsartan in patients with heart failure and after myocardial infarction will address this question.54,58 The Valsartan Heart Failure Trial (Val-HeFT) evaluated the effect of adding the ARB valsartan to optimally treated patients, of whom 85% were receiving ACE inhibitors and 34% were receiving beta blockers.52 There was no difference in survival but a 13% lower incidence of the coprimary endpoint of mortality and heart failure morbidity (primarily admissions to the hospital for worsening CHF). The most impressive finding in this study was the highly significant reductions in mortality and combined mortality and morbidity in the 366 patients who were not taking ACE inhibitors.53 This trial provides the first evidence that ARBs share the beneficial effects on prognosis observed with ACE inhibitors.
Indications and Recommendations for Use Although confirmation is awaited from current trials, it is reasonable to recommend an ARB for patients with heart failure who do not tolerate an ACE inhibitor because of cough and, possibly, angioedema. However, the relative efficacy of these two classes is not clear, and the results with losartan raise the possibility that they are not equivalent.
Aldosterone Antagonists Clinical Trial Results
Indications and Recommendations for Use Although the RALES results are striking, they should not be extrapolated to very different groups of patients. Thus, spironolactone should be given to patients with NYHA class IV CHF who are receiving ACE inhibitors or those with advanced class III symptoms who are receiving substantial doses of loop diuretics. Although routine use of spironolactone in patients with milder CHF is not recommended, it may be reasonable to use this agent in place of potassium replacement in those with diuretic-induced hypokalemia. It should not be substituted for an ACE inhibitor and probably should not be used in place of standard diuretics in patients with fluid retention. Additional information is required before recommendations can be made concerning eplerenone.
Adverse Effects The main concern with aldosterone antagonists is hyperkalemia, and close monitoring is required. In RALES, potassium concentrations were measured every 4 weeks for 12 weeks and then at 3-month intervals, but an earlier measurement 7 to 14 days after initiation is prudent. Breast enlargement or pain was observed in 10% of men. Eplerenone, which has a lower affinity for androgen and progesterone receptors, may minimize this side effect,
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Beta Blockers Mechanisms of Action Activation of the sympathetic nervous system in CHF and its adverse prognostic significance have been recognized for many years.61 However, it has been uncertain whether sympathetic activation is an adaptive response that serves as a marker for severe CHF, whether it has a mechanistic role in the progression of myocardial dysfunction, or whether it exerts both roles at different stages of the disease. High concentrations of catecholamines are known to cause acute and chronic myocardial damage in humans (e.g., with pheochromocytomas) and in experimental models, but whether this process occurs in CHF and how it occurs are unclear. Potential mechanisms by which excessive catecholamine stimulation may cause myocardial damage include energetic imbalance (oxygen requirements exceeding supply), stimulation of pathologic myocardial hypertrophy, down-regulation and uncoupling of adrenergic receptors, desensitization of contractile proteins, increased oxidative stress, and induction of apoptosis.16,61-63 In addition, sympathetic activation and catecholamines can provoke arrhythmias by a variety of mechanisms. However, the conclusive evidence for the deleterious effects of sympathetic nervous system activation has come not from the laboratory but from the clinic, as treatment with beta blockers has proved not dangerous but rather protective and beneficial.
Results of Clinical Trials More than 14,000 patients with CHF have now been studied in randomized, placebo-controlled trials of beta blockers with mortality or mortality and morbidity endpoints.25,63 This experience substantially exceeds that with ACE inhibitors in CHF. Of the large-scale trials, three have used the b1-selective agents bisoprolol and metoprolol: the Cardiac Insufficiency Bisoprolol (CIBIS I) study,64 the CIBIS II trial,20 and the Metoprolol Randomized Intervention Trial in Heart Failure (MERIT-HF).21 Three have used the nonselective agents carvedilol and bucindolol: the U.S. carvedilol trials,19 the Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS),65 and the Beta-blocker Evaluation of Survival Trial (BEST).66 Carvedilol also has alpha-blocking activity, and bucindolol produces mild vasodilatation by a mechanism that is not clearly defined but may be intrinsic sympathomimetic activity. In all these studies, the beta blocker was added to background treatment that included diuretics and ACE inhibitors in the great majority and digoxin in many of the participants. Most of the patients had NYHA class II or class III symptoms, with a smaller number having class IV symptoms. The patients in COPERNICUS had severe class III or class IV symptoms but were required to be stable at the time of entry to the study. The upper limit for ejection fraction was generally 35% or 40%, but it was 25% in COPERNICUS. Table 72.8 summarizes the results from these trials. With the important exception of BEST, in each of the trials with more than 1000 participants, beta-blocker therapy produced substantial and highly significant reductions in mortality, exceeding 30%. In BEST, the 10% lower mortality rate with bucindolol was not statistically significant and differed substantially from that observed with the other agents.66 Whether
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In the past, it was assumed that ACE inhibitors would suppress aldosterone concentrations, and therefore spironolactone was not considered for treatment of CHF. Indeed, because of the potential risk of hyperkalemia with the two agents together, spironolactone was generally considered to be contraindicated. However, the observation that aldosterone concentrations remain increased in CHF despite chronic treatment with ACE inhibitors and experimental data indicating that spironolactone prevents myocardial fibrosis in models of hypertension and left ventricular hypertrophy led to a reconsideration of its role.43 To this end, the Randomized Aldactone Evaluation Study (RALES) trial—a survival study in 1663 patients with severe CHF defined by NYHA class IV symptoms at entry or within the previous 30 days and ejection fractions of less than 35%— was undertaken, comparing spironolactone (25 mg/day) with placebo.59 To the surprise of most physicians and many investigators, spironolactone was associated with a 30% reduction in mortality (95% CI, 18%-40%; P < .001) and a 35% lower occurrence of death plus admission to the hospital because of CHF (95% CI, 23%-46%). Serious hyperkalemia was uncommon, but patients were observed carefully, with frequent laboratory testing. In practice, spironolactone has been used in less severe heart failure, sometimes in place of or in the absence of concomitant diuretic treatment, raising important safety concerns.60 A new, more selective aldosterone antagonist, eplerenone, should become available shortly. This agent has been investigated in hypertensive patients and appears to be as effective as spironolactone. Eplerenone has not been studied in CHF, but a large trial of post–myocardial infarction patients with heart failure or left ventricular dysfunction, EPHESUS (EPlerenone’s neuroHormonal Efficacy and SUrvival Study),55 demonstrated a 17% reduction in death, with the main impact being on sudden death, and a significant decrease in heart failure hospitalizations. Importantly, these benefits were observed on top of ACE inhibitors and beta blockers in most patients.
but a relatively high risk of hyperkalemia has been noted in hypertension studies, especially in diabetic patients.
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MAJOR BETA-BLOCKER HEART FAILURE TRIALS
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Drug and Trial
Starting Dose
Target Dose
Population
Main Results
Metoprolol (b1 selective) MERIT-HF21
12.5-25 mg q24h (SR)
200 mg q24h
Class II-IV*
34% # mortality, 41% # sudden death, #hospitalizations
Bisoprolol (b1 selective) CIBIS I64 CIBIS II20
1.25 mg q24h
5 mg q24h
Class II-III
Trend toward # mortality, #hospitalizations
1.25 mg q24h
10 mg q24h
Class III-IV*
34% # mortality, 44% # sudden death, #hospitalizations
Carvedilol (nonselective, weak alpha blockade)
3.125 mg q12h
25-50 mg q12h
Class II-III
38% # death þ cardiovascular hospitalizations
U.S. trials program19 COPERNICUS65
3.125 mg q24h
25 mg q12h
Class III-IV
35% # death, 24% # death or hospitalization
Bucindolol (nonselective, weak vasodilator) BEST66
3 mg q12h
50-100 mg q12h
Class III-IV
Nonsignificant 10% # in mortality, #hospitalizations
Carvedilol vs. metoprolol IR COMET67
Carvedilol, 3.125 mg bid
Carvedilol, 25 mg bid
Class II-IV*
17% # in mortality with carvedilol compared with metoprolol IR
Metoprolol IR, 5 mg bid
Metoprolol IR, 50 mg bid
*Class IV patients in MERIT-HF and CIBIS II had relatively low mortality rates and probably did not have very severe CHF.
Table 72.8 Major beta-blocker heart failure trials.
this can be attributed to differences in characteristics of the patients (BEST included sicker patients and a substantial proportion of blacks, neither of which groups benefited), differences in the pharmacology of the study drug (possible intrinsic sympathomimetic activity), or chance is unclear. However, COPERNICUS enrolled patients with equally severe or more severe CHF and had a strikingly positive result with carvedilol, which is a nonselective beta blocker.65 Sudden cardiac death was also reduced by 40% to 50%.25 When assessed in these trials, symptoms consistently improved, but exercise capacity did not increase. Importantly, in all of these large studies, there were significant reductions in CHF hospitalizations. Although early deterioration was observed in some patients treated with beta blockers, during long-term therapy, withdrawals for worsening heart failure were generally less frequent in the beta blocker–treated patients.
Indications and Recommendations for Use
990
This large favorable clinical trial experience supports a recommendation that beta blockers be used in all patients with CHF who have stable class II or class III symptoms attributable to left ventricular systolic dysfunction unless contraindicated.4,5 On the basis of the results of COPERNICUS and the small numbers of patients with severe heart failure in CIBIS II and MERIT, patients with current or recent class IV symptoms should also be treated if they are clinically stable and free of volume overload and the treating physician is experienced in management of these patients. The role of beta blockers in asymptomatic left ventricular dysfunction is less well established, but the favorable results from a group of 366 patients within the U.S. carvedilol trials and the extensive experience with beta blockers in postinfarction patients suggest that beta blockers should be considered in these patients also. Evidence for the use of beta blockers in postinfarction patients with reduced systolic function has been strengthened by the findings of the Carvedilol
Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) study,11 in which 1959 patients with recent myocardial infarction and ejection fraction no greater than 40% were treated with carvedilol titrated to 25 mg twice daily or placebo. Mortality was lower in the carvedilol group (hazard ratio, 0.77; CI, 0.60-0.98; P =.03), as was the composite of death or recurrent nonfatal infarction (hazard ratio, 0.71; CI, 0.57-0.89; P =.002). The keys to the successful use of beta blockers are the selection of appropriate candidates, initiation of treatment at very low doses, and gradual up-titration with close monitoring (Table 72.9). In general, patients should be stable and free of significant volume overload when beta blockers are initiated because early deterioration may occur. Diuretics and ACE inhibitors should be initiated, and their doses should be stabilized. However, recent trials have demonstrated that once they are stabilized, patients with advanced heart failure and patients in whom treatment with beta blockers is initiated at the end of hospital admissions may actually exhibit the greatest benefit, although some of them will not tolerate these drugs. Contraindications to the use of beta blockers include asthma or severe chronic obstructive pulmonary disease with bronchospasm, symptomatic bradycardia or atrioventricular block, and insulin-requiring diabetes with frequent hypoglycemic episodes. Most patients with chronic obstructive pulmonary disease, however, tolerate at least low-dose betablocker treatment well, although use of a b1-selective agent is preferable. Patients with heart rates below 60 beats per minute need to be monitored closely and may benefit less than those with resting tachycardia. Asymptomatic hypotension (systolic blood pressure 60 beats per minute and absence of more than first-degree atrioventricular block No noncardiac contraindications to beta blockade Starting doses Carvedilol, 3.125 mg q12h Metoprolol tartrate, 6.25-12.5 mg q12h or q24h in severe heart failure Metoprolol succinate (extended release), 12.5-25 mg q24h Bisoprolol, 1.25 mg q24h Monitoring If pretreatment systolic blood pressure 50 beats per minute Consider pacemaker if indication for beta blocker is strong Management of decompensation Diuretics are first line of therapy Try to avoid abrupt discontinuation of beta blocker, but may reduce by 50% and taper gradually if necessary Inotropic support with dobutamine or milrinone (milrinone may be more effective with beta blocker)
Table 72.9 Recommendations for administration of beta blockers in chronic heart failure.
treatment. Titration should occur in intervals of no less than 2 weeks and may be performed at routine visits at longer intervals. Approximately 10% of stable patients will experience some degree of worsening heart failure, usually several days after the first or second titration step. This can generally be managed by increasing the doses of diuretics while maintaining or dropping back one step on the dose of beta blocker. The other relatively frequent side effects during
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Stable class II or class III symptoms and left ventricular ejection fraction 85
80–84
75–79
60–64
55–59
50–54
45–49
40–44
35–39
30–34
25–29
20–24
15–19
10–14
50% and LVEDVI < 97 mL/m2
Evidence of abnormal LV relaxation, filling, diastolic distensibility, and diastolic stiffness
Invasive hemodynamic measurements mPCW > 12 mm Hg or LVEDP > 16 mm Hg or τ > 48 ms or b > 0.27
TD E/E’ > 15
15 > E/E’ > 8
Biomarkers NT-proBNP > 220 pg/mL or BNP > 200 pg/mL
Biomarkers NT-proBNP > 220 pg/mL or BNP > 200 pg/mL
Echo-blood flow Doppler E/A>50yr < 0.5 and DT>50yr > 280 ms or Ard − Ad > 30 ms or LAVI > 40 mL/m2 or LVMI > 122 g/m2 ( );149 g/m2 ( ) or Atrial fibrillation
TD E/E’ > 8
DHF
HEART FAILURE AND CARDIOMYOPATHY: CONGESTIVE HEART FAILURE: Diastolic Heart Failure
Symptoms or signs of heart failure
Figure 73.8 Diagnostic flow chart to diagnose diastolic heart failure in a patient suspected of having diastolic heart failure. Ad, duration of mitral valve atrial wave flow; Ard, duration of reverse pulmonary vein atrial systole flow; b, constant of left ventricular chamber stiffness; BNP, brain natriuretic peptide; DHF, diastolic heart failure; DT, deceleration time; E, early mitral valve flow velocity; E0 , early TD lengthening velocity; E/A, ratio of early (E) to late (A) mitral valve flow velocity; LAVI, left atrial volume index; LVEDP, left ventricular end-diastolic pressure; LVEDVI, left ventricular end-diastolic volume index; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; mPCW, mean pulmonary capillary wedge pressure; NT-proBNP, N-terminal pro brain natriuretic peptide; TD, tissue Doppler; t, time constant of left ventricular relaxation.
(t > 48 ms), or the LV stiffness modulus (b > 0.27). Noninvasive diagnostic evidence of diastolic LV dysfunction is preferably derived from myocardial tissue Doppler examination (E/E0 > 15; E, early mitral valve flow velocity; E0 , tissue Doppler early diastolic lengthening velocity). If myocardial tissue Doppler examination yields values suggestive of but nondiagnostic for diastolic LV dysfunction (15 > E/E0 > 8), tissue Doppler examination needs to be implemented with other noninvasive investigations to provide diagnostic evidence
of diastolic LV dysfunction. These noninvasive investigations can consist of the following: n a blood flow Doppler study of mitral valve flow velocity (E/A ratio < 0.5 and deceleration time > 280 ms combined, for patients older than 50 years; A, atrial mitral valve flow velocity) eventually combined with pulmonary vein flow velocity (Ard Ad > 30 ms; Ard, duration of atrial reverse pulmonary vein flow velocity; Ad, duration of atrial mitral valve flow velocity);
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n n
an echocardiographic measure of left atrial volume index (>40 mL/m2) or of LV mass index (women, >122 g/m2; men, >149 g/m2); an electrocardiogram with evidence of atrial fibrillation; or a determination of plasma level of BNP (>200 pg/mL) or NT-proBNP (>220 pg/mL).
If the plasma level of NT-proBNP is above 220 pg/mL or the plasma level of BNP is above 200 pg/mL, diagnostic evidence of diastolic LV dysfunction also requires additional noninvasive investigations, which can consist of the following: n tissue Doppler evaluation (E/E0 ratio); n mitral or pulmonary vein blood flow Doppler study (E/A ratio and deceleration time combined; Ard Ad index); n echocardiographic measures of LV mass index or left atrial volume index; or n electrocardiographic evidence of atrial fibrillation. The use of different echocardiographic techniques allows a comprehensive noninvasive assessment of LV relaxation, LV diastolic stiffness, and LV filling pressures.37
Scoring Systems for the Diagnosis of Diastolic Heart Failure The updated diagnostic flow chart provided by the Heart Failure and Echocardiography Associations of the European Society of Cardiology35 uses a dichotomous approach for the diagnosis of diastolic heart failure, which is either present or absent. A more refined approach consists of scoring systems that yield distinct levels of evidence for diastolic heart failure labeled definite, probable, and possible34 or that list major and minor criteria38; at least two major criteria need to be satisfied, eventually implemented with minor criteria such as LV hypertrophy, left atrial enlargement, or evidence of diastolic LV dysfunction. Unfortunately, these scoring systems antedate the widespread clinical use of tissue Doppler examination, which is now recognized to provide the most accurate noninvasive measures of LV diastolic stiffness.39
How to Exclude Diastolic Heart Failure
1006
Diastolic heart failure is frequently a challenging differential diagnosis in a work-up for breathlessness in the absence of detectable signs of fluid overload. The Heart Failure and Echocardiography Associations of the European Society of Cardiology therefore also proposed a set of criteria for the exclusion of diastolic heart failure (Fig. 73.9).35 If a patient with breathlessness and no signs of fluid overload has an NT-proBNP level of less than 120 pg/mL or a BNP level of less than 100 pg/mL, any form of heart failure is virtually ruled out because of the high negative predictive value of plasma natriuretic peptides, and pulmonary disease becomes the most likely cause of breathlessness. If an echocardiogram confirms the absence of valvular or pericardial disease, LVEF and LV volumes should be measured. If the LVEF exceeds 50%, if the LV end-diastolic volume index is below 76 mL/m2, and if the patient has no atrial fibrillation, atrial dilatation (left atrial volume index < 29 mL/ m2), LV hypertrophy (LV mass index: women, 120 pg/mL or BNP > 100 pg/mL
Yes Echo
No Evidence of pulmonary disease No Yes Consider pulmonary disease
Evidence of valvular or pericardial disease
Consider valvular or pericardial disease Yes
No LVEF > 50%
Consider systolic heart failure No
Yes LVEDVI < 76 mL/m2
Consider high output state No
Yes LAVI < 29 mL/m2 and no atrial fibrillation
No
Yes LVMI < 96 g/m2 ( ); < 116 g/m2 ( )
Consider diastolic heart failure No
Yes
TD
S > 6.5 cm/s and E/E’ < 8
No
Yes No diastolic heart failure
a hypertensive response to exercise and diastolic LV dysfunction, losartan significantly improved exercise tolerance compared with either placebo46 or hydrochlorothiazide.47 The VALIDD trial studied the same population of hypertensive patients with diastolic LV dysfunction and reported an improvement of diastolic LV relaxation velocity after valsartan.31 A similar improvement, however, was also observed with blood pressure–lowering agents, which did not specifically target interstitial myocardial fibrosis. This nonsuperiority of valsartan suggests other mechanisms, such as cardiomyocyte resting tension, to be more important. This suggestion is supported by the lower myocardial collagen volume fraction7 and the higher cardiomyocyte resting tension6 observed in patients with diastolic heart failure
Consider coronary artery disease with deficient angina warning
compared with systolic heart failure. A large randomized trial looking at the effects of candesartan in patients with diastolic heart failure (CHARM-Preserved)32 resulted, like PEPCHF, in a reduction of heart failure hospitalizations but no survival benefit. These results were clearly inferior to the results obtained with the same drug in patients with systolic heart failure. Patient recruitment in CHARM-Preserved did not require objective evidence of diastolic LV dysfunction as evident from an echocardiographic substudy of CHARMPreserved, in which only 44% of patients had moderate to severe evidence of diastolic LV dysfunction. The majority of patients in CHARM-Preserved therefore did not satisfy the criteria for diastolic heart failure recently proposed by the Heart Failure and Echocardiography Associations of
HEART FAILURE AND CARDIOMYOPATHY: CONGESTIVE HEART FAILURE: Diastolic Heart Failure
Breathlessness, without signs of fluid overload
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1008
Trial
Drug
Result
DIG
Digoxin
Survival =
PREAMI
Perindopril
Remodeling #
PEP-CHF
Perindopril
Symptoms #
CHARM-Preserved
Candesartan
Symptoms #
VALIDD
Valsartan
LV relaxation =
I-Preserve
Irbesartan
Survival =
TOPCAT
Spironolactone
?
ALDO-DHF
Spironolactone
?
PREDICT
Eplerenone
?
SWEDIC
Carvedilol
LV relaxation =
Japanese-DHF
Carvedilol
?
SENIORS
Nebivolol
Survival "
Table 73.2 Clinical trials in diastolic heart failure.
the European Society of Cardiology,35 and many of them could have suffered from a noncardiac cause of dyspnea. The I-Preserve trial, which was just completed, uses the angiotensin receptor blocker irbesartan in diastolic heart failure, but in contrast to CHARM-Preserved, it requires enrolled patients to have left atrial enlargement as an indicator of diastolic LV dysfunction.48,49 Finally, the use of spironolactone for treatment of diastolic heart failure is currently being assessed in the TOPCAT trial. Calcium channel blockers improve exercise tolerance in patients with hypertrophic cardiomyopathy because of reduced outflow tract obstruction and improved diastolic LV function. Similar improvement of exercise tolerance was also observed in diastolic heart failure patients treated with verapamil.50 This improvement related not only to amelioration of LV filling50 but also to reduction of ventriculovascular stiffening51 because of verapamil’s effects on arterial stiffness and LV elastance. From a pathophysiologic point of view, use of beta blockers in diastolic heart failure could be deleterious. Because of an almost vertical LV end-systolic pressure-volume relation and a steep diastolic LV pressure-volume relation (see Fig. 73.7, right-hand panel), the left ventricle of patients with diastolic heart failure functions as a fixed stroke volume pump, which is exclusively dependent on heart rate to increase its output. A blunted heart rate response to exercise because of administration of beta blockers could therefore unfavorably affect exercise tolerance in these patients. Furthermore, isolated cardiomyocytes procured from patients with diastolic heart failure have a high in vitro diastolic stiffness, which significantly contributes to the high in vivo LV diastolic stiffness.9 Administration of protein kinase A corrects this high in vitro cardiomyocyte stiffness.9 Use of beta blockers lowers myocardial protein kinase A activity and could theoretically worsen diastolic LV stiffness in diastolic heart failure. Clinical observations on the use of beta blockers in diastolic heart failure seem to confirm these pathophysiologic drawbacks, and trials with beta blockers in diastolic heart failure have been less convincing than in
systolic heart failure. In elderly postinfarction patients with a preserved LVEF, propranolol had a favorable and significant effect on mortality and reinfarction rate.52 In a similar population with a history of heart failure, a preserved LVEF, and a high prevalence of prior myocardial infarction, beta-blocker use was also associated with a significant reduction in mortality.53 Like the PREAMI study, both these studies addressed the usefulness of beta blockers in a population of patients with a limited prior myocardial infarction and not in a typical population of diastolic heart failure patients, who are characterized by concentric LV remodeling and a high prevalence of arterial hypertension. A community-based registry of heart failure patients with LVEF above 40%, many of them elderly hypertensive women, revealed symptomatic improvement and fewer hospitalizations but no survival benefit during carvedilol treatment.54 In the SWEDIC trial, 6 months of carvedilol treatment also failed to improve diastolic LV function in diastolic heart failure patients.55 No improvement in diastolic LV function was also observed in the SENIORS trial despite improved survival in heart failure patients with a preserved or a reduced LVEF during nebivolol treatment.56 The beta blocker nebivolol has myocardial nitric oxide–releasing properties, and it is therefore unclear if the observed survival benefit relates to blockade of beta receptors or to antihypertrophic properties of nitric oxide. In summary, in contrast to patients with systolic heart failure, convincing evidence is still lacking that modern pharmacologic heart failure therapy improves prognosis in patients with diastolic heart failure. So far, mostly symptomatic improvement has been observed in patients with diastolic heart failure with use of a variety of drugs, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, and beta blockers. The divergent results of modern pharmacologic heart failure therapy in patients with systolic and diastolic heart failure imply that different myocardial signal transduction pathways are operative during the eccentric and concentric LV remodeling observed, respectively, in systolic and diastolic heart failure. Furthermore, these divergent results also suggest that modern heart failure therapy predominantly addresses signal transduction pathways activated in eccentric but not in concentric LV remodeling. The inefficacy of modern heart failure therapy in patients with diastolic heart failure was recently also illustrated by a large epidemiologic survey that observed improved prognosis over time in patients with systolic heart failure but not in patients with diastolic heart failure.2
PROGNOSIS Earlier data on prognosis of patients with diastolic heart failure suggested better prognosis in diastolic heart failure than in systolic heart failure. Most of these data were derived from ambulatory populations, with relatively less information on hospitalized patients. Moreover, similar to therapeutic trials in diastolic heart failure, inclusion criteria for diastolic heart failure varied widely. A large population-derived cohort study overcame most of these inadequacies and demonstrated similar 1-year mortality rates in patients with systolic and diastolic heart failure of 26% and 22%, respectively.1 This study also revealed similar rehospitalization rates and heart failure– related rehospitalization rates in both groups.
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HEART FAILURE AND CARDIOMYOPATHY: CONGESTIVE HEART FAILURE: Diastolic Heart Failure
Diastolic heart failure currently accounts for more than 50% of all heart failure patients in Western societies. Specific causes of diastolic heart failure include constrictive pericarditis, endomyocardial fibrosis, hypertrophic cardiomyopathy, infiltrative cardiomyopathy, and ischemic and hypertensive heart disease. Diastolic heart failure patients frequently are elderly and more commonly women. They often have multiple comorbidities, such as arterial hypertension, obesity, and diabetes mellitus, and a concentrically hypertrophied left ventricle with a high LV wall mass-volume ratio, prominent cardiomyocyte hypertrophy, and abnormal extracellular matrix. The diagnosis of diastolic heart failure rests on a triad consisting of signs or symptoms of congestive heart failure,
normal LVEF (>50%), and objective evidence of diastolic LV dysfunction. Objective evidence of diastolic LV dysfunction is preferably derived from invasive measurements of LV filling pressures or from noninvasive tissue Doppler indices of abnormal diastolic function. Current guidelines for the management of diastolic heart failure recommend control of arterial hypertension, volume overload, ischemia, and diabetes. Modern heart failure therapy with angiotensinconverting enzyme inhibitors, angiotensin receptor blockers, and beta blockers provides a symptomatic benefit but no prognostic benefit in patients with diastolic heart failure. One-year mortality of patients with diastolic heart failure approaches 22%, and prognosis in diastolic heart failure is therefore comparable to prognosis in systolic heart failure.
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chapter
John G. F. Cleland, Ahmed Tageldien Abdellah, Nidal Maarouf, and Neil Hobson
The basic premise of cardiac resynchronization therapy (CRT) is that cardiac dyssynchrony complicates or causes heart failure and that retiming of the sequence of contraction can improve cardiac function, thereby improving symptoms and reducing cardiovascular morbidity and mortality (Fig. 74.1). There is no doubt that atriobiventricular pacing is clinically effective, but the reasons that it is effective are far from certain.1 Ultimately, it may be that cardiac dyssynchrony is the basis for the effects of CRT but that cardiac dyssynchrony is so poorly understood, so difficult to measure, or so ubiquitous that it is clinically irrelevant to select patients for this therapy on this basis.2 This chapter reviews the existing data, focusing on substantial randomized controlled trials and existing guidelines, and attempts to interpret them for current clinical practice and future research.
PATHOPHYSIOLOGY OF CARDIAC DYSSYNCHRONY Conceptually, cardiac dyssynchrony means that the orderly sequence of cardiac contraction and relaxation is disturbed, leading to a decline in cardiac efficiency (Fig. 74.2).3 Cardiac dyssynchrony can take many forms, which commonly coexist. Atrioventricular (AV) dyssynchrony is caused by delayed ventricular contraction. Atrial relaxation leads to a fall in atrial pressure and the backward flow of blood through the AV valves during late diastole that leads, in turn, to a decline in diastolic ventricular pressures and volume that impairs ventricular contractile performance. Intraventricular dyssynchrony refers to late activation of parts of the left ventricular (LV) myocardium, usually the posterolateral wall. It may affect circumferential or longitudinal contraction. Late activation of some segments leads to a slower rise in systolic pressure and delayed LV ejection and also to slower relaxation and delayed LV filling. The left ventricle expends energy changing shape as regions that are contracting deform regions that either have not yet started to contract or have already started to relax. Blood is thus moved around the LV chamber rather than ejected from it. If the interventricular septum—which forms part of both ventricles—is activated before the LV free wall (i.e., left intraventricular mechanical delay), this will result in right ventricular (RV) ejection greatly preceding LV ejection and interventricular dyssynchrony, unless the right ventricle is also severely diseased, which is a poor prognostic sign. Delayed activation of papillary muscles leading to mitral regurgitation during systole is another important aspect of dyssynchrony. Whether
interatrial dyssynchrony or dyssynchronous contraction within the thickness of the myocardial wall has an important effect on cardiac function is uncertain.1-3 Which aspect of dyssynchrony is most important overall is uncertain, and it is likely that the most important aspect of dyssynchrony varies from patient to patient and over time.4
THE EPIDEMIOLOGY OF HEART FAILURE AND CARDIAC DYSSYNCHRONY Heart failure is common but complex and the final expression of many different cardiac diseases and pathophysiologic processes. Ischemic heart disease, hypertension, and atrial fibrillation, alone or in combination, are common causes. The prevalence of heart failure is maintained at relatively low levels because most patients die within a few years of diagnosis. Heart failure is better described by its incidence.5 About one person in every five will develop heart failure, and most of these patients will die as a complication of it. Indeed, recent reports show that 80% of people who die as a consequence of myocardial infarction will first develop heart failure.6 The prevalence and incidence of dyssynchrony are essentially unknown because no robust definition exists. It is exceedingly unlikely that dyssynchrony is an all-or-nothing problem, and so any definition would have to choose an arbitrary number to define dyssynchrony.7 This is further complicated by the fact that there are many more than a dozen different measures of dyssynchrony assessing widely varying aspects of its pathophysiology. No one is sure which are relevant. Different types of dyssynchrony may have additive adverse effects on cardiac function. Dyssynchrony may vary over time and with stress, and its nature will vary from patient to patient.8 Historically, a QRS duration of more than 120 ms has been taken as supportive evidence of ventricular dyssynchrony. Surveys suggest that about one quarter of patients with heart failure have a QRS width of 120 ms or more but that among patients with LV systolic dysfunction (LVSD), it may be nearer 40%.9 In the EuroHeart Failure Survey, of 5934 hospital deaths and discharges with an electrocardiogram and assessment of LV function, 2107 (36%) had LV ejection fraction (LVEF) of 35% or less, and of these, 42% had QRS of 120 ms or more (Fig. 74.3).9 However, QRS duration is only a rough guide to the prevalence of intraventricular and interventricular dyssynchrony at rest and may better reflect the severity of LVSD rather than dyssynchrony.9 There are no
HEART FAILURE AND CARDIOMYOPATHY: CONGESTIVE HEART FAILURE: Cardiac Resynchronization Therapy
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Cardiac Resynchronization Therapy
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detailed echocardiographic studies in large populations. One of the largest included just 158 patients with LVEF of 35% or less. The prevalence of both inter-dyssynchrony (>40 ms difference in onset of aortic and pulmonary flow) and
THE PREVALENCE OF QRS PROLONGATION IN PATIENTS WITH LEFT VENTRICULAR SYSTOLIC DYSFUNCTION
AF LBBB QRS > 149 4%
EFFECTS OF CARDIAC RESYNCHRONIZATION THERAPY
AF LBBB QRS 120–149 6%
Cardiac resynchronization therapy
↑ LV ejection fraction
SR LBBB QRS > 149 10%
↓ Mitral regurgitation
↑ Blood pressure ↑ Organ perfusion ↓ Atrial pressure
Remodeling
↓ Hospitalization
SR RBBB AF RBBB QRS > 149 QRS 120–149 2% 1% AF RBBB QRS > 149 1%
SR QRS < 120 44%
↓ Death
Cardiac remission
Figure 74.1 Effects of cardiac resynchronization therapy.
SR LBBB QRS 120–149 14%
intraventricular dyssynchrony (>50 ms in an eightsegment model using tissue Doppler imaging) was more than 70% in patients with QRS of more than 150 ms, around 55% in those with QRS of 120 to 150 ms, and, for intraventricular dyssynchrony, about 30% in those with QRS duration of less than 120 ms.10 The incidence of dyssynchrony and whether it can resolve are unknown. The incidence of new-onset bundle branch block is about 10% per annum. Patients with LVSD and left bundle branch block have an adverse prognosis, and patients with new-onset left bundle branch block have an even worse outcome (Fig. 74.4).11
PATHOPHYSIOLOGY OF HEART FAILURE DUE TO LEFT VENTRICULAR SYSTOLIC DYSFUNCTION
Injury to myocytes and extracellular matrix
Neurohumoral imbalance, increased cytokine expression, immune and inflammatory changes, altered fibrinolysis
Ventricular remodeling
Apoptosis, altered gene expression, energy starvation, oxidative stress
Electrical Ventilatory Vascular Muscle Renal Hematologic and other effects
Syndrome of heart failure
1012
AF QRS < 120 15%
Figure 74.3 The prevalence of QRS prolongation in patients with left ventricular systolic dysfunction. AF, atrial fibrillation; LBBB, left bundle branch block; RBBB, right bundle brunch block; SR, sinus rhythm.
↓ LV volumes
↓ Symptoms
SR RBBB QRS 120–149 3%
Figure 74.2 Pathophysiology of heart failure due to left ventricular systolic dysfunction. (From McMurray JJ, Pfeffer MA. Heart failure. Lancet 2005;365:1877-1889.)
1.0
Cumulative survival
0.9 0.8 0.7 0.6 0.5
CONTAK
0.4 12
24
36
48
Time (months) QRS < 120 ms (N=424) Baseline LBBB (N=248) HR 1.47 (95% Cl: 0.98–2.21) P =0.06 New LBBB (N=49) HR 2.43 (95% Cl: 1.35–4.38) P =0.003
Figure 74.4 Kaplan-Meier survival curves for patients with a 12-lead electrocardiogram (ECG) at 12 months. Patients are split by QRS duration. Shown are those patients with a QRS of less than 120 ms at baseline and follow-up, those with left bundle branch block (LBBB) at baseline, and those developing new left bundle branch block during the first year’s follow-up.11
It may be that increased QRS duration just signifies worse ventricular function and that ventricles with worse function are more likely to show dyssynchrony. Many studies show that QRS duration predicts prognosis in patients with heart failure, but the majority of the evidence shows that dyssynchrony, after correction for the severity of ventricular dysfunction, predicts a better outcome.12 This probably reflects the fact that for a given severity of ventricular dysfunction, there is more surviving myocardium in a dyssynchronous rather than in a synchronous ventricle. In other words, an ejection fraction of 30% is true in a patient without dyssynchrony but is an underestimate of the “true” synchronous ejection fraction when dyssynchrony is present.
A SHORT REVIEW OF CLINICAL TRIALS There is powerful evidence from a series of randomized controlled trials that CRT is an effective treatment of patients with heart failure who fulfilled their entry criteria (Table 74.1), which universally included patients with LV dilatation and systolic dysfunction, predominantly with wide QRS and in sinus rhythm.1,13 Patients with a broad range of symptoms were included. Echocardiographic evidence of dyssynchrony was generally not required.
MUSTIC TRIALS These trials were conducted single blind, that is, the investigator but not the patient knew whether the CRT device was switched on. Patients who had a successful implantation and
This study started as a double-blind crossover study in patients with a successful device implantation but evolved into a parallel-arm study lasting 6 months and including 490 patients.16 At least 257 patients (52%) were in New York Heart Association (NYHA) class II and at least 209 (43%) were in NYHA class III-IV at the time of randomization. The primary endpoint of the study was initially peak exercise oxygen consumption but was changed to worsening heart failure events. The trial failed to meet its revised primary endpoint but did show that patients assigned to CRT-on had a greater improvement in exercise capacity and LV function. Clinical benefit at 6 months was greater in more symptomatic patients, but recovery of LV function was similar regardless of symptom severity.
MIRACLE This was a double-blind study (Fig. 74.5). All patients had a device implanted. Patients who survived a postimplantation run-in period were randomly assigned to atriobiventricular pacing switched on or off for 6 months. The primary endpoints of this study were NYHA class, quality of life score on the MLWHF scale, and distance walked in 6 minutes, all of which improved significantly (P =.005 or better).17 This study established CRT as an effective treatment of symptoms. Hospitalization for heart failure was also reduced (P 150
Singleblind
3
CRT on vs. off VVI backup 70 bpm
No
No
III
60
>200 (RV paced)
Study
N
Design
MUSTIC14
48
MUSTIC AF15
41
CONTAK CD16
490
Doubleblind crossover
3-6
CRT on vs. off
Yes
Yes
II-IV
35
Median 71
120
MIRACLE17
453
Doubleblind parallelarm
6
CRT on vs. off
No
Yes
III-IV
35
55
130
MIRACLE ICD18
369
Doubleblind parallelarm
6
CRT on vs. off
Yes
Yes
III-IV
35
55
130
MIRACLE ICD II19
186
Doubleblind parallelarm
6
CRT on vs. off
Yes
Yes
II
35
55
130
1520
Unblinded parallelarm
12 (for control group)
CRT-D vs. CRT vs. control
No
Yes
III-IV
35
Median 67
120
CARE-HF and extension21,22
813
Unblinded parallelarm
30 (38 for extension)
CRT vs. control
No
Yes
III-IV
35
>30 mm/m (height)
120-149 þ interventricular dyssynchrony or 150
REVERSE
610
Doubleblind parallelarm
12 (24 in Europe)
CRT on vs. off
Optional
Yes
I-II
40
55
120
COMPANION20
EF, ejection fraction; ICD, implantable cardioverter-defibrillator; LVEDD, left ventricular end-diastolic diameter; NYHA, New York Heart Association
Table 74.1 Entry criteria for randomized controlled trials of cardiac resynchronization therapy.
response were not improved. This may reflect the difficulty in showing improvement in patients with mild symptoms and the need for longer follow-up to show differences in the rate of deterioration.
COMPANION
1014
This trial (Fig. 74.6) compared the effects of CRT (n = 617), CRT-D (cardiac resynchronization therapy pacemaker plus backup defibrillation; n = 595), and pharmacologic management alone (n = 308) on morbidity and mortality20 in patients who had been hospitalized for heart failure in the previous year and satisfied standard entry criteria (see Table 74.1). The primary outcome was a composite of allcause hospitalization or all-cause mortality and was dominated by the former. It is likely that many hospitalizations were for minor problems. Although the prestated intention was to compare each intervention with control, because two patients were allocated to each intervention for every control patient and because numerically more events occurred in the intervention groups, it was better powered to show differences between devices. At 6-month follow-up, CRT and
CRT-D had improved symptoms, quality of life, and exercise capacity by a similar amount. The study was stopped early because there was a highly significant reduction in the primary endpoint in both groups and in all-cause mortality in the CRT-D group and because of a high rate of implants in the control group. Trials that stop early overestimate the benefit in the arm of the trial that drove the decision. Overall, this trial showed that CRT and CRT-D could improve morbidity and mortality to a similar extent. As CRT is less expensive and associated with fewer complications, it suggests that CRT is the preferred treatment for most patients with heart failure. It also shows that the benefits of CRT are not diminished in the presence of an ICD, which was a concern raised by MIRACLE ICD.
CARE-HF This trial (Fig. 74.7) compared the effects of CRT (n = 409) with pharmacologic management alone (n = 404).21,22 In addition to the criteria shown in Table 74.1, patients with QRS of 120 to 149 ms also had to have an echocardiographic measure of dyssynchrony. The primary outcome was
SECTION
5
MIRACLE STUDY
CHAPTER
Exercise Capacity
50 –5
P=0.005 40 Units
mL/kg/min x 10 or meters
74
Quality of Life*
0
30
–10
20 P=0.009
–15
10 0
A
P=0.001
–20
B
6MWT
PeakVO2
Echocardiography
Global Patient Response
6
80
P50 mm Hg at
Aortic Stenosis Patients with mild or moderate degrees of obstruction usually tolerate the hemodynamic changes of pregnancy without sequelae; however, patients with severe fixed stenosis, including those with significant subvalvular obstructions (i.e., membranes) or supravalvular obstructions, are at high risk of morbidity and mortality during pregnancy.32,33 A recent retrospective analysis by Hameed and coworkers34 found unfavorable maternal and fetal outcomes in patients with moderate to severe aortic or mitral stenosis. Pregnancies in these patients were complicated by a 38% incidence of maternal congestive heart failure, a 15% incidence of maternal arrhythmias, and significantly higher rates of hospitalization during pregnancy. In addition, a higher incidence of intrauterine growth retardation, preterm deliveries, and lower birth weights were noted in patients with severe leftsided valve stenoses.34 If the patient has moderate or severe aortic stenosis, an exercise treadmill test before pregnancy may offer further prognostic information. Both failure of the blood pressure to rise, indicating a fixed stroke volume, and ST depression consistent with subendocardial ischemia are poor prognostic markers, and valve replacement should be considered before conception (Fig. 136.2). If a patient with severe aortic stenosis presents in the pregnant state and refuses abortion, careful monitoring with serial ECGs and echocardiograms should be done. Hospital
IMPACT OF AORTIC STENOSIS, MITRAL STENOSIS AND COARCTATION OF THE AORTA ON THE CIRCULATION IN PREGNANCY
Fixed stroke volume ↓ Placental blood flow Congestive heart failure Aorta Aortic stenosis
Coarctation of the aorta
Left atrium Thickened valve leaflets that reduce orifice Mitral stenosis Left ventricle
Figure 136.2 Impact of aortic stenosis, mitral stenosis, and coarctation of the aorta on the circulation in pregnancy.
admission should be considered if the velocity across the aortic valve (as measured by Doppler echocardiography) decreases during pregnancy or if the patient becomes symptomatic with angina, congestive heart failure, or syncope. If left ventricular function is normal, careful treatment with a beta blocker and nitrates to reduce venous return is indicated. Aortic valvuloplasty35,36 can be considered in an emergency situation and may be preferred over valve replacement, because cardiothoracic surgery during pregnancy is associated with high fetal loss. The development of severe aortic regurgitation is a possible consequence of this procedure. Valvuloplasty in such patients is clearly a temporary solution and only delays anticipated valve replacement (see Chapter 93).
Mitral Stenosis Mitral stenosis is the most common valvular lesion in women of childbearing years (see Chapter 89), and in many cases symptoms may not become apparent until after the patient is pregnant and has the typical hemodynamic changes. The classic murmur of mitral stenosis can be difficult to detect. If a patient presents with symptoms of unexplained dyspnea or congestive heart failure, echocardiography is indicated to rule out the possibility of occult mitral stenosis. Because of the stenosis, stroke volume cannot be increased, which results in a worsening of tachycardia to preserve or augment cardiac output, decreased left ventricular filling, a rise in left atrial pressures, and acute pulmonary edema. For those with mild to moderate mitral stenosis, careful treatment with small doses of a diuretic and a beta blocker (metoprolol should be chosen over atenolol, which has been associated with a higher incidence of fetal growth retardation) to reduce the heart rate and improve diastolic left ventricular filling are indicated. Mortality among pregnant patients with mild to moderate mitral stenosis typically is less than 1%.37 In contrast, those with severe symptomatic mitral stenosis have a maternal mortality of 3.5% and a neonatal mortality of 7.5%.38 Accordingly, if medical management fails, the patient should be evaluated for a percutaneous balloon mitral valvuloplasty; this can be done by performing a transesophageal echocardiogram to evaluate the suitability of the valve and to exclude the presence of a left atrial or appendage thrombus. Percutaneous balloon mitral valvuloplasty has proved to be safe and successful in pregnant patients.39,40 This procedure preferably should be delayed until the second trimester because of the risk of radiation exposure of the fetus, and transesophageal echocardiographic guidance may be helpful in reducing radiation. Although cardiac surgery usually can be performed on pregnant patients with low maternal morbidity and mortality, fetal mortality remains high (20% to 38%) because of reduced placental blood flow and hypothermia.41,42
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136 SECONDARY HEART DISEASE: CARDIAC RESPONSES TO PHYSIOLOGIC STRESS: Pregnancy in the Heart Disease Patient
rest). Patients with severe pulmonary valve stenosis should be considered for balloon valvuloplasty before pregnancy.29 Case reports have shown valvuloplasty to be a safe, effective procedure during pregnancy if deemed necessary (see Chapter 97).30,31
Regurgitant Valve Disease Regurgitant valve disease usually is well tolerated in pregnancy, owing to the associated hemodynamic changes. Systemic vasodilatation actually reduces the regurgitant volume and murmur. Mitral valve prolapse is the most common cause of mitral regurgitation in pregnancy and generally is well tolerated. Tachycardia is well tolerated when left ventricular filling is unimpeded, and diuretic therapy is indicated only in the setting of pulmonary congestion. Pharmacologic
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vasodilatation usually is not required, unless associated hypertension is present. Because ACE inhibitors are contraindicated, hydralazine is the agent of choice. The etiology of the regurgitant disease is important in assessing the patient’s suitability for pregnancy. Aortic regurgitation secondary to aortic root dilatation from Marfan’s syndrome or other causes of cystic medial necrosis carries a higher risk of aortic rupture or dissection than aortic regurgitation secondary to a congenitally abnormal valve (see Marfan’s syndrome; also see Chapters 12 and 95).43
Before conception
Conception
Prosthetic Heart Valves A woman may want to become pregnant after the placement of a prosthetic valve (see Chapter 101b). The best course is to discuss the issue of pregnancy and its risks with every woman of childbearing potential before placement of a prosthesis. Bioprosthetic valves have the advantage of not requiring anticoagulation; however, accelerated deterioration has been reported during pregnancy. In addition, owing to the limited life span of these valves, placement of such a valve in a young woman almost invariably necessitates a second operation. Mechanical valves often are the optimal choice for young patients. Homograft placement or a Ross procedure might be the best option for a young woman who needs aortic valve replacement and is planning pregnancy in the future. For patients with a preexisting valve prosthesis, it is important that the integrity of the valve and the patient’s functional status be assessed before pregnancy. Patients with NYHA class I or class II symptoms and a normally functioning prosthetic valve probably will tolerate pregnancy without difficulty. However, owing to the hypercoagulable state of pregnancy and the difficulty in achieving a stable pattern of anticoagulation with subcutaneous heparin, these patients are at higher risk of valve thrombosis, thromboembolic events, and even death. Patients with older, single-disk prosthetic valves (e.g., Bjo¨rk-Shiley valves) and those with mitral prostheses appear to have a higher risk of thromboembolic events.9 If a patient is at relatively low risk of valve thrombosis (i.e., status post valve replacement with a mechanical bileaflet valve, such as a St. Jude valve, in the aortic position), anticoagulation with subcutaneous heparin may suffice throughout pregnancy. Patients at high risk of valvular thrombosis should be considered for an approach that involves intravenous heparin at the onset and end of pregnancy (which requires hospitalization) and oral anticoagulation in the middle (Fig. 136.3). The role of LMWH in anticoagulation in either group of patients is uncertain, but it may provide a more efficacious and safe approach (see previous discussion of LMWH).
Infective Endocarditis
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MANAGEMENT OF PREGNANT PATIENTS WITH PROSTHETIC HEART VALVES WHO REQUIRE ANTICOAGULATION
Before publication of the American Heart Association’s current guidelines for the prevention of infective endocarditis, antibiotic prophylaxis was not recommended for patients with valvular disease undergoing uncomplicated vaginal delivery or cesarean section unless infection was suspected, and prophylaxis was considered optional for high-risk patients. In clinical practice, antibiotic prophylaxis was used liberally, with many citing several studies that showed a significant incidence of bacteremia (5% to 19%) in patients immediately after labor with organisms capable of causing bacterial endocarditis.44,45
Second trimester starts
Preconception counseling
Stop warfarin and begin heparin
Low risk of valvular thrombosis
High risk of valvular thrombosis
Continue heparin
Switch to warfarin
Switch to heparin
Third trimester starts
Induction of labor
Stop heparin
Delivery Resume heparin Day 1 after delivery
Day 2 after delivery
Switch to warfarin
Figure 136.3 Management of pregnant patients with prosthetic heart valves who require anticoagulation.
Furthermore, maternal and fetal mortality rates from bacterial endocarditis as a complication of pregnancy are alarmingly high (22% and 15%, respectively).46 However, according to the new guidelines published by the American Heart Association in 2007,47 only a few specific groups of pregnant patients warrant endocarditis prophylaxis for dental procedures (see Table 136.2). These include patients with prosthetic heart valves, a previous history of bacterial endocarditis, unrepaired cyanotic congenital heart disease (including those with palliative shunts), repaired defects within the first 6 months of the repair (either surgical or catheter-based repair), residual defects at the site of a previous repair, and cardiac transplant recipients with a valvulopathy. Although routine prophylaxis for labor and vaginal delivery is not recommended in the current guidelines except in the cases noted previously, it is too early to know how the guidelines will be applied in a complicated vaginal or cesarean delivery.
DISEASES OF THE AORTA Coarctation of the Aorta In the largest published series to date, maternal and neonatal outcomes were retrospectively assessed for 50 women with coarctation.48 The incidence of miscarriages
Marfan’s Syndrome Patients with Marfan’s syndrome, especially those with aortic root dilatation, are at increased risk of aortic dissection or further dilatation of the aorta during pregnancy (see Chapter 12). The absence of aortic root dilatation appears to reduce but does not eliminate the risk of aortic dissection.49 Recently, a prospective study found no significant difference in the growth of the aortic root during 6.4 years of follow-up in pregnant patients with Marfan’s syndrome, compared with a matched childless group. A subgroup of patients with aortic roots equal to or greater than 40 mm showed a small but significant increase in growth of the aortic root. The only dissection in this study was a type B in a patient with a previous type A dissection. This study therefore suggests that pregnancy may be relatively safe in patients with Marfan’s syndrome who have had no previous aortic dissection and whose aortic root measures less than 45 mm.50 Data are lacking on the safety of pregnancy in a patient with Marfan’s syndrome whose aortic root is larger than 45 mm and on the long-term effects of pregnancy on the cardiac status of patients with Marfan’s syndrome. Currently, both the Canadian29 and European51 guidelines discourage pregnancy in patients with an aortic root greater than 45 mm or 40 mm, respectively. In contrast, the guidelines established by the American College of Cardiology and the American Heart Association (ACC/AHA) advise against pregnancy in all women with Marfan’s syndrome because of an increased risk of aortic rupture or dissection during pregnancy, even in patients with a normal or minimally dilated aortic root.13 All patients with Marfan’s syndrome need to be counseled about the risk of pregnancy, and the patient should be advised against pregnancy if she has even mild preexisting aortic root dilatation or a personal history of previous aortic dissection. Further genetic counseling should be offered to inform parents about the 50% risk of transmission of this syndrome to their children. Pregnant patients with Marfan’s syndrome should be followed closely with periodic echocardiograms, regardless of
aortic size, and surgery should be considered if aortic root dilatation progresses or if the aortic root reaches 5.5 cm.49 Physical activity should be minimized, and beta-blocker therapy should be used throughout pregnancy to reduce the risk of aortic root dilatation and dissection. If dissection is suspected, diagnostic assessment of the aortic root and arch is most safely performed during pregnancy by transesophageal echocardiography or magnetic resonance imaging (MRI) to avoid exposure to ionizing radiation. Currently, elective cesarean delivery is advised in patients with significant aortic root dilatation or dissection to decrease the risk of increased shear stress on the aorta from labor. Patients without cardiovascular involvement generally tolerate a vaginal delivery.
CARDIAC ARRHYTHMIAS DURING PREGNANCY Palpitations are a common complaint of pregnant women. During normal pregnancy, the heart rate increases 10 bpm above baseline. Greater degrees of sinus tachycardia, supraventricular tachycardia, or even nonsustained ventricular tachycardia (including a new onset) are not uncommon during pregnancy. Some investigators have reported up to a fivefold increase in the onset of paroxysmal supraventricular tachycardia during pregnancy,52 indicating the possibility of an independent gestational (hormonal) arrhythmogenic effect. A study by Rosano and colleagues53 showed that the incidence of supraventricular tachycardia correlated with hormonal fluctuations during the menstrual cycle. They concluded that the incidence of supraventricular tachycardia showed a positive correlation with the progesterone level but an inverse relationship with the estrogen level. An increase in the frequency of arrhythmias in patients with mitral valve prolapse or preexcitation syndromes also is seen.54 In the absence of underlying structural or organic heart disease, most of these arrhythmias resolve in the postpartum period. However, a symptomatic arrhythmia may be the first clue to the presence of significant structural heart disease. Any suspected or documented sustained arrhythmia should prompt an evaluation by a cardiologist and a screening echocardiogram to rule out obstructive valvular lesions, intracardiac shunts, or cardiomyopathy. Prompt and appropriate management of the maternal cardiovascular condition may prove crucial in preventing fetal hemodynamic compromise. Analysis of data from the International LQTS (long QT syndrome) Registry by Seth and colleagues55 found a reduced risk of cardiac events for women with long QT syndrome during pregnancy. Interestingly, they found an increased risk (2.7fold for any cardiac event, 4.1-fold for fatal events) during the first 9 months postpartum; the risk returned to the baseline prepregnancy level after this period of transient increase. In confirmation of a previous report,56 women with the LQT2 genotype were at considerably higher overall risk for cardiac events, compared with those with the LQT1 or LQT3 genotypes. The authors suggested that several physiologic changes that occur abruptly in the postpartum state (i.e., fluid shifts that affect preload, a decline in cardiac output compared with the pregnant state, an increase in afterload, and a marked decline in estrogen levels) all may contribute to the increased risk of arrhythmias during this period. The Registry analysis55
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and pre-eclampsia in women with coarctation did not seem to differ from that in the general population. The greatest morbidity in this group of patients appears to be maternal hypertension, which was found to occur more frequently in patients with a hemodynamically significant coarctation (gradient 20 mm Hg). In this series only one maternal death occurred, in a woman with Turner’s syndrome who died in week 36 of pregnancy from a type A aortic dissection. This woman had undergone repair of the coarctation as a child and had a normalsized ascending aorta. Given the morbidity and mortality from maternal hypertension, these findings suggest that surgical correction of any coarctation with a gradient equal to or greater than 20 mm Hg should be performed before pregnancy. Surgical or percutaneous correction should be considered in the gestational period in cases of uncontrollable maternal hypertension or left ventricular failure. Cesarean section probably is the preferred mode of delivery in women with a coarctation and a significant gradient, an enlarged aorta, or uncontrolled hypertension. The role of percutaneous correction of coarctation of the aorta during pregnancy to prevent an aortic catastrophe is undefined (see Chapter 120).
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Annualized cardiac event rate
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4.00 3.50 3.00 2.50 2.00 1.50 1.00 0.50 0.00 Pregnancy
Postpartum
OFF beta blockers
Post-postpartum ON beta blockers
Figure 136.4 Long QT syndrome and beta-blocker use during pregnancy and the postpartum period. In women with long QT syndrome, beta-blocker use in the 9-month postpartum period is associated with a greater than fourfold reduction (P ¼ .01) in the cardiac event rate. No significant effect of beta-blocker therapy was noted during pregnancy or during the post-postpartum period (>9 months after parturition).55
also found that women who took beta blockers had a significant reduction (P ¼ .01) in cardiac events during the postpartum period (Fig. 136.4). This finding is consistent with previous hypotheses,57,58 which suggested that increased adrenergic activity in the postpartum period may cause an increase in postpartum cardiac events. It currently is recommended that all women, even those breast-feeding, who have long QT syndrome be prescribed beta blockers post partum.55 For women with implantable cardiac defibrillators (ICDs), a recent study revealed that pregnancy does not result in an increased number of discharges or complications related to the ICD.59 This finding suggests that, in the absence of significant underlying structural heart disease, women with an ICD should not be discouraged from pregnancy.
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Cardiac arrest is a rare complication during pregnancy, occurring only once in every 30,000 deliveries. The significant hemodynamic changes that take place during the gravid period, including compression of abdominal vessels, which results in decreased venous return and reduced cardiac output, must be taken into consideration during an arrest. In addition to resuscitation, identification of the etiology of the cardiac arrest is mandatory. Causes may include amniotic fluid embolism, pulmonary embolism, cardiac arrhythmia, hemorrhage, aortic dissection, congestive cardiomyopathy, or drug toxicity (particularly with magnesium sulfate). To prevent an impending arrest or during an arrest, the patient should be placed in the left lateral decubitus position, or the uterus should be manually positioned to relieve aortocaval compression, and a fluid bolus and 100% oxygen should be administered. Basic life support procedures and advanced life support procedures should be followed routinely, and an emergency cesarean section should be considered within 5 minutes of the arrest to preserve fetal viability.60
ISCHEMIC HEART DISEASE Acute Myocardial Infarction during Pregnancy Myocardial infarction (see Chapter 27) during pregnancy is rare, with an overall incidence of 6.2 cases per 100,000 live births.61 This incidence is a threefold to fourfold increase over that of nonpregnant women of reproductive age.61 Significant risk factors for pregnancy-related myocardial infarction include age older than 30 years, hypertension, thrombophilia, diabetes mellitus, smoking, transfusion, and postpartum infection.61 Of note, smoking during pregnancy is associated with an eightfold increase in the risk of myocardial infarction, compared with a twofold increase in nonpregnant smokers.61 The highest incidence of myocardial infarction occurs in the third trimester (commonly during labor and delivery) in women older than 33 years.62 A recent study found a lower maternal mortality rate (5.1%)61 compared with previous reports, which reported a high maternal death rate (21%), with most deaths occurring at the time of the infarction or within the first 2 weeks after it.62 This difference may be attributed to improvements in care, earlier recognition, possible underreporting of less severe cases in the past, and changes in the definition of acute myocardial infarction. A review of 125 cases found the most common etiology of the infarct to be atherosclerotic disease, with or without associated thrombus (43%). A fair number of cases (21%) were due to coronary thrombosis without atherosclerotic disease, which suggests a hypercoagulable state. Coronary dissection was evident in 16% of the cases, and up to one third of the patients were found to have normal coronary arteries, which suggests transient thrombus formation or spasm as the etiology.62 The amount of experience with systemic thrombolysis in pregnancy is not considerable, and the potential risk of fetal or placental bleeding, or both, would favor primary percutaneous coronary intervention (if available) as the preferred treatment.
CARDIOMYOPATHIES Hypertrophic Obstructive Cardiomyopathy Patients with hypertrophic obstructive cardiomyopathy (see Chapter 79) should be counseled in the prenatal period, because a 50% risk exists that a child will be affected as a result of autosomal dominant inheritance. Most patients who have hypertrophic obstructive cardiomyopathy do well during pregnancy, because increases in blood volume also increase left ventricular size, relieving outflow obstruction, and significant diastolic dysfunction rarely is present in young patients. Left ventricular volume typically is able to increase to meet the hemodynamic demands of pregnancy, and the gradient and the typical systolic murmur may even be reduced (see Fig. 136.4). Sudden death has been reported infrequently, and no evidence exists that it is increased during pregnancy. Treatment with pharmacologic agents is warranted only for symptomatic relief of dyspnea or angina and is best accomplished with a beta blocker. No agreement has been reached on the anesthetic choice in pregnant patients with significant left ventricular outflow obstruction. Some advocate general anesthesia with pulmonary
Peripartum Cardiomyopathy Peripartum cardiomyopathy is defined as the development of a dilated cardiomyopathy (of unexplained etiology) that results in congestive heart failure, which is temporally related to the gestational period. Heart failure most often occurs from 1 month before to 6 months after childbirth. It is a rare condition, with an estimated incidence of 1 in 4000 live births.66 A large, population-based study in southern California highlighted significant racial differences, finding much higher incidences in African Americans (1:1421) and Asians (1:2675).66 A higher incidence also is found in twin gestations, in women over age 30, and in multiparous women.67,68 The observed mortality rate now is believed to be lower than previously thought, ranging from 2.1% to 3.3%.66,68 The etiology of this illness is not fully understood, and several causes have been suggested, including myocarditis of viral or immune origin, nutritional deficiency, small-vessel coronary artery abnormalities, hormonal effects, and toxemia. The incidence of biopsy-proven myocarditis is unclear; although an infrequent finding in most series, some have indicated a higher incidence.67 The diagnosis is one of exclusion, and the spectrum of the illness is broad, ranging from mild to severe. The disorder is manifested by the typical presenting signs and symptoms of congestive heart failure. Other potential causes of pulmonary edema or compromise must be excluded. The more fulminant cases tend to occur within days of childbirth. A transthoracic echocardiogram should be obtained immediately to assess cardiac chamber sizes, right and left ventricular function, and valve function. The diagnosis of acute myocardial infarction must be entertained and can be difficult to make in this group of patients, because ECG changes consistent with myocardial infarction, segmental wall motion abnormalities on echocardiogram, and elevated creatine kinase-MB or troponin biomarkers can be seen in patients with peripartum cardiomyopathy. For these reasons, prompt cardiac catheterization may be warranted in some patients to rule out epicardial coronary disease or other pathology, such as dissection. The mother also should be questioned about the use of cocaine as a possible etiology of myocardial infarction. Treatment with ergonovine or bromocriptine, which are used to prevent uterine hemorrhage and lactation, also has been implicated (rarely) as an iatrogenic cause of myocardial infarction by causing coronary spasm.69 Other causes of pulmonary edema need to be excluded in a postpartum patient who
presents in respiratory distress, including the use of b2-agonists (e.g., ritodrine or terbutaline) for premature labor, venous thromboembolism, or amniotic fluid embolism. Hemodynamic decompensation from a preexisting, undiagnosed dilated cardiomyopathy may be difficult to distinguish from a true peripartum cardiomyopathy. Immediate supportive care should be initiated with oxygen, an ACE inhibitor (or hydralazine if the patient is still pregnant), digoxin, and diuresis. If fulminant congestive heart failure is present, respiratory support and inotropic support with a b1-agonist or even an intra-aortic balloon pump or a left ventricular assist device should be considered. Anticoagulation should be considered, especially with a left ventricular thrombus or severe left ventricular dysfunction. Immunosuppressive therapy with corticosteroids or azathioprine rarely is used unless biopsy evidence of myocarditis is seen. A biopsy result consistent with active myocarditis would defer the decision for potential cardiac transplantation. More than half of patients have complete or nearly complete recovery of left ventricular systolic function within 6 months. Patients who have had a fulminant course or who have residual left ventricular dysfunction should be discouraged from future pregnancies because of the risk of relapse. Some think that the left ventricles of patients who apparently have made a complete recovery have decreased contractile reserve, which may impair their ability to respond to hemodynamic stress.70 Unfortunately, even patients who fully recover left ventricular function have an increased risk of a recurrent cardiomyopathy and even death with subsequent pregnancies.71-73 Further work is needed to define better the group of patients at increased risk of recurrent peripartum cardiomyopathy despite seemingly full recovery of cardiac function. All patients should be counseled that future pregnancies are not without risk.
PREGNANCY IN THE HEART TRANSPLANT PATIENT Limited information is available about maternal and fetal morbidity and mortality after transplantation. Most patients are able to tolerate the hemodynamic changes of pregnancy, and no episodes of rejection during pregnancy have been reported. High incidences of maternal hypertension, preeclampsia, and maternal infections (e.g., Cytomegalovirus infection) have been observed.73,74 No fetal deaths have been reported; however, many of the births (up to 40%) are preterm with fetal growth retardation.74,75 Frequent monitoring of cyclosporin levels is necessary because of unpredictable fluctuations. No direct teratogenic effects of immunosuppressive therapy have been detected. Breast-feeding is discouraged because of the presence of cyclosporin A and Imuran in breast milk. Excess late mortality may be an issue, because at least three maternal deaths have been reported within 30 months of gestation.76 Given the current experience, patients with a heart transplant can safely tolerate pregnancy without an excessively adverse outcome. However, they must be informed of the possible maternal and fetal morbidity associated with pregnancy and lactation and of the possible limitation of life expectancy, given the reports of late deaths.
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artery catheter placement,63 whereas others64,65 have safely used regional anesthesia (epidural or spinal) during both labor and cesarean delivery, despite concerns of vasodilatation. In general, most believe that cesarean section typically should be performed only for obstetric indications or cardiac instability. Clearly, more investigation is warranted to define the safest mode of delivery and the anesthetic choice in this group of patients. Sustained supraventricular or ventricular arrhythmias are uncommon in this young age group. During delivery and in the early postpartum period, it is important to prevent significant blood loss and to maintain an adequate blood pressure and heart rate to ensure adequate left ventricular volume, cardiac output, and placental perfusion.
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PULMONARY HYPERTENSION Pregnancy is contraindicated in patients with pulmonary hypertension, regardless of the etiology, because of high maternal and fetal morbidity and mortality. The peripartum maternal mortality rate in primary pulmonary hypertension has been reported to be as high as 30% to 40%,77,78; a high incidence of fetal loss (at least 10%) and prematurity also are seen.78 Close postpartum monitoring is warranted, because maternal death has been reported to occur as late as 1 week after delivery.78 A recent review shows that patients with secondary pulmonary hypertension caused by vasculitis, illicit drug or appetite suppressant use, or chronic venous thromboembolic disease have an even greater maternal mortality (>50%) than patients with idiopathic pulmonary hypertension (30%) or pulmonary hypertension resulting from Eisenmenger’s syndrome (36%).78 The maternal prognosis appears to depend on early diagnosis and early hospital admission.78 Patients should be encouraged to undergo an elective abortion early in gestation. If the patient insists on continuing the pregnancy, physical activity should be limited, and the patient should be closely monitored for evidence of hypoxemia. The use of anticoagulant therapy is controversial, and adverse outcomes have been reported both with and without its use. Symptoms of right ventricular failure, syncope, and chest pain typically occur in the second trimester, and hospitalization with careful monitoring should be instituted immediately. A spontaneous vaginal delivery with close hemodynamic monitoring is preferable; however, if anesthesia is necessary for a cesarean section, negative inotropic agents should be avoided because of preexisting right ventricular failure. Likely mechanisms responsible for death include right ventricular failure, pulmonary embolism, and arrhythmia (see Chapter 83).
HYPERTENSION DURING PREGNANCY In the United States, hypertension complicates 8% to 10% of all pregnancies and is an important cause of maternal and fetal morbidity and mortality. Hypertension during pregnancy is defined as an increase in the systolic blood pressure of 30 mm Hg or more or an increase in the diastolic blood pressure of 15 mm Hg or more. The Working Group on High Blood Pressure in Pregnancy has classified hypertension into four categories79: n chronic hypertension; n pre-eclampsia or eclampsia; n pre-eclampsia or eclampsia superimposed on chronic hypertension; and n gestational or transient hypertension.
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Chronic hypertension is defined as a systolic blood pressure (BP) greater than 140 mm Hg or a diastolic blood pressure greater than 90 mm Hg (or both) diagnosed before pregnancy or before 20 weeks’ gestation or that persists longer than 6 weeks postpartum. Patients with chronic hypertension have a 15% maternal and fetal complication rate. The value of bed rest for any type of hypertension during pregnancy is controversial and without evidence from large randomized trials.80 Nevertheless, some degree of bed rest is recommended for the theoretical benefit of improving uteroplacental flow
when the mother is in the left lateral decubital position. Benefits of strict bed rest must be weighed against the potential increased risk of venous thromboembolic disease. Currently it is recommended that, for women with uncomplicated (no endorgan damage), mild hypertension (a systolic BP of 140 to 159 mm Hg or a diastolic BP of 90 to 99 mm Hg), antihypertensive therapy should be tapered off during pregnancy and the maternal blood pressure should be monitored closely.79 These women not uncommonly continue to have acceptable blood pressure readings in the absence of their usual therapy because of the normal physiologic decrease in blood pressure during the second trimester. Controlled studies have not demonstrated that pharmacotherapy for mild hypertension lowers the risk of pre-eclampsia or convincingly improves fetal or maternal outcomes. Some evidence indicates that antihypertensive agents in these patients may reduce the incidence of severe hypertension; however, many think that this potential benefit is outweighed by the potential for intrauterine growth retardation in neonates exposed to these agents.81 Drug therapy is recommended for any patient with a systolic blood pressure greater than 150 to 160 mm Hg or a diastolic blood pressure greater than 100 to 110 mm Hg or for evidence of end-organ damage (left ventricular hypertrophy or renal insufficiency).79 In women without end-organ damage, the blood pressure goal is a systolic pressure of 140 to 150 mm Hg and a diastolic pressure of 90 to 100 mm Hg.82 Subgroups of patients with mild hypertension who may benefit from institution of antihypertensive therapy outside of the previously discussed guidelines include women with secondary hypertension (i.e., concomitant renal disease, collagen vascular disease, or coarctation of the aorta), end-organ damage, dyslipidemia, maternal age older than 40, microvascular disease, a history of stroke, diabetes, and previous perinatal loss.82 Methyldopa is the treatment of choice because of its proven safety and efficacy. It also is the treatment with the longest follow-up (longer than 8 years) with regard to long-term effects on children whose mothers were treated with it (see Chapters 45 and 46). Intravenous labetalol is recommended for acute therapy.83 Pre-eclampsia or eclampsia is defined as the development of hypertension (as stated previously) in a previously normotensive woman after more than 20 weeks’ gestation that is accompanied by new proteinuria (>0.3 g/24 hours) or edema, or both. If the fetus is mature enough, the best treatment for the hypertension is parturition. If the fetus is too immature for delivery, the mother needs to be treated medically, with the goal of reducing the diastolic blood pressure to at least 85 to 100 mm Hg. In general, the guidelines for initiation of antihypertensive therapy would be followed; however, more intensive control could be considered, depending on the severity of the pre-eclampsia and any associated symptoms. If the blood pressure cannot be controlled or if clinical findings are predictive of an adverse fetal or maternal outcome (Table 136.4), labor should be induced regardless of fetal maturity. Pre-eclampsia or eclampsia superimposed on chronic hypertension is defined as a further increase in blood pressure compared with the prepregnant state (as outlined previously) and the development of pre-eclampsia or eclampsia. Patients with preexisting chronic hypertension, especially
PREDICTORS FOR HIGH MATERNAL AND FETAL RISK IN WOMEN WITH PRE-ECLAMPSIA n
n n
n n n n n n
Modified from Lindheimer MD. Hypertension in pregnancy. Hypertension 1993;22:127-137.
Table 136.4 Predictors for high maternal and fetal risk in women with pre-eclampsia.
those with chronic renal disease, are three to seven times more likely to develop pregnancy-induced hypertension and pre-eclampsia than normal women.84 Gestational or transient hypertension is defined as hypertension that develops after 20 weeks’ gestation or within 24 hours postpartum but that is not associated with other manifestations of pre-eclampsia. Patients with this condition need to be treated according to the guidelines stated previously and followed carefully, because some will develop proteinuria and thus be considered preeclamptic. Hypertension in this group of patients tends to predict the development of hypertension in the future (unrelated to pregnancy), as well as atherosclerotic disease. The etiology of pre-eclampsia and pregnancyinduced hypertension is not fully understood, but it most likely involves endothelial dysfunction. Trials examining prophylaxis with low-dose aspirin85-87 or calcium88 have not shown any benefit.
VENOUS THROMBOEMBOLIC DISEASE Pulmonary embolism (see Chapter 85) remains the leading cause of maternal death in developed countries.89 The incidence of lower extremity deep venous thrombosis during pregnancy is estimated to be 0.1% as diagnosed by ultrasound,90 whereas the incidence of pregnancy-related pulmonary embolism has been found to be 0.01% to 0.03%.91 The coagulopathy associated with pregnancy and venous stasis caused by uterine compression increase the incidence of deep venous thrombosis and subsequent pulmonary embolism during pregnancy.
SUMMARY During the coming decades, the population of women giving birth will be increasingly complex. Mothers will be older and will be more likely to have cardiovascular disease (whether congenital or acquired) and cardiovascular complications during pregnancy. In addition, more multiple births will occur, and an increased number of children will have congenital heart defects. A recent task force recommended that, to ensure optimal medical care for these mothers and infants, pregnant women with heart disease who are at intermediate or high risk for cardiovascular complications be managed at a high-risk perinatal unit by a multidisciplinary team composed of an obstetrician, a cardiologist, an anesthesiologist, and a pediatrician. Although much remains to be learned in important areas, a knowledge of the physiologic changes associated with pregnancy and their impact on the heart’s ability to compensate for chronic and acute diseases will facilitate the care of pregnant women with heart disease.
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n
Systolic blood pressure 60 mm Hg or diastolic blood pressure 110 mm Hg New proteinuria 2.0 g/24 hr (2þ or 3þ on qualitative examination) or a decrease in urine volume New increased serum creatinine level (>2.0 mg/dL) Platelet count 500 disease-causing mutations have been reported,34,37 including b-myosin heavy chain, cardiac myosin–binding protein C, cardiac troponin T and I, a tropomyosin, essential and regulatory light chains of myosin, a actin, a-myosin heavy chain, titin, and muscle limb protein (MLP). In the general population, HCM is the most common genetic disease, occurring in about 1 in 500 individuals.38 Not uncommonly, HCM is responsible for sudden cardiac death in young and asymptomatic individuals, frequently occurring in association with moderate or severe exertion.34 The stress of intense training and competition (and associated alterations in blood volume, hydration, and electrolytes) undoubtedly increases the risk to some degree in certain susceptible athletes. With HCM, particularly strenuous physical activity during sports may act as a trigger mechanism (Fig. 137.4), generating potentially lethal ventricular tachyarrhythmias, given the underlying electrophysiologically unstable myocardial substrate composed of replacement fibrosis (probably the consequence of smallvessel disease–mediated ischemia) and disorganized myocardial architecture (see Fig. 137.2). Disease variables that appear to identify individuals with HCM at greatly increased risk include a previous aborted cardiac arrest or spontaneous and sustained ventricular tachycardia; a family history of sudden or other premature HCM-related death; multiple-repetitive, nonsustained ventricular tachycardia on 24-hour ambulatory Holter electrocardiographic (ECG) recordings; unexplained syncope, particularly in the young; massive LV hypertrophy (wall thickness 30 mm); and a hypotensive blood pressure response to exercise.31,39-41 Patients with HCM who are judged to be at high risk for sudden death based on one or more of these markers and are considered for primary prevention of sudden death with a prophylactic ICD.31 In a cohort of high-risk patients with HCM, the annual appropriate ICD discharge rate is 5.5% overall and about 4% for primary prevention.31 Although HCM may be suspected during preparticipation sports evaluations by the previous occurrence of syncope, a family history of HCM or premature cardiac death, or detection of a systolic heart murmur, these features are relatively uncommon among all individuals affected by the disease.24,26,34 In particular, a loud heart murmur rarely is encountered in screening for HCM, because a substantial proportion of affected individuals have the nonobstructive form of the disease under resting conditions (which is associated with no or only a soft systolic murmur).24 Consequently, screening procedures for high school and collegeaged competitive athletes, limited to a history and physical examination (as is customary in the United States), cannot be expected to consistently identify HCM.
Hypertrophic Cardiomyopathy and Athlete’s Heart In young athletes with mild segmental ventricular septal thickening (13 to 15 mm), it may be difficult to distinguish the physiologic and benign form of LV hypertrophy, which represents an adaptation to athletic training (i.e., “athlete’s
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Ao
B
RV
M
FW VS
A
C
D
Figure 137.2 Morphologic components of the disease process in hypertrophic cardiomyopathy (HCM), the most common cause of sudden death in young competitive athletes. A, A gross heart specimen sectioned in a cross-sectional plane similar to that of the echocardiographic (parasternal) long axis. Left ventricular wall thickening shows an asymmetric pattern and is confined primarily to the ventricular septum (VS), which bulges prominently into the left ventricular outflow tract. The left ventricular cavity appears reduced in size. B to D show histologic features characteristic of left ventricular myocardium in HCM. B, Markedly disordered architecture with adjacent hypertrophied cardiac muscle cells arranged at perpendicular and oblique angles. C, An intramural coronary artery with a thickened wall, primarily from medial hypertrophy, and an apparently narrowed lumen. D, Replacement fibrosis in an area of ventricular myocardium adjacent to an abnormal intramural coronary artery. Ao, aorta; FW, left ventricular free wall; FW, left atrium; RV, right ventricle. (From Maron BJ, Shirani J, Poliac LC, et al: Sudden death in young competitive athletes: clinical, demographic and pathological profiles. JAMA 1996;276:199-204.)
heart”) from a pathologic condition such as HCM (albeit with a mild morphologic expression), which conveys a risk for sudden death.42 Athletes in this ambiguous morphologic “gray zone”2,42,43 represent an important and not uncommon clinical dilemma, for which the differential diagnosis between HCM and athlete’s heart often can be resolved by noninvasive testing (Fig. 137.5).42 This distinction may have particularly important implications, given that young athletes with an unequivocal diagnosis of HCM are discouraged from participation in intense competitive sports to reduce arrhythmic risk, with the possible exception of low-intensity activities (e.g., golf and bowling).36 On the other hand, improper diagnosis of cardiac disease in an athlete may lead to an unnecessary withdrawal from athletics, thereby
depriving that individual of the varied benefits of participation in sports.
Congenital Coronary Anomalies The second most frequent cause of sudden death in young athletes is a variety of congenital coronary anomalies of wrong aortic sinus origin, which account for about 15% to 20% of these deaths.3,28,31 The most common of these lesions appears to be anomalous origin of the left main coronary artery from the right (anterior) sinus of Valsalva44-46 or, less commonly, anomalous right coronary artery from the left aortic sinus (the mirror image malformation).45 Such malformations are exceedingly difficult to recognize during life, including with customary preparticipation history and
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A
B
C
D
Figure 137.3 Cardiac morphologic findings at autopsy in four competitive athletes who died suddenly of causes other than HCM. A, Gross specimen from an athlete with greatly enlarged ventricular cavities, consistent with dilated cardiomyopathy. B, Histologic section of the left anterior descending coronary artery (left) and a diagonal branch (right) showing severe (>95%) cross-sectional luminal narrowing by atherosclerotic plaque. C, Foci inflammatory cell infiltrate consistent with myocarditis. D, Histologic section of the right ventricular wall showing islands of myocytes within a matrix of fatty and fibrous replacement, characteristic of arrhythmogenic right ventricular dysplasia. (Modified from Maron BJ, Shirani J, Poliac LC, et al: Sudden death in young competitive athletes: clinical, demographic and pathological profiles. JAMA 1996;276:199-204.)
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physical examination screening, given an uncommon association with symptoms (such as exertional syncope or chest pain) or alterations in the scalar 12-lead or exercise ECG.44 Therefore, clinical diagnosis requires a high index of suspicion, utilizing imaging with coronary arteriography, cardiac magnetic resonance, two-dimensional echocardiography, or computed tomography angiography.46 When identified, coronary anomalies of wrong sinus origin are amenable to surgical correction.44 Myocardial ischemia in young people (and athletes) with congenital coronary artery anomalies probably occurs in infrequent bursts, cumulative with time and ultimately resulting in patchy myocardial necrosis and repair in the form of replacement fibrosis. This scarring can predispose to lethal ventricular tachyarrhythmias by creating an electrically unstable myocardial substrate. Potential mechanisms proposed for myocardial ischemia resulting from coronary anomalies of wrong sinus origin, particularly during exercise and in the presence of aortic expansion, include (1) acute angled takeoff and kinking or flap-like closure at the origin of the coronary artery; and (2) compression of the anomalous artery between the aorta and pulmonary trunk during exercise, particularly when the coronary artery is intramural (i.e., within the aortic tunica media). Other coronary anomalies rarely reported to cause
sudden death in athletes include hypoplasia of the right coronary and left circumflex arteries, left anterior descending or right coronary artery from the pulmonary trunk, virtual absence of the left coronary artery, and spontaneous coronary arterial intersusception and dissection.45
Atherosclerotic Coronary Artery Disease Atherosclerotic coronary artery disease may be responsible for sudden death during physical exertion in youthful athletes,37,10,47,48 often associated with acute plaque rupture.49 Corrado and coworkers47 emphasized the occurrence of premature atherosclerotic coronary disease as a prominent cause of sudden death in young people (including competitive athletes) in the Veneto region of northeastern Italy. In that report, coronary artery disease usually was confined to the left anterior descending coronary artery and resulted from obstructive fibrous and smooth muscle cell plaques in the absence of an acute thrombus.
Myocarditis Myocarditis is an acknowledged cause of sudden death in young athletes, even in the absence of previous symptoms. Definitive diagnosis may be difficult clinically (or even at autopsy, particularly in the healed phase).1,3,6,9,50 The
PROPOSED MECHANISMS BY WHICH SUDDEN CARDIAC DEATH MAY OCCUR IN ATHLETES WITH HCM
CRITERIA USED TO DISTINGUISH HCM FROM ATHLETE'S HEART WHEN THE LV WALL THICKNESS IS WITHIN THE SHADED GRAY ZONE OF OVERLAP
ia hem c s I
↑obstruction
Inte phy nse exer sical tion
HCM*
AF
n tio uc e nd e a s is
Co d
Athlete’s heart
“Gray zone” of LV wall thickness (13–15 mm)
Substrate (disorganized myocardial architecture)
Ventricular tachyarrhythmias
+
Unusual patterns of LVH†
+
LV cavity 45 mm
+
+
LA enlargement
–
+
Bizarre ECG patterns
–
+
Abnormal LV filling
–
+
Female gender
–
–
– ↓ Thickness with deconditioning +
Figure 137.4 Proposed mechanisms by which sudden cardiac death may occur in athletes with hypertrophic cardiomyopathy (HCM). AF, atrial fibrillation.
importance of myocarditis as an etiology for sudden death in the young may have been previously exaggerated as a result of overinterpretation of histologic findings, as well as a lack of standardized morphologic criteria.50 In a large autopsybased registry of competitive athletes, only about 5% showed areas of myocardium with inflammatory and necrotic changes diagnostic of acute myocarditis or idiopathic myocardial scarring consistent with healed myocarditis.13 The inflammatory process of myocarditis (see Fig. 137.3) can be triggered by a number of viral agents, most often enterovirus but also adenovirus51; however, it also can be associated with chronic cocaine use.52 Although myocarditis can be overlooked at routine autopsy examination, the diagnosis can be verified by direct analysis of the viral genome.49 A diagnosis of myocarditis does not necessarily require permanent withdrawal from competitive athletics.36 The guidelines of the Thirty-Sixth Bethesda Conference permit athletes to undergo a prudent convalescent period of about 6 months after the onset of clinical manifestations; they can return to competition if ventricular function and cardiac dimensions normalize and clinically relevant arrhythmias are absent on ambulatory monitoring and stress testing.36
Coronary Arterial Bridging An unresolved question is whether short “bridged” segments of the left anterior descending coronary artery (usually 1 to 3 cm) completely surrounded by LV myocardium per se constitute a potentially lethal anatomic variant responsible for sudden death in otherwise healthy young individuals during physical exertion.53-55 Some observers regard such muscle bridges as harboring the potential to produce critical systolic arterial narrowing (and residual diastolic compression)
+ –
Family history of HCM . VO2 max >50 mL/kg/min
– +
Figure 137.5 Criteria used to distinguish hypertrophic cardiomyopathy (HCM) from athlete’s heart when the left ventricular (LV) wall thickness is within the shaded gray zone of overlap, consistent with both diagnoses. *Assumed to be the nonobstructive form of HCM in this discussion, because the presence of substantial mitral valve systolic anterior motion would confirm, per se, the diagnosis of HCM in an athlete. {May involve a variety of abnormalities, including heterogeneous distribution of left ventricular hypertrophy (LVH) in which asymmetry is prominent and adjacent regions may be of greatly different thicknesses, with sharp transitions evident between segments; also, patterns in which the anterior ventricular septum is spared from the hypertrophic process and the region of predominant thickening may be in the posterior portion of the septum; anterolateral or posterior free wall or LVapex. #, decreased; ECG, electrocardiogram; LA, left atrial; O2max, maximum oxygen consumption. (From Maron BJ, V Pelliccia A, Spirito P: Cardiac disease in young trained athletes: insights into methods for distinguishing athlete’s heart from structural heart disease with particular emphasis on hypertrophic cardiomyopathy. Circulation 1995;91:1596-1601.)
responsible for myocardial ischemia and, in one report associated with, an increased risk for cardiac arrest in young patients with HCM.53 Short-acting beta blockers have been reported to alleviate anginal symptoms and ischemia by increasing the luminal diameter of tunneled coronary segments and normalizing flow velocities.54 Nevertheless, coronary blood flow occurs predominantly during diastole, and necropsy studies frequently have documented tunneled coronary arteries to be a common incidental finding in patients who died of chronic noncardiac diseases. The finding that 3% to 5% of young athletes who die suddenly have no other pathologic finding is at least circumstantial evidence favoring tunneled coronary arteries as the cause of death in that population.1,3,13
8
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137 SECONDARY HEART DISEASE: CARDIAC RESPONSES TO PHYSIOLOGIC STRESS: Athlete’s Heart and Causes of Sudden Death in Athletes
Triggers
SECTION
1809
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Aortic Dissection/Rupture (and Marfan Syndrome) Uncommonly, young athletes die suddenly as a result of rupture of the aorta,1,3,5,6,9,10,13 including some with the physical stigmata of Marfan syndrome, in whom disruption of the aortic media associated with decreased numbers of elastic fibers is evident at autopsy (i.e., “cystic medial necrosis”). Some athletes with Marfan syndrome may participate successfully in strenuous competitive sports for many years without experiencing a catastrophic event, presumably before the time of marked aortic dilatation, when predisposition for dissection or rupture increases critically. The presence of aortic dilatation is the primary determinant of whether athletes with Marfan syndrome are judged medically ineligible for competition.36
Valvular Heart Disease Aortic valvular stenosis is an uncommon cause of sudden death in young athletes,3,5,13 although older hospital-based studies suggested that this lesion was a much more common cause of sudden unexpected death in asymptomatic young people. The low frequency of aortic stenosis in athletes who die suddenly probably is due to identification early in life (including during preparticipation screening) by virtue of the characteristically loud systolic heart murmur, leading to disqualification from competitive sports.24 Despite its relative frequency in the general population (probably about 2% to 4%),56 mitral valve prolapse appears to be a particularly uncommon cause of morbidity or sudden death in young competitive athletes.24,36 In most cases, this diagnosis does not lead to disqualification from competitive sports.36 Reliable stratification of risk level in the mitral valve prolapse population has proved to be particularly challenging.57
Cardiac Conduction System Abnormalities Congenital or acquired abnormalities confined to the cardiac conduction system (in the absence of other structural cardiac abnormalities) have been regarded as occasional causes of sudden death in competitive athletes and other young people, presumably by producing heart block and bradyarrhythmias.3,5,6,9,10 These include malformations of the atrioventricular conduction tissue (e.g., accessory atrioventricular pathways) and morphologically abnormal small intramural arteries (serving the sinoatrial or atrioventricular nodes) with thickened walls and narrowed lumen. Such vascular abnormalities have been incriminated as determinants of myocardial ischemia and sudden death by virtue of the observed tissue degeneration, scarring, and hemorrhage in the surrounding conducting tissue.
Arrhythmogenic Right Ventricular Cardiomyopathy
1810
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial condition caused by mutations in seven disease genes (desmoplakin, cardiac ryanodine receptor, plakophilin2; transforming growth factor, desmoglein 2, plakoglobin, and desmocollin 2), which are responsible for cell-to-cell adhesion or calcium homeostatis.7,8,58,59 ARVC may be associated with important ventricular or supraventricular arrhythmias and has been cited as a cause of sudden cardiac death in young people, including athletes.1,3,15,16 ARVC is characterized morphologically by myocyte death in the right ventricular wall with replacement by fibrous or adipose tissue as part of a
repair process, often associated with myocarditis (see Fig. 137.3). ARVC may be segmental or may diffusely involve the right ventricle. In autopsy studies of sudden death in young athletes from the United States, ARVC has been reported uncommonly (i.e., 30-35 Gy)
þ
þ
Fractionated dose (2.0 Gy/day)
þ
þ
All Causes of CD
Reference
Arrhythmia
Valvular Disease
þ
þ
þ
þ
9, 16, 24
þ
Likely
Likely
þ
9
CAD
Volume of heart exposed
þ
þ
þ
Likely
Likely
þ
9
Relative weighting of radiation portals and thus the amount of radiation delivered to different parts of the heart without subcarinal blocking
þ
þ
þ
Likely
Likely
þ
9, 21
Presence of tumor next to the heart
þ
9
Younger age at exposure
þ
þ
Likely
Likely
þ
9, 22, 45 21, 31, 34, 52
Increased time since exposure
þ
þ
þ
þ
þ
Type of radiation source
þ
þ
þ
Likely
Likely
þ
9
Use of adjuvant cardiotoxic chemotherapy
þ
þ
þ
þ
9
Presence of other known risk factors in each individual (e.g., current age, weight, lipid profile, and habits, such as smoking)
þ
þ
9, 28
, no known association; likely, unknown but likely association; þ, association of specific risk factors with specific presentation. CAD, coronary artery disease; CD, cardiac death; CM, cardiomyopathy; Gy, gray.
Table 140.3 Risk factors for the different manifestations of radiation-induced heart diseases.
does not have long-term consequences. Radiotherapy generally is continued. If it occurs, delayed pericarditis develops 4 months to several years after radiotherapy, although most cases occur within the first year. Both delayed acute pericarditis and delayed chronic pericardial effusion may occur. The former presents as described previously, and it may be recurrent. Of patients with delayed acute pericarditis, about half develop some degree of tamponade, presenting with paradoxic pulse or Kussmaul’s sign. Delayed chronic pericardial effusion often is discovered on routine chest radiography, which reveals an enlarged cardiac silhouette; a minority of patients present with tamponade. Most effusions clear spontaneously, but clearance may take up to 2 years. About 20% of patients with delayed pericarditis experience chronic or constrictive pericarditis 5 to 10 years after therapy. The risk for development of chronic pericarditis is substantially greater if pericardial effusion was present previously.14 Chronic pericarditis also can develop without antecedent acute pericarditis. Pancarditis, or severe inflammation throughout all layers of the myocardium, often occurs with pericarditis. Although it is rare and probably requires at least 60 Gy of mediastinal irradiation, most patients with pancarditis have severe, often intractable congestive heart failure.
Cardiomyopathy
1836
Cardiac dysfunction, as evidenced by congestive heart failure or asymptomatic cardiomyopathy, may result from mediastinal radiotherapy. However, cardiac dysfunction caused by radiotherapy differs from that caused by anthracyclines. Radiation causes myocardial fibrosis, which leads to a restrictive cardiomyopathy characterized by diastolic dysfunction. In contrast, systolic dysfunction usually is the primary
abnormality in survivors treated with anthracyclines without irradiation. Nevertheless, given high enough doses and time, mediastinal radiotherapy has been shown to lead to systolic dysfunction.2 Recent studies have documented this greater impact on diastolic dysfunction than on systolic dysfunction after mediastinal radiotherapy.15-18 The frequency of diastolic dysfunction ranges from 12% to 83% when measured at a mean 15 to 17 years after diagnosis, whereas the prevalence of systolic dysfunction is lower, ranging from 9% to 36%. In a study by Heidenreich and colleagues15 of 294 HD survivors treated with at least 35 Gy of mediastinal irradiation at any age, a substantial percentage of survivors with diastolic dysfunction experienced ischemia with exercise. Adams and associates17 noted that in 48 HD survivors treated with mediastinal radiotherapy between 15 and 25 years of age, 14 had an abnormally low peak oxygen consumption with exercise.17 These two studies established, respectively, that HD survivors with diastolic dysfunction have substantially worse cardiac event–free survival and worse quality of life than those without diastolic dysfunction.15,17 The prevalence of dysfunction increases with higher radiation dose-volumes, higher anthracycline dose, and longer follow-up. Prevalence also depends on the screening modality. Radiation also increases the cardiotoxicity of anthracyclines, which directly damage myocardiocytes and can cause dilated cardiomyopathy. In long-term survivors of childhood cancer, left ventricular function has been shown to be lower in survivors who received anthracyclines and chest irradiation than in those who received chest irradiation alone and than in a group that received anthracyclines alone at a substantially higher mean total dose.19 In a Dutch cohort of 1474 survivors of HD treated before age 41 (between 1965 and 1995), anthracyclines greatly added to the elevated risks
Coronary Artery Disease and Overall Cardiac Mortality High-dose mediastinal radiation (>30 to 35 Gy), especially during childhood, increases the risk of coronary artery disease. Coronary artery disease may be silent or may cause anginal pain or sudden death. Silent myocardial infarction appears to occur more often in survivors of mediastinal radiotherapy than in the general population. A retrospective review of 635 patients treated before age 21 years for HD at Stanford University between 1961 and 1991 reported a relative risk for fatal myocardial infarction of 41.5 over that of the age-matched general population.21 Death occurred 3 to 22 years after therapy, but only among those exposed to 42 Gy or more of mediastinal radiation. Although few children today are treated with more than 30 Gy, survivors of childhood malignancy who received higher doses are still alive. The Stanford group also retrospectively evaluated 2232 patients of all ages treated for HD between 1960 and 1991. The relative risk for cardiac death from all causes increased when total mediastinal radiation was greater than 30 Gy, and the risk rose with increasing dose. These studies included patients treated with both older and current techniques, in terms of portal weighting, use of blocks, and daily fraction size.22 Data relating to coronary artery disease and overall mortality from cardiac causes in HD survivors who have received mediastinal radiotherapy with modern techniques are encouraging but not as conclusive. A multicenter study of 4655 adults and children treated for HD from 1940 to 1966 and from 1967 to 1985 found no significant increase in myocardial infarction mortality after an average follow-up of 7 years in those treated with mediastinal radiotherapy, compared with those who did not receive irradiation.23 Although the relative risk for fatal myocardial infarction was 6.33 for those treated during the early period, the risk fell to 1.97 for the later period, and the confidence interval for the estimate crossed 1.00 and therefore was not significant. The study by the Stanford group of 2232 patients found that the relative risk of non–myocardial infarction cardiac deaths, compared with that in the general population, declined from 5.3 to 1.4 with subcarinal blocking, but the relative risk for fatal myocardial infarction did not change significantly (3.7 versus 3.4).22 These apparently contradictory findings can be explained. Some preventive maneuvers, such as subcarinal blocking, do not protect the proximal part of the coronary arteries but do protect other parts of the heart. Therefore, the incidence of coronary artery disease would not be expected to change as much as disease caused by radiation damage to other structures of the heart. Other confounding factors include a shorter follow-up time in those treated with newer forms of therapy and lack of control for other cardiac risk factors in both studies.
One retrospective study of 352 HD patients treated with modern mediastinal radiotherapy, except that total doses exceeded 40 Gy in some cases, found a significantly higher than expected incidence of fatal myocardial infarctions or sudden death at a mean follow-up of 11.2 years.24 The risk of fatal or nonfatal cardiac events in patients without other known cardiac risk factors, however, was not significantly different from that predicted for the age-matched population. This finding underscores the fact that radiotherapy is one of several risk factors for cardiac disease. Breast cancer survivors treated with adjuvant radiotherapy for a left-sided malignancy also appear to be at 1.5 to two times the risk of coronary heart disease, depending on the dose-volume of exposure. Evidence comes from followup studies comparing cardiac mortality in patients treated with or without irradiation,25 studies comparing cardiac mortality and morbidity in left- versus right-sided survivors treated with irradiation,26 and similar but smaller studies comparing myocardial perfusion defects using stress testing with radionuclide imaging techniques.12,27 Treatment of the IMNs with older techniques exposed the heart to larger dose-volumes of radiation, and multiple studies have reported that such exposure increases the risk of ischemic heart disease.26,28 Although some follow-up studies have not found a significantly increased risk of myocardial infarction with radiotherapies used since the mid-1990s, these studies obviously have relatively shorter follow-up periods (median, 10 years) than those that have found an increased risk.27 Furthermore, studies that have looked at time since radiation as a risk factor have noticed an increased risk only after 10 to 15 years.28-30 Taken together, these studies suggest that the increased risk of ischemic heart disease depends on the heart’s dose-volume of exposure, the length of time since irradiation, and the presence of traditional coronary heart disease risk factors, such as smoking.
Valvular Disease Although autopsy studies reported a prevalence of valvular fibrosis of 70% to 80% after radiation doses in excess of 35 Gy,50,51 as late as the early 1990s, clinically important valvular disease was believed to be uncommon after mediastinal radiotherapy.31 Recent studies have found that valvular disease is quite common and that the need for cardiac valve surgery is elevated in HD survivors. In their studies of HD survivors, both Adams and associates17 and Heidenreich and colleagues16 reported that the rate of valve disease for which endocarditis prophylaxis should be considered was significantly greater than that expected in historical age- and gender-matched controls. In both studies, valvular insufficiency was more common, particularly aortic regurgitation (19% and 26%, respectively, in the two studies), but aortic stenosis was also quite common (6% and 4%). Heidenreich also found that the rate of left-sided valvular insufficiency increased with age and time since therapy, which suggests that radiation-associated valvular disease is progressive. A study of 415 HD survivors treated between 1962 and 1998 revealed the impact of radiation-associated valvular disease by finding that the observed-to-expected ratio for valve surgery was 8.42 (95% confidence interval, 3.20 to 13.65).32 Signs and symptoms of valvular abnormalities are
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of congestive heart failure and valvular disorders from mediastinal radiotherapy alone, which was already increased twofold to sevenfold for myocardial infarction, angina, congestive heart failure, and valvular disorders.20 The 25-year cumulative incidence of congestive heart failure was 10.7% after combined radiation and anthracycline therapy but just 7.5% after radiotherapy alone.
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no different from those seen for regurgitation and stenosis arising from other causes, although these patients may be less symptomatic. In general, the radiotherapy techniques used to treat breast cancer have not been associated with abnormal cardiac function, but they do worsen the effects of cardiotoxic chemotherapy agents. However, the largest study to date of breast cancer survivors treated with adjuvant radiotherapy suggests that those whose IMNs were exposed to radiation had an increased risk of valvular defects and congestive heart failure and that this risk did not decrease significantly with more modern techniques, in contrast to the reduced risk of myocardial infarction.28 However, this IMN-treated cohort was more likely to be exposed to cardiotoxic chemotherapy because they had a less favorable prognosis, and whether the analysis was adjusted for this likelihood is unclear.
Arrhythmias and Conduction Disturbances Life-threatening arrhythmias and conduction disturbances may occur years after radiation exposure and are quite distinct from the common asymptomatic, nonspecific, and transient repolarization abnormalities that occur soon after irradiation. Serious abnormalities reported after radiotherapy range from bradycardia (including atrioventricular nodal bradycardia), to prolonged QTc intervals, and all levels of heart block (including complete heart block and sick sinus syndrome). Cardiac dysfunction often is seen with persistent, monotonal tachycardia and loss of circadian and respiratory phasic heart rhythms.17 This picture is similar to a denervated heart, which suggests autonomic nervous system dysfunction. Patients who have received radiation to the heart also may have a decreased perception of anginal chest pain. Radiation may increase the risk of potentially serious ventricular arrhythmia in children receiving anthracyclines. With outdated, anterior-weighted mediastinal radiotherapy techniques, the prevalence of conduction abnormalities in childhood cancer survivors has been observed to be as high as 12.5% for prolonged QTc interval and 11% for complete or incomplete heart block; however, the length of follow-up and cumulative radiation doses were not provided.33 Given that other cardiac late effects seem to increase with time, arrhythmias and conduction defects also may be progressive. In general, symptoms associated with dysrhythmias are uncommon but can range from palpitations to syncope to sudden death. These conditions may not occur until years after exposure; therefore establishing causation is difficult. Irradiation of implanted pacemakers can cause them to malfunction or fail entirely. Criteria have been proposed for associating atrioventricular heart block with radiation therapy, based on a review of 19 cases (Table 140.4).34 Radiation also causes infranodal blocks more commonly than nodal blocks. Symptomatic conduction delays rarely occur in isolation and may worsen. The presence of a bundle branch or bifascicular block suggests imminent life-threatening problems.
Indirect Effects on the Heart
1838
Radiation may damage other structures in the neck and chest that the heart depends on to function properly (see Table 140.2).35 Fibrosis in the lung and its vessels may
PROPOSED CRITERIA FOR ASSOCIATING CARDIAC CONDUCTION ABNORMALITIES WITH RADIATION THERAPY n n n n n
Radiation dose to the heart >40 Gy Appearance 10 years or more after therapy Abnormal interval on electrocardiogram (ECG), such as bundle branch block Previous pericardial involvement, not necessarily requiring clinical intervention Cardiac conduction abnormalities that occur with other cardiac or mediastinal abnormalities or in patients who have had such abnormalities
From Slama MS, Le Guludec D, Sebag C, et al: Complete atrioventricular block following mediastinal irradiation: a report of six cases. PACE 1991;14:1112-1118.
Table 140.4 Proposed criteria for associating cardiac conduction abnormalities with radiation therapy.
greatly affect cardiopulmonary function. Stenosis and fibrosis may occur to the major arteries, including but not limited to the carotid arteries, the aorta, and the branch pulmonary arteries. Clinical presentations have included transient ischemic attacks, stroke, carotid bruits, vertebrobasilar insufficiency, and arterial insufficiency in the extremities. The lymphatic system also may be disrupted by radiationinduced fibrosis, which leads to chylous pleural effusions.36 Thyroid dysfunction after mantle irradiation is common and occurs from 6 months to longer than 10 years after therapy. Hypothyroidism may cause decreased ventricular contractility, ventricular diastolic dysfunction, arrhythmias, abnormalities of peripheral vessels, congestive heart failure, dyslipidemias, and coronary artery disease.37 Myxedema may cause a chronic effusion that may lead to symptoms and, rarely, tamponade. Prevention is the key element, because cardiovascular dysfunction may not resolve when the patient is treated and becomes euthyroid. Other neuroendocrine functions, such as those of the hypothalamus-pituitary axis, may be affected by radiation exposure or chemotherapy, and their effects on the heart and coronary heart disease risk factors need to be considered as well (see Chapter 129). In particular, growth hormone deficiency is a common problem in children who received cranial irradiation of 20 Gy or greater, and growth hormone deficiency has been associated with metabolic syndrome abnormalities.38,39 Furthermore, growth hormone deficiency may prevent optimal recovery from cardiac injury; growth hormone replacement therapy has been shown to be beneficial in increasing wall thickness in childhood acute lymphocytic leukemia survivors who had been treated with anthracyclines and were growth hormone deficient.40
DIAGNOSTIC TECHNIQUES The large number of possible radiation-associated abnormalities may require screening with multiple diagnostic modalities (Table 140.5). Nevertheless, the cardiac evaluation of a person previously exposed to radiation still begins with a thorough history and physical examination. The evaluation should begin by assessing the medical record for at least
EVALUATION OF PATIENTS AT RISK FOR LATE EFFECTS OF MEDIASTINAL RADIATION Screening and Diagnostic Tests
Management and Intervention
Treatment*
Signs and Symptoms
Pericarditis
>35 Gy
Fatigue, dyspnea on exertion, chest pain, cyanosis, ascites, peripheral edema, hypotension, friction rub, muffled heart sounds, venous distention, pulsus paradoxus, Kussmaul’s sign
ECG Chest radiograph Echocardiogram
Pericardiocentesis Pericardiectomy
Cardiomyopathy (myocardial)
>35 Gy or >25 Gy and anthracycline
Fatigue, cough, dyspnea on exertion, peripheral edema, hypertension, tachypnea, rales, tachycardia, murmur, extra heart sounds, hepatomegaly, syncope, palpitations
ECG ECG and/or radionuclide angiography (evaluate diastolic and systolic function) Pulmonary function testing and NT-proBNP with symptoms of congestive heart failure
Education regarding risks of alcohol, isometric exercise, smoking and other drug use, pregnancy, and anesthesia Afterload reducers, antiarrhythmics, diuretics, digoxin Cardiac transplantation
Coronary artery disease
>30 Gy
Chest pain, dyspnea, diaphoresis, hypotension, pallor, nausea, arrhythmia
Lipids and hsCRP Exercise stress test with or without radionuclide angiography, or dobutamine stress echocardiography (frequency depends on risk factor profile and symptoms) Consider thin slice CT for coronary artery calcium scoring Troponin and cardiac enzymes with chest pain
Risk factor modifications, including diet and conditioning regimens Cardiac medications and lipidlowering agents Coronary artery bypass graft or angioplasty
Valvular disease
>40 Gy
Cough, weakness, dyspnea on exertion, new murmur, rales, peripheral edema or any other sign of congestive heart failure
Echocardiogram Cardiac catheterization
American Heart Association antibiotic recommendations for endocarditis prophylaxis Valve replacement
Arrhythmia
>35 Gy
Palpitations, light-headedness, syncope
ECG and 24-hour ECG Evaluation for other abnormalities
Pacemaker
Modified from Constine LS: Late effects of cancer treatment. In Halperin EC, Constine LS, Tarbell NJ, et al, eds. Pediatric Radiation Oncology. 3rd ed. New York, Lippincott, Williams & Wilkins, 1999:457-537. *Total cumulative radiation exposure of the chest at this level or higher clearly indicates increased risk for the specific complication and thus the need to screen for it; however, the complication may occur at lower doses as well. CT, computed tomography; ECG, electrocardiogram; Gy, gray; hsCRP, highly sensitive C-reactive protein; NT-proBNP, serum N-terminal pro-BNP brain natriuretic peptide.
Table 140.5 Evaluation of patients at risk for late effects of mediastinal radiation.
the 10 risk factors listed in Table 140.3. Habits related to coronary artery disease risk factors should be discussed, as should any family history of cardiac disease. Cardiomegaly apparent on chest radiography may represent a pericardial effusion and can be definitively diagnosed by echocardiography. However, asymptomatic pericarditis generally does not require treatment; therefore screening for it makes little sense. On the other hand, because electrical conduction abnormalities may remain silent until fatal, electrocardiographic (ECG) screening for these abnormalities is quite important. Screening tests for indirect effects also should be performed, particularly for pulmonary function and thyroid function, as well as routine screening for other coronary artery disease risk factors (e.g., lipid profile and highly sensitive C-reactive protein [hsCRP]).
Myocardial function can be assessed by echocardiography and radionuclide angiography. Both are reliable, noninvasive methods of measuring left ventricular systolic performance. Echocardiography has the added advantage of allowing visualization of particular portions of the heart, such as the pericardium, valves, aorta, and branch pulmonary arteries. Diastolic function can (and should) be measured indirectly by echocardiography. Unfortunately, echocardiograms are of poor quality in some adults because of body habitus and bone density. Radionuclide imaging, therefore, may be preferable for repeated quantitative analysis of systolic function in certain patients. Such imaging also may be adapted to look at myocardial perfusion, and it is a strong predictor of future ischemic heart events. However, diastolic function is difficult to
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140 SECONDARY HEART DISEASE: CARDIAC RESPONSES TO ENVIRONMENTAL STRESS: Radiation-Induced Heart Disease
Late Effects
SECTION
1839
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1840
measure with the radionuclide technology available in most hospitals. Other modalities also may be useful for assessing myocardial function. Cardiac magnetic resonance imaging appears to be a powerful modality for evaluating both cardiac function and perfusion, but its limited availability and expense make it unrealistic to use for regular screening. Continued research to determine whether it provides significant advantages in irradiated patients with possible cardiac damage should be encouraged (see relevant chapters on cardiac imaging modalities). Serum N-terminal pro-BNP brain natriuretic peptide (NT-proBNP) appears to be a very useful tool for evaluating whether dyspnea is caused by heart failure, but its usefulness for serial screening for asymptomatic cardiomyopathy is less clear.41 In summary, myocardial function should clearly be assessed with echocardiography, with or without radionuclide studies, depending on the quality of each in a particular patient, while other modalities are reserved for answering specific questions. The increased risk of fatal coronary artery disease may occur as soon as 5 years after therapy. Investigating other risk factors for coronary artery disease is extremely important in all survivors of high-dose irradiation, regardless of age. Exercise stress testing is a noninvasive method to assess ischemia. Radionuclide myocardial perfusion scanning during exercise has a sensitivity and specificity for detecting ischemic heart disease of about 90% in the general population. Heidenreich and colleagues42 reported the usefulness of such screening in their series of 294 HD survivors treated with more than 35 Gy of mediastinal radiotherapy who had no history or symptoms of cardiovascular disease.42 Of these patients, 21.4% had abnormal ventricular images at rest, suggesting myocardial injury, and 42 patients (14%) experienced perfusion defects with exercise. Of the 44 patients who proceeded to have angiography, half had 50% or greater stenosis in one coronary artery, and seven went on to have coronary bypass graft surgery. Furthermore, 23 of the 294 patients experienced coronary events during a median of 6.5 years of follow-up, and 10 had acute myocardial infarctions. Maximal myocardial oxygen consumption during exercise provides additional information about myocardial health and has had prognostic value in patients with cardiomyopathy. We found myocardial oxygen consumption to be surprisingly low in some patients with a history of mediastinal irradiation who did not have marked symptoms.17 Hypotension, syncope, and rate-related conduction changes or rhythm abnormalities also were found unexpectedly in some of these same patients during exercise testing. Coronary calcium scoring using magnetic resonance imaging (MRI) or thin slice computed tomography (CT) scanning also may be useful for assessing the risk of ischemic heart disease, but research specific to this population has not been performed. Angiography and cardiac catheterization are appropriate to evaluate symptoms of angina and heart failure. Some experts argue that these procedures should be done if any other clinically important cardiac lesions are found, because coronary artery disease often occurs with other abnormalities in survivors exposed to greater than 35 Gy of radiation, and it often is asymptomatic.43 Cardiac biopsy may be helpful in evaluating a patient in congestive heart failure.
Although data do not exist to support definitive recommendations on test frequency, we recommend annual evaluations of survivors of childhood malignancy exposed to radiation. The course of cardiac disease progression is unknown and may vary considerably among patients. In addition, cardiac complications can be life-threatening but in some cases may be easily identified with routine testing. Children may be at higher risk because maturation of the irradiated heart may not keep pace with the growing body. Echocardiograms should be obtained annually to assess systolic and diastolic function, valvular and pericardial abnormalities, and coronary flow. Annual ECG, Holter monitoring, and exercise stress testing is performed to detect high-grade ectopy, conduction defects, ischemia, and abnormal hemodynamic response to exercise. Lipid profiles and thyroid and pulmonary function tests are also performed regularly. Radionuclide imaging is not performed regularly, but others have proposed that it should be done at least every 5 years because of the risk of silent ischemia.24
MANAGEMENT Prevention is the best way to “treat” radiation-induced cardiotoxicity. Although modern radiation techniques seem to reduce the risk of most types of cardiac disease, they do not appear to eliminate it, nor is it clear whether they substantially reduce the most serious risk, that of fatal myocardial infarction in HD survivors. Modern techniques include the use of a linear accelerator as a radiation source, a daily fraction size less than 2 Gy, equally weighted anterior-posterior portals each treated daily, a subcarinal block implemented before a cumulative dose of 30 Gy is reached, and shrinking field technique to minimize the dose-volume of exposure to the heart. Although permanent complications tend to occur less frequently at total doses less than 40 Gy, systematically limiting therapy to this dose is not a good idea, because such a dose may not control the cancer. Steroids should not be used prophylactically to prevent fibrosis. They have little clinical effect and have an unacceptably high incidence of side effects with long-term administration. Dexrazoxane, an agent that binds iron and, when delivered before each dose of anthracycline, reduces the amount of free radical myocardial injury from the formation of iron-anthracycline complexes, may also hold promise as a cardioprotectant against radiation damage. Acute pericarditis rarely requires extensive treatment. More than half of patients require no treatment, and another 40% respond to bed rest, nonsteroidal anti-inflammatory medications, and mild diuretics. Asymptomatic effusions may be followed while awaiting spontaneous resolution, which may take 2 years. Chronic effusions that cause symptoms or hemodynamic abnormalities of cardiac compression should be treated with a subtotal parietal pericardiectomy. In one series, pericardiocentesis alone was completely unsuccessful in treating radiationinduced chronic effusions that required intervention.44 Pericardiectomy may reduce the propensity of radiationrelated effusions to evolve into constrictive pericarditis, and it is more easily carried out if an effusion is present. Waiting until constriction occurs is associated with a higher mortality from acute dilatation and heart failure. However, if tamponade is present, pericardiocentesis should be performed using a local anesthetic just before pericardiectomy because
coronary artery bypass.48 Appropriate endocarditis prophylaxis should be given as well, regardless of surgical intervention. Atrioventricular sequential pacing is important for patients with complete heart block, because they tend to have stiff ventricles. In some cases, the appropriate treatment for survivors with severe radiation-induced heart disease in whom other therapies have failed is heart or heart-lung transplantation. Such patients should not be denied this option solely because of their history of cancer, and they deserve an appropriate and careful transplant evaluation. In summary, manifestations of radiation-induced heart disease are treated in the same way as these problems would be treated in the general public. However, extra precautions and a special appreciation of the changes irradiation causes in the heart and other structures in the chest should be kept in mind in the treatment of affected patients.
PROGNOSIS Although most people who receive therapeutic mediastinal irradiation remain asymptomatic from a cardiac perspective, virtually all patients with HD who are treated with radiation using older techniques have subclinical dysfunction 5 to 10 years after therapy. Clinically important dysfunction can occur during therapy or many years later. Subclinical dysfunction may be progressive and eventually may cause complications and death. Although refined therapeutic radiation techniques generally have reduced the percentage of patients with subclinical abnormalities and clinically meaningful problems,49 followup has been shorter with these newer techniques. In addition, the absolute risk of cardiac mortality for a given dose also appears to increase with longer follow-up. This suggests that the higher risk of cardiac complications associated with chest irradiation is lifelong. Continued evaluations for longer periods are needed to determine whether newer radiation techniques have eliminated the increased risk of cardiovascular disease or simply delayed the appearance of its manifestations.
SUMMARY Radiation-induced heart disease has been a major cause of complications and death among patients treated with mediastinal radiation. The spectrum of disease is broad, in terms of both manifestation and severity. Radiotherapy for left-sided breast cancer causes a lesser degree but still seriously increased risk of ischemic heart disease. Damage is caused primarily by microvascular injury. The resulting symptoms may not occur until decades later, although subclinical abnormalities commonly occur much earlier. Radiation should be considered one of many cardiac risk factors, which emphasizes the need to reduce other risk factors as much as possible. Unfortunately, radiation is not widely recognized as a risk factor for cardiac disease, even among cardiologists; therefore, it is incumbent on those of us who recognize this fact to inform our colleagues. More important, we must also teach this awareness to those who routinely care for these patients (primary care providers) and those who might care for these patients in a crisis (emergency department doctors). Longitudinal monitoring of patients exposed to radiation is needed not only to provide the best care for individual patients, but also to identify the best treatment options for those exposed to therapeutic irradiation as a group.49
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of the higher risk of general anesthesia in such conditions. This operation usually is successful unless myocardial fibrosis or constrictive pericarditis is present, in which case the prognosis is poor. Before surgery, however, hypothyroidism should be ruled out, because it is common after mantle irradiation and may cause chronic effusion. Also, the pericardial fluid and the pericardium should be analyzed to rule out tumor invasion and infectious agents. Coronary artery bypass surgery may be preferable for relieving acute coronary blockage in these patients, even in those whose lesions are treatable with percutaneous transluminal coronary angioplasty. Complications during angioplasty may require placement of an emergency coronary artery bypass graft. However, under emergency conditions, coronary bypass can be especially difficult because of extensive fibrosis in the mediastinum. In addition, left main coronary artery and ostial lesions are quite common in these patients and have been reported not to be amenable to angioplasty. Several studies report good long-term results with nonemergency bypass surgery in these patients.5,45,46 Hicks45 described his experience in operating on 14 patients who had received greater than 35 Gy of chest radiotherapy. Standard operative technique (moderate hypothermia and cold blood cardioplegia) was used in all patients, with good results. He recommends that anterior pericardiectomy be routine, with the initial operation on the heart, regardless of whether the pericardium is thickened, because this seemed to reduce complications. Postoperative complications depended largely on the extent of radiation injury to the lungs and right ventricle and on the maintenance of normal sinus rhythm. Many patients had moderate to severe right ventricular fibrosis with an elevated right atrial pressure and failure of the right ventricle to empty on cardiopulmonary bypass. Therefore, the right ventricle must be protected by maintaining higher filling pressures and by restoring normal sinus rhythm with its coordinated atrial contraction after bypass. Although the internal mammary artery is preferable to the saphenous vein for the bypass graft, the internal mammary artery was too damaged for use in 11 of the 14 patients. Therefore, shielding the mammary arteries from radiation is a good idea if it does not minimize therapy. A recent single institution review of 230 cancer survivors treated with chest radiotherapy who subsequently underwent surgery showed that HD survivors had significantly more complications and worse surgical outcomes, whereas women treated with tangential radiotherapy for breast cancer had similar outcomes to the general population.47 These researchers recommended that for the highest risk survivors, the techniques chosen should minimize the length of time pulmonary function is compromised in recovery and the time during the surgery that the heart is kept ischemic. They noted that, at a minimum, operations must be carefully planned and executed and that definitive repairs must be performed to minimize the risk of future surgeries. Heart block or valve disease requiring surgery often occurs with other manifestations of radiation-induced heart disease, such as chronic pericarditis or coronary artery disease. These other manifestations may explain why a 1991 retrospective review found the mortality rate among 35 patients with valvular disease undergoing surgical repair to be 66%.31 More recent reports suggest that patients do well even when valve repair is performed concurrently with
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Stuart J. Hutchison
Definition n
The progressive hypoxia of exposure to high altitude may result in a number of cardiovascular events ranging from subtle to increasing morbidity (acute mountain sickness with progression to high altitude pulmonary edema or high altitude cerebral edema) and death.
Key Features n
Acute mountain sickness, the most common altitude-related medical disorder, is not itself life-threatening; however, it is a marker of poor acclimatization and indicates a risk of complicated forms of altitude illness (high altitude pulmonary edema and high altitude cerebral edema), which may prove fatal.
n
Acute mountain sickness, in all its forms, is likely to occur at higher altitudes, after a more rapid ascent, and when greater levels of exertion are performed on attaining altitude.
Therapy n
The primary strategy is prevention—a progressive ascent to altitude.
n
Several pharmacologic means (the vasodilators nifedipine, sildenafil/tadalafil, and salbutamol and dexamethasone) have been shown in small trials to prevent forms of high altitude illness. Bosentan has been shown to reduce pulmonary pressures but has not been established as preventive or therapeutic for pulmonary edema.
n
Once symptoms have developed, prompt descent of more than 1000 vertical meters, together with supplemental oxygen, is effective.
n
Pulmonary and cerebral edema are medical emergencies.
Exposure to high altitude may initiate life-threatening medical illness and may also aggravate preexisting medical disorders. Exposure of a few hours to moderate altitude is seldom a risk to individuals with or without recognized cardiovascular disease, but longer stays may incite altitude-related illness. The most common altitude-related medical disorder is acute mountain sickness (AMS). Although not life-threatening, this nonspecific disorder is a marker of poor acclimatization and of susceptibility to the life-threatening forms of altituderelated illness. The life-threatening forms of altitude-related illness are high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE). HAPE is a noncardiogenic pulmonary edema of unpredictable nature. It typically affects healthy and fit individuals who ascend rapidly to high altitude
and promptly engage in strenuous exertion. Similarly, HACE is of unknown medical basis and affects individuals who ascend rapidly to high altitude; it can be viewed as a terminal and fulminant state of AMS. Although debate persists concerning the optimal treatment of all forms of altituderelated disorders, there is no debate that prevention should be the primary strategy, and that once significant symptoms have developed, no further altitude gain should be attempted—and risk incurred. Exposure to high altitude occurs principally in the great mountain ranges of the world, which are visited by tourists and recreational adventurers such as skiers, trekkers, and climbers. Across America, more than 1 million individuals ski at or over moderately high altitudes of 3050 m (10,000 feet) each year. More than 1500 individuals attempt to climb Mount McKinley (Denali) in Alaska each year, and approximately 50% reach the 6198-m (20,320 feet) summit each year. Roads enable vehicular ascent to the summit of the Rocky Mountains, including the summit of Pike’s Peak (4300 m [14,100 feet]), to which hundreds of thousands of individuals drive yearly. Similarly, more than 300,000 individuals a year drive from sea level to two thirds of the way up Japan’s Mount Fuji (i.e., to 2440 m [8000 feet]), and many thousands continue the ascent to the summit (3776 m [12,380 feet]). Increasing numbers of individuals trek and climb to very high and extreme altitude in the Himalayas; the numbers have dipped only in 2002. An individual must be exposed to altitude for 6 to 24 hours for AMS, HAPE, or HACE to ensue. The fact that most individuals who ascend rapidly do so in one “tourist” mode or another and spend only a few hours at altitude likely accounts for the relatively low incidence of altituderelated health problems. Individuals who engage in recreational or other pursuits for longer intervals and those who venture into higher and more remote regions assume a greater risk, both of contracting an altitude-related disorder and of adverse outcomes to the disorder. Fatalities have occurred at altitudes as low as 2135 m (7000 feet), but altitude-related symptoms generally are very mild between 1525 m (5000 feet) and 2440 m (8000 feet) above sea level. Altitude-related disorders start at approximately 2440 m (8000 feet), and most cases occur between 3050 m (10,000 feet) and 4575 m (15,000 feet). The threshold effect of 2440 m (8000 feet) on altitude illness is best seen at alpine ski resorts:
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n
those such as Tahoe, at 2135 m (7000 feet), have very few cases of altitude illness; those such as Vail, at 2440 m (8000 feet), have occasional cases; and those such as Mammoth, at 2745 m (9000 feet), have more cases.
Interestingly, the elevation at which the individual sleeps is a greater influence on the development of altitude-related illness than is the altitude attained during the day—the elevation of the ski resort matters at least as much as the height of the ski hill—hence the climber’s dictum, “carry high, sleep low.” Above 4575 m (15,000 feet), the incidence of altituderelated illness increases. Therefore, most cases of altituderelated disorders are suffered by tourists, mainly at moderately high altitude and generally in areas with better facilities and access to treatment. The absolute number of cases in those who proceed to greater heights is smaller, but the incidence is greater, as is the mortality. Few definitive medical treatments are available for high altitude pulmonary and cerebral edema; the principal “treatment” is prevention.
PHYSIOLOGIC EFFECTS OF ALTITUDE AND ACCLIMATIZATION
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The goal of acclimatization is to minimize intracellular hypoxia. Acclimatization to high altitude occurs principally at the pulmonary level but also at the peripheral cellular level. Acclimatization to extreme altitude represents a complex and notable physiologic feat. The scientific community initially held that survival, let alone exertion, at the summit of Mount Everest (8854 m [29,028 feet]) was impossible. However, early British climbs in the 1920s established that, with and without supplemental oxygen, strenuous exertion could be performed at extreme altitude. In 1978, the summit of Mount Everest was reached for the first time without supplemental oxygen by Reinhold Messner; he subsequently repeated his feat, to be followed over many years by many others.1 Exposure to the hypobaric hypoxia of altitude results in an immediate decrease in the resting (and exertional) partial pressure of oxygen (PaO2) and in oxygen (O2) saturation. The extent of the decrease in PaO2 and O2 saturation is altitude dependent. At 2135 m (7000 feet), the PaO2 is 8.0 kPa (60 mm Hg) and O2 saturation is still high (92%). However, above 2440 m (8000 feet), the decrease in O2 saturation accelerates as the decline in the O2 saturation curve accelerates. Concentrations of 2,3-diphosphoglycerate in the red blood cells increase. Decreases in O2 saturation stimulate carotid body chemoreceptors, which in turn stimulate an increase in ventilation by means of a greater increase in tidal volume than in rate of ventilation. This hyperventilation persists throughout the stay at altitude. As a result of the hyperventilation, the partial pressure of carbon dioxide (PaCO2) decreases, and respiratory alkalosis develops. Over 3 to 4 days, renal adaptation occurs and blood pH is normalized, although the PaCO2 remains low. With further hypoxia, further hyperventilation occurs. Alkalosis shifts the O2 dissociation curve to
retain greater saturation for any degree of hypoxia. The extent of hyperventilation is considerable, and at the summit of Mount Everest, an end-alveolar PaCO2 concentration as low as 1.0 kPa (7.5 mm Hg) has been measured.1 With an extremely low PaCO2, a greater PaO2 can be achieved, but the extreme hypoxic ventilatory response is believed to contribute to the cerebral artery vasoconstriction and neurologic sequelae of climbing to extreme altitude.2 Exposure to altitude-related hypoxia, as with exposure to any form of hypoxia, stimulates complex changes in sympathetic output. Field and laboratory studies have yielded widely divergent observations on indices of sympathetic activity at altitude. A predominance of data affirms that sympathetic output increases promptly and decreases to normal or even subnormal levels after several days, and thus potentially may be viewed as a marker of acclimatization.3 For several days after altitude is attained, the heart rate and blood pressure are increased, resting cardiac output increases (mainly as a result of the increase in heart rate), venoconstriction occurs, and basal metabolic indices are increased. An increased heart rate is consistent with a nonacclimatized state, and tachycardia suggests HAPE. For the first several days at altitude, total blood volume decreases as a result of a reduction in serum plasma volume; often, within hours of altitude being attained, plasma volume has decreased by 10% to 15%. This is caused partly by a shift of fluid out of the intravascular compartment; the proportion of shift into the interstitial compartment compared with that into the intracellular compartment is unclear. The basis of the fluid shift is not understood, but vascular integrity and permeability are a factor in most altitude-related diseases. In addition, fluid intake often does not match fluid shifts and insensible loss, and degrees of intravascular hypovolemia are common. Therefore, edema is not unusual after exposure to altitude, before acclimatization has occurred, and intravascular depletion may occur concurrently. Because of loss of plasma volume, the hematocrit increases acutely. Also, the circulating erythrocyte mass increases slightly as a result of reduced splenic sequestration of erythrocytes. The total erythrocyte mass does not increase significantly unless exposure to altitude and hypoxia are of sufficient duration that erythrogenesis, with its 10-day intramedullary phase, has occurred. Most individuals acclimatize to altitudes such as 3050 m (10,000 feet) within 3 to 4 days and clearly do so without relying on erythrogenesis and an increase in the hematocrit. Notably, the llama, an animal that performs the most efficiently and powerfully at altitude, has a hemoglobin concentration of less than 100 g/dL. Rather than being essential to acclimatization, polycythemia is only a late and minor contributor to acclimatization, and it is strongly suspected of contributing to some cases of altituderelated ischemic events. Initially, the cardiac response to altitude exposure consists of a decrease in cardiac chamber cavitary size (as a result of plasma volume contraction) and stroke volume, but proportionally a greater increase in heart rate, such that resting cardiac output increases. The resting heart rate tends to normalize with acclimatization; however, the maximum heart rate is very significantly reduced—130 beats per minute (bpm) at 6100 m (20,000 feet)4 —throughout the time at altitude.
and clinically insignificant benefit at elevations of 3050 m (10,000 feet) or so; however, above 6100 m (20,000 feet), it confers a very important advantage in terms of maintaining O2 saturation (Fig. 141.1).
PATHOPHYSIOLOGY Acute Altitude Exposure As with loss of pressurization in an aircraft, acute exposure to altitude may compromise an individual through both acute hypoxia and acute hypobaria. The severity of the symptoms relates to the severity of the hypoxia. Increasing hypoxia causes initially mild sensory impairment, then mild cognitive impairment, then worsening cognitive impairment, then lethargy, loss of consciousness, coma, and death. In the 20th century, several early French balloonists ascended to remarkable heights, greater than 15,250 m (50,000 feet), in hot air paper balloons and then returned to earth as fatalities of hypoxia. Acute decompression syndromes (the formation of nitrogen bubbles within the joints, organs, and bloodstream) also can occur with abrupt loss of pressurization, similar to the acute decompression syndromes related to
EFFECT OF ALTITUDE, HYPOXIA, AND ALKALOSIS ON ARTERIAL OXYGENATION AT REST AND WITH EXERCISE
Altitude (m) 0 (feet) 0
1525 5000
3050 10,000
4575 15,000
6100 20,000
7625 25,000
9150 30,000
100 90
Everest 8854 m (29,028 ft) AtmPressure: 250 PaO2 = 3.73 kPa (28 mm Hg) PaCO2 = 1.07 kPa (8 mm Hg) SatRest = 72%
80
Saturation (%)
70 60 50 40 30 20 10
Vail 2440 m (8000 ft) AtmPressure: 565 Ayers Rock PaO2 = 8.00 kPa 458 m (1500 ft) (60 mm Hg) PaO2 = 12.67 kPa = 4.93 kPa (95 mm Hg) PaCO2 (37 mm Hg) PaCO2 = 5.33 kPa = 92% (40 mm Hg) SatRest SatRest = 97% Barometric pressure = 750
0 (mm Hg)
100
(kPa) 13.33
Matterhorn 4507 m (14,777 ft) AtmPressure: 420 PaO2 = 5.87 kPa (44 mm Hg) PaCO2 = 4.27 kPa (32 mm Hg) SatRest = 80%
Denali 6198 m (20,320 ft) AtmPressure: 325 PaO2 = 4.27 kPa (32 mm Hg) PaCO2 = 2.13 kPa (16 mm Hg) SatRest = 50%
Extreme hyperventilation
With hyperventilation/ alkalosis
90
80
70
60
50
40
30
20
10
12.00
10.67
9.33
8.00
6.67
5.33
4.00
2.67
1.33
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The most striking aspect of arriving at altitude is the profound decrease in exercise capacity. Several factors contribute, and the dominant cause is unknown. A lower maximum cardiac output occurs at the cardiac level because of the lower maximum heart rate and also at the pulmonary vascular level because of hypoxic-induced vasoconstriction. Decreased O2 saturation and a greater decrease in saturation with exertion impair exercise capacity by reducing intracellular O2 tension. Peripheral cellular responses are important in adaptation to altitude. The intracellular machinery of respiration (i.e., oxidative enzymes, myoglobin, mitochondrial numbers, and capillary density) all increase with hypoxic exposure at altitude. This has been well demonstrated in hypobaric chamber experiments with quadriceps muscle biopsy sampling. In summary, the principal adaptation to altitude occurs at the pulmonary level and is achieved through hyperventilation; the secondary response occurs through peripheral cellular respiratory changes. Consequently, any pulmonary disease acquired at altitude, such as HAPE, is potentially life-threatening. Respiratory alkalosis has the important effect of increasing the saturation at any PaO2. This confers only a very small
0 0 PaO2
Figure 141.1 Effect of altitude, hypoxia, and alkalosis on arterial oxygenation at rest and with exercise. Above 2440 m (8000 feet), arterial saturation (Sat) begins to decline. Hyperventilation and alkalosis confer increasing benefit at higher elevations. Exertion leads to increasing desaturation with increasing altitude. Atm, atmospheric; PaCO2, partial pressure of carbon dioxide; PaO2, partial pressure of oxygen.
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scuba diving. Climbers who are poorly acclimatized and who ascend using inadequate supplies of supplemental oxygen that become depleted may experience acute hypoxic symptoms as described previously.
High Altitude Pulmonary Edema Few pathologic studies have been done on individuals who succumb to HAPE. Dickinson and colleagues5 described the autopsy findings in seven trekkers who died of altituderelated illness. All had wet lungs, edematous with exudative, protein-rich fluid; many had alveolar hemorrhage; and some had hyaline membranes. In 50% of these individuals, thrombosis was observed in pulmonary arteries, which suggests that in situ thrombosis of the pulmonary arteries may complicate the course of HAPE. The right ventricles were dilated, consistent with pressure strain on the right side of the heart. The pathophysiology of HAPE is incompletely understood, despite decades of observational studies, and is the subject of a high degree of debate. Four schools of thought attempt to explain the development of the disorder: n an abnormal pulmonary vascular response underlies HAPE; n permeability alone is the central cause of the disorder; n increased pulmonary capillary pressure causes HAPE; and n impaired sodium-driven clearance of alveolar fluid may underlie susceptibility to HAPE.
Excessive Pulmonary Artery Vasoconstriction A substantial body of evidence indicates that an abnormal pulmonary vascular response underlies HAPE. The response is abnormal in two ways: an excessive pulmonary artery (PA) vasoconstrictor response occurs, as does a highly heterogeneous response. The patchy vasoconstricted areas are protected from local hyperemia, but the less constricted areas are exposed to disruptive flow and pressure that result in edema. The site of leakage and the mechanisms are controversial, but failure of hemodynamic stress of capillaries or arterioles is believed to be responsible. It has been shown that6,7: n individuals with HAPE have severely increased PA pressures; n individuals susceptible to HAPE at altitude (i.e., who have a history of HAPE but do not currently have the condition) have moderate increases in PA pressure; and n individuals with no history of HAPE at altitude have lesser increases in PA pressure.
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Individuals susceptible to HAPE have greater PA pressures after exposure to hypoxia and with exercise than do individuals who are not susceptible to the condition.8 The relationship of pulmonary hypertension to HAPE is strong, well documented, and intuitively logical, although it remains difficult to prove whether this is an association or a matter of causality. Situations that increase PA pressure (e.g., exertion) clinically worsen HAPE, and interventions that reduce PA pressure (e.g., supplemental O2, descent from altitude, nifedipine, and nitric oxide) improve HAPE. The mechanism of the excessive and patchy pulmonary vasoconstriction is not well understood, but a number of
studies support the concept that endothelial injury or activation underlies HAPE. Concentrations of endothelin 1 increase twofold at 4575 m (15,000 feet), and correlate with PA pressure. Bosentan, a mixed Eta/Etb endothelin receptor antagonist, has been shown to attenuate altitude-induced increases in pulmonary artery pressure.9 Nitric oxide markers may be reduced in individuals with HAPE,10 and nitric oxide supplementation does improve HAPE.6 Concentrations of E-selectin, which is produced only by endothelial cells, increase at altitude, which supports the suggestion that endothelial injury participates in HAPE.11 Specific endothelial nitric oxide gene polymorphisms have not yet been associated with HAPE. A magnetic resonance imaging (MRI) study using a spin labeling technique demonstrated that the relative dispersion of pulmonary blood flow was no different in normoxic conditions between HAPE-susceptible, HAPE-resistant, and unselected patients; however, when under hypoxic stress, HAPEsusceptible individuals showed greater pulmonary blood flow heterogeneity, whereas HAPE-resistant and unselected individuals did not show heterogeneity.12 The theory that regional heterogeneity of pulmonary vasoconstriction incites high altitude pulmonary edema proposes that lung regions that develop greater arteriolar vasoconstriction protect their capillary beds from excess hydrostatic forces, but regions with lesser constriction do not adequately protect the capillary beds, exposing them to excess physical forces that disrupt the capillary integrity, causing edema. A further cause of nonuniform vascular obstruction in HAPE is the development of thrombosis of the pulmonary arteries. Intra-arterial acetylcholine infusion studies in HAPEsusceptible individuals have shown systemic endothelial function to be impaired by hypoxic stress.13 Although this observation pertains solely to the endothelial nitric oxide pathway, the study indirectly and considerably supports the theory that endothelial dysfunction, including other components of pulmonary endothelial function, is involved.
Permeability Alone as the Central Cause of HAPE The second school of thought regarding the pathogenesis of HAPE is that permeability alone is the central cause of the disorder. Edema is common at altitude, both the generalized edema seen in individuals who have nonspecifically failed to acclimatize and the disorders of HAPE and HACE. Bronchoscopic studies carried out at 4422.5 m (14,500 feet) on Mount McKinley, in individuals with HAPE, established that the protein content of bronchial fluid in these individuals was the same as that of serum, providing one of the cornerstone arguments of the permeability concept.14 More detailed studies have shown that the nature of the bronchoalveolar lavage fluid suggests a “large pore” leak15 and that, despite the presence of markers of inflammation (leukotrienes B4 and C5a), HAPE fluid does not contain the prominent neutrophil cellular material that is seen with acute lung injury states.15 The cause of such an acute failure of vascular integrity is not well understood, but some evidence indicates that inflammation participates in the process.16 The 12- to 24-hour interval between exposure to altitude and the development of HAPE is intriguing and indirectly may suggest a number of cellular
transcriptional mechanisms that result in uncontrolled permeability. Inflammation has been proposed as a central mediator of permeability in HAPE16 but has been refuted as such by others.17
The third school of thought holds that HAPE is caused by increased pulmonary capillary pressure. Although increased pulmonary capillary pressure customarily is equated with cardiogenic pulmonary edema, hypoxic pulmonary venoconstriction18 (which may account for 20% of the increase in pulmonary resistance in pulmonary edema19) direct PA-capillary connections increase capillary pressure.20 A recent study demonstrated increased pulmonary capillary wedge pressure (PCWP) in individuals with early HAPE: Early HAPE cases HAPE-susceptible individuals Controls
PCWP: 22 mm Hg PCWP: 16 mm Hg PCWP: 12 mm Hg
In addition, increased pulmonary permeability (as measured by the transport of gallium 67–labeled transferrin protein) has been reported to occur when the capillary pressure was greater than 19 mm Hg.21 Experimental work in dogs has shown that lung weight increases when the capillary pressure exceeds 17 to 24 mm Hg.22 However, older studies demonstrated low-normal capillary pressures (4 mm Hg), mildly reduced cardiac indices (31/min/m2), and greatly increased pulmonary vascular resistance (19 Woods units) and pulmonary arterial hypertension.23-26 Therefore, no evidence indicates that HAPE is a cardiogenic pulmonary edema, but increased capillary pressure may participate through complex mechanisms of small-vessel vasoreactivity. Left ventricular diastolic dysfunction, documented in healthy mountaineers ascending to altitude, is believed to be imparted by secondary changes in left-sided heart filling caused by acute right ventricular hypertension. The occurrence of overt diastolic heart failure has not been established.27
Impaired Sodium-Driven Clearance of Alveolar Fluid The most recent school of thought proposes that impaired sodium-driven clearance of alveolar fluid may underlie susceptibility to HAPE.28 HAPE-susceptible individuals are approximately four times as likely to have a patent foramen ovale, intracardiac shunting as a result of it, and worse hypoxemia as HAPE-resistant individuals.29 Although the patent foramen ovale has been proposed to worsen hypoxemia and thereby aggravate pulmonary vasoconstriction, its significance in HAPE is unclear.
High Altitude Cerebral Edema Most patients who develop HACE have previously had AMS, and a prior history of HACE is common. Brain edema occurs in all cases, and petechial hemorrhages are common, as is spongiosis. In affected individuals who die, focal necrosis and brain herniation have been observed.5 The pathophysiology of HACE is poorly understood. Initially, volume overload was thought to be the cause; however, even moderate to severe volume overload does not cause cerebral edema.
CLINICAL PRESENTATIONS Acute Mountain Sickness As mentioned, AMS is a nonspecific disorder that is not lifethreatening but that serves as a marker of poor acclimatization to date and therefore of the risk of development of more severe altitude illness. It is far more common than HAPE or HACE, and generally takes 6 to 24 hours at altitude to develop. The principal symptom of AMS is headache. It typically is worse in the morning, which suggests that sleep-impaired hyperventilation may contribute. The headache typically is bifrontal and throbbing. The mountains beside the 4819 m (15,800 feet) Kilik Pass in Afghanistan are known as the Great Headache and Little Headache Mountains. In addition to headache, nonspecific complaints are common, such as fatigue, lethargy, irritability, anoxia, nausea, vomiting, light-headedness, personality changes, and insomnia. No physical findings are specific to the diagnosis of AMS. Edema is common but is not specific for AMS. Nocturnal periodic breathing also is not specific for AMS. Overt neurologic findings (especially ataxia) are strongly suggestive of HACE, severe hypoxia from HAPE, or other lung disease. Susceptibility to AMS is highly variable. Some individuals show no AMS symptoms, whereas others are incapacitated. Prediction on the basis of patient-related parameters remains elusive. Physical conditioning does not reduce the incidence of AMS. Older individuals are not more likely to develop AMS, but children are. Rapid ascent (e.g., traveling from sea level to a ski resort at 2440 m [8000 feet] in a day), exertion (e.g., skiing), and male gender typify most patients with AMS. Individuals who spend 2 days at an intermediary elevation (e.g., Denver on the way to Vail) have few symptoms of AMS. The irresistible accessibility of mountain resorts and recreational areas contributes to most cases of AMS, as does neglecting the process of acclimatization.
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Increased Pulmonary Capillary Pressure
The current theory is that HACE is vasogenic in origin; that is, it is the result of a local failure of maintenance of fluid compartment partitioning of the intracranial vasculature. Recent MRI data have characterized the pattern of edema in HACE25 as reversible white matter edema; however, a vasogenic basis for the disorder has not been conclusively established.30
High Altitude Pulmonary Edema High altitude pulmonary edema is a life-threatening disorder. Its basis is incompletely understood, and no fully reliable treatment, other than descent and supplemental oxygen, is available. HAPE accounts for most deaths from high altitude medical illness and for an important proportion of all deaths at altitude (Fig. 141.2). The first death likely from HAPE was recorded in AD 403, involving a Chinese monk who died foaming at the mouth while traveling at high altitude in Afghanistan. The first recorded impression that HAPE was an acute edema was made nearly a century ago, by a physician on an expedition to climb the Abruzzi Ridge of K2. The physician recorded that a young member died of “fluid on the lungs.” For many decades, HAPE was not understood, and cases invariably
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Unusual basic grounds of HAPE include backgrounds such as congenital absence of a pulmonary artery34 or previous pneumonectomy.35 The natural history of HAPE is variable and unpredictable. In addition to the pulmonary features, cerebral symptoms frequently are observed as a result either of concurrent disorders (50% of those with HAPE have AMS, and 15% have HACE36) or of severe hypoxia. Many cases stabilize, and some improve even without therapeutic intervention, but some progress to a fatal outcome. Loss of consciousness portends death within the day. One of the most distinctive features is nocturnal progression. The reasons for this are unclear, but many deaths occur at night. Nocturnal hypoventilation may contribute to this nocturnal deterioration. Mortality rates are increased by unavailability of treatment, unavailability of descent or evacuation, and higher altitude at which HAPE occurred. In the author’s experience, three of 21 cases (14%) died.
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Exposure
Falls
Avalanches
HACE
CO poisoning
Stroke
HAPE
Figure 141.2 Deaths at altitude. Deaths observed on 10 Alaskan climbs and four Himalayan climbs. Exposure (death from cold) and falls are the most common causes of death. High altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE) are the next most common causes of death. CO, carbon monoxide.
were regarded as pneumonia. HAPE was first documented and described in the modern era in 1965.31 The incidence of HAPE is influenced both by the altitude to which the individual is exposed and the rate of ascent to that altitude. It is n much less than 1 in 1000 for skiers at resorts at 2135 m (7000 feet); n approximately 1 in 1000 for those at resorts at 2440 m (8000 feet); n 1 in 100 for those who ascend rapidly to higher than 3050 m (10,000 feet); and n approximately 5 in 100 at altitudes approaching 4575 m (15,000 feet).
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Cases have occurred at altitudes higher than 8500 m (27,869 feet) on Mount Everest. Some individuals appear to harbor a susceptibility to HAPE and repeatedly develop HAPE at the same elevation. Children appear to be particularly predisposed to HAPE.32 The third factor that influences the incidence of HAPE is exertion performed at altitude: exertion increases cardiac output and pulmonary artery pressures. The individuals who incur the greatest risk are fit and strong individuals who ascend rapidly to above 3050 m (10,000 feet) and engage in strenuous exertion upon arriving at altitude and before having acclimatized. An unusual form of high altitude pulmonary edema is seen among individuals who live at high altitude and who return to altitude after several days or weeks at low altitude (i.e., “re-entry” or “reascension” pulmonary edema).33
High Altitude Cerebral Edema High altitude cerebral edema is a potentially life-threatening altitude-related disorder. As with HAPE, it is much less common than nonspecific AMS and can be viewed as the endstage and worst form of AMS. The reported incidence is about 25% that of HAPE. HACE may be present in an individual who also has HAPE. The principal symptom is headache. Nausea, vomiting, visual disturbances, lethargy, and personality changes may occur. Loss of consciousness precedes death. Seizures are uncommon but may occur. Lack of coordination, ataxia, mental status changes, abnormal reflex responses, and retinal hemorrhages and papilledema are common.
DIAGNOSTIC TECHNIQUES Acute Mountain Sickness No serologic or radiologic tests are available to assist with the diagnosis of AMS. It therefore remains a clinical diagnosis consisting of: n a context of recent altitude gain; n headache; and n nonspecific symptoms. For most individuals, as long as no progressive altitude gain has occurred, AMS is a time-limited disorder and symptoms will subside within several days. A small subset of patients never acclimatizes.
High Altitude Pulmonary Edema The diagnosis of HAPE is made clinically based on the following factors: 1. A susceptible individual (one who has ascended rapidly to altitude) 2. An individual who develops respiratory distress after a short latent period 3. The presence of at least two of the following symptoms: n Dyspnea at rest n Cough n Exertional intolerance n Chest pressure n Undue weakness
The most compelling and elegant description of the symptoms of HAPE was provided in a personal account by a prominent physician, James Wilkerson III: fatigue, possible mild AMS symptoms a few days before, shortness of breath on exertion, a sensation of breathing deeper when at rest, but not of frank shortness of breath at rest, and no orthopnea.37 The principal findings are respiratory. Patients with HAPE appear agitated and distressed from hypoxia and increased ventilatory effort. The ventilatory rate and effort typically are greatly increased. Tachycardia is a valuable sign. Crepitations inevitably are heard throughout the lung fields, and wheezing is common. Cyanosis is present in all severe cases. A few patients have overtly frothing pink bubbly secretions. Somnolence suggests respiratory fatigue and an increased mortality as a result either of the terminal state of pulmonary edema or concurrent cerebral edema. Jugular venous pressures are rarely described in the literature. In the author’s experience, despite the increased right ventricular and systolic pressures, jugular pressures tend to be low, usually as a result of concurrent volume depletion because of the high insensible water losses in the low-humidity environment of high altitude. Abnormalities on cardiac auscultation are seldom detected. Low-grade fever is quite common for the first several days among patients with substantially increased respiratory work.
Differential Diagnosis It is important to recall the differential diagnosis of respiratory distress at altitude. Bronchial and tracheal irritation from the dry if not desiccating air at high altitude is clearly the most common reason for cough at altitude. The “Himalayan hack” or “Karakoram cough” is nearly ubiquitous among expedition members to very high altitude peaks. Up
A
to 10% of individuals taking part in high attitude expeditions have fractured ribs as a result of intractable dry cough. This cough is not associated with airflow obstruction. Some individuals develop an exacerbation of bronchial asthma as a result of the cold air or exercise (or both) at altitude. Bronchitis and bronchopneumonia are encountered among Western climbers who go to altitude and in local porters and Sherpas. Some fulminant cases of HAPE, with an abrupt onset, lowgrade fever, and red, frothy secretions may be misinterpreted as pneumococcal pneumonia. Pulmonary embolism has been described among expedition members who ascend to high altitude, particularly those immobilized for a period of days, typically waiting out storms in small tents. An inadequate fluid intake and immobility are the presumed precipitants of venous thrombosis and subsequent embolization.
Radiographic Findings The typical radiographic findings of HAPE differ from those of cardiogenic edema and other noncardiogenic edemas.38 The radiographic features of HAPE (interstitial, central, with peribronchial cuffing, ill-defined vessels, and patchy air space consolidation) have been elegantly summarized by Gluecker and associates.38 Typically, the size of the heart in individuals with HAPE is normal, and the pattern of HAPE, in contradistinction to that of cardiogenic pulmonary edema, is typically supradiaphragmatic sparing (Fig. 141.3a). With descent and/or supplemental oxygen, complete resolution within 24 to 48 hours is common (Fig. 141.3b). Patients who develop HAPE in remote settings generally never undergo chest radiography because of a lack of immediate availability and because the survivors, once evacuated down to developed areas, have clinically recovered. Given the lag phase of clearance of pulmonary edema, infiltrates often persist at least 48 hours after clinical resolution.
Echocardiographic Findings The typical echocardiographic findings, described in research studies of HAPE, are an increase in the right ventricular systolic pressure. The degree of increase is greater among individuals susceptible to HAPE than it is among those who are not susceptible (i.e., have no previous history of pulmonary edema): 5810 mm Hg, compared with 37 mm Hg (P ¼.0001) at 4575 m (15,000 feet).7 In cases of HAPE that
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4. The presence of at least two of the following physical findings: n Rales n Wheezing n Tachycardia n Tachypnea at rest n Central cyanosis 5. An individual in whom no other cause of pulmonary disease is likely.
B
Figure 141.3 Chest radiographs of a young man with high altitude pulmonary edema (HAPE). A, The patchy supradiaphragmatic distribution, normal-sized heart, and prominent pulmonary arteries are typical. B, Near-complete resolution after 48 hours of supplemental oxygen is typical.
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occurred in research studies, right ventricular systolic pressures greater than 100 mm Hg have been described.39 Patent foramen ovale with right-to-left shunting is observed more frequently in HAPE-susceptible individuals than in those who are HAPE resistant.
Predictive Testing No laboratory tests are available that predict with sufficient clinical accuracy those who will develop HAPE. Standard pulmonary function testing that assesses lung volumes and flow rates has no clinical value in this regard. Hypoxicinduced ventilation testing has been proposed as predictive, but clinical data are lacking. For individuals who have previously been to high altitude and remained healthy, the risk of development of HAPE is low. Conversely, in individuals who have previously developed pulmonary edema, the likelihood of developing pulmonary edema again is considerable; specifically, there is a 60% recurrence rate in individuals who ascend to the same altitude. Stress echocardiography appears to offer some ability to differentiate HAPE-susceptible individuals; they appear to be those individuals who develop a right ventricular systolic pressure greater than 45 mm Hg during supine bicycle exercise in normoxic conditions.8 Most cases of HAPE develop in a milieu of unrestrained rapid ascent followed promptly by heavy exertion on achieving altitude. The disorder, therefore, can be considered preventable, other than in a small number of individuals who are unusually susceptible to it.
High Altitude Cerebral Edema The diagnosis of HACE is a clinical one and is based on the following factors: n the context of recent altitude gain (within 1 week); n development of a change in mental status or of ataxia in an individual with previous AMS; or n development of a change in mental status and ataxia in an individual without AMS. Truncal ataxia is a useful finding, because it is seldom observed in individuals with HAPE. Other neurologic disorders that may manifest at altitude should be recalled when the diagnosis of HACE is considered. Stroke and transient ischemic attack have been described at altitude. They may be caused by a number of mechanisms, including sympathetic activation and relative polycythemia. Seizures related to high altitude (hypoxic seizures) have been described in individuals both with and without a previously recognized seizure disorder. Subarachnoid hemorrhage at altitude has occurred and may have an increased incidence at high altitude. Some individuals with HACE have focal findings that confuse the diagnosis.
MANAGEMENT Acute Mountain Sickness
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Appropriately sized and controlled clinical studies on the prevention and treatment of AMS have been few. The best prevention is graded, or progressive, ascent to altitude,40 with a rate on average of less than 305 m (1000 feet) per day above 2440 m (8000 feet). Staged intervals of rest, maintaining the same approximate overall rate of ascent, may be helpful and often is more practical.
For individuals who are mildly or moderately symptomatic, descent of 500 to 1000 m (1640 to 3280 feet) or supplemental oxygen, if available, is the treatment of choice. Most of these individuals experience complete improvement. Further ascent can be entertained after improvement, but with caution. Severely symptomatic individuals improve with supplemental oxygen, if available, and with descent of 1000 m (3280 feet). Both acetazolamide and dexamethasone are used to prevent symptoms of AMS. However, the clinical evidence for use of these drugs is scant; there is no proven basis that either prevents the development of life-threatening forms of altitude-related disease. Acetazolamide, 250 mg given every 12 hours by mouth, reduces symptoms of AMS when given prophylactically or for established AMS.31 Unwanted side effects include diuretic effects, tingling of the fingers or toes, myopia (dose dependent), and hypersensitivity. A dose of 125 mg given every 12 hours by mouth is less likely to produce finger and toe tingling and probably is as effective. Dexamethasone, 4 mg given orally every 6 hours, has been shown to reduce the symptoms of AMS both prophylactically41 and for established symptoms.42 The prophylactic effect appears greater. However, the use of dexamethasone is controversial. Clinical evidence of its efficacy is scant, whereas evidence exists that it is simply an antinausea and mood-enhancing drug. Dexamethasone is not recommended for routine use to prevent or treat AMS because of its side effects. In fact, its use is discouraged. Dexamethasone and acetazolamide may reduce the symptoms of AMS but in so doing may potentially mask failure to acclimatize and continuing susceptibility to more serious forms of altitude illness. Furthermore, the actual benefit of these medications is widely overestimated by both physicians and patients. Neither medication should be used as a substitute for graded or staged acclimatization. Too commonly, and out of convenience, the drugs are taken in lieu of a graded acclimatization.
High Altitude Pulmonary Edema It must be emphasized that prevention is the principal desired strategy for HAPE. Most individuals do very well, particularly when the disease occurs in developed areas; however, cases that occur in remote settings, particularly those in remote settings at high or extreme altitude, may easily be fatal. It also is important to recall that fulminant and fatal cases of HAPE have occurred at altitudes below 3050 m (10,000 feet). All patients should be treated with rest if they are not in descent, because exertion increases cardiac output and thus pulmonary artery pressures. The definitive treatment for HAPE, whether mild or severe, is prompt descent of more than 1000 vertical meters (3280 feet); this is effective in terminating the disorder in most individuals. Supplemental oxygen is useful to increase O2 saturation, and leads to symptomatic and objective improvement; it is the definitive treatment in most cases of mild to moderate HAPE.43 It can reduce pulmonary artery pressures by up to 50%. A review of 166 cases of HAPE demonstrated the clinical impact of descent and supplemental oxygen: when descent was impossible and oxygen unavailable, the mortality of HAPE was 44%; with descent and supplemental oxygen, the overall mortality was 11%.44 Patients who do not improve with descent likely are suffering from complicated forms of
in pulmonary artery pressures incurred with altitude ascent, but it has not yet been studied in a preventive or therapeutic role for HAPE. Bosentan was associated with reduced urinary volume and free water clearance.9 Most patients who survive experience complete recovery.
High Altitude Cerebral Edema As with HAPE, the principal treatment for HACE should be prevention of the disorder. Individuals who develop HACE may be difficult to evacuate because of the neurologic compromise. No definitive medical interventions are available for HACE. Acetazolamide, dexamethasone, and nifedipine have not been shown to prevent HACE. Diuretics (acetazolamide and furosemide), nifedipine, mannitol, and dexamethasone have been found to improve cases of HACE. Administration of supplemental oxygen, if available, and descent of more than 1000 m (3280 feet), if possible, are the best therapeutic options. As with HAPE, most cases improve, if not normalize, with this strategy. Like supplemental oxygen, the portable hyperbaric chamber (Gamov bag) may improve temporarily the symptomatology and findings of HACE, but it is not considered definitive treatment for the disorder. Its contribution may be to stabilize the patient while evacuation is planned.
Other Clinical Manifestations Edema Peripheral edema is common in individuals who have ascended rapidly to altitude. The edema generally is mild, but approximately 10% of individuals gain 4.54 kg (10 pounds) of edema. Edema occurs during the preacclimatized period and is generalized to the legs, hands, and face. Upon acclimatization, the edematous state subsides, often with conspicuous diuresis. The pathophysiologic basis is incompletely understood but may involve atrial natriuretic peptides. Edema of the hands but not of the legs is a spurious finding and is not attributable to a lack of acclimatization or to a cardiovascular abnormality; rather, it generally is the result of backpack straps that are too tight and compress the subclavian veins. Few individuals who develop edema go on to develop a life-threatening form of altitude-related disease, such as pulmonary edema or cerebral edema.
Coronary Artery Disease Until a decade or so ago, only a few individuals with recognized coronary artery disease (CAD) ascended to altitude. The great explosion in the number of people who ascend to altitude means that many individuals with coronary disease, both recognized and unrecognized, now make such ascents. In addition, up to 60% of individuals who ascend to altitude are older than 60 years. The augmented sympathetic output engendered by altitude-related hypoxia increases both the heart rate and blood pressure in patients with CAD, thereby increasing the incidence of angina, particularly during the first several days at altitude but lasting for a week. Twenty veterans of the U.S. 10th Mountain Division (mean age, 68 years), most of whom had known CAD or were at high risk of CAD, underwent cardiopulmonary testing at low altitude (Dallas, Texas) and at an altitude of 2440 m (8000 feet) (Vail, Colorado).46 Predictably, the threshold to ischemia in the presence of the ambient hypoxia of moderate altitude was lower, and plasma catecholamines were increased at altitude.
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HAPE, such as pulmonary arterial thrombosis, or have a concurrent or alternative diagnosis, such as pneumonia. Portable hyperbaric chambers (Gamov bags) are widely available and have the advantage over oxygen cylinders of being more portable, renewable, and safer to airdrop. The additional 13.8 kPa (2 psi) of pressure confers equivalence to a descent of 1500 m (4918 feet) if applied at 4575 m (15,000 feet), and a greater equivalence of descent at higher altitudes (2000 m [6557 feet]) when applied at 6100 m (20,000 feet). It is important to note that supplemental oxygen cannot be administered to an individual on the inside of a Gamov bag because of the fear that static electricity may initiate a spark. Sartori and coworkers28 recently demonstrated that prophylactic administration of salmeterol reduced the incidence of HAPE by more than 50% in susceptible individuals and improved arterial saturation, the AMS score, and the radiographic score. Given the acceptable safety profile of salmeterol, its use to prevent HAPE in susceptible individuals should be considered. Corroborative studies of this therapy are eagerly awaited. Acetazolamide, regularly used to ward off the morning headaches of uncomplicated AMS, has not been shown to reduce the incidence of HAPE. The use of diuretics is controversial and even illogical, because elevated filling pressure on the left side of the heart is not the dominant cause of the edema, and no proven evidence supports the benefit of diuretics. Indeed, many cases of HAPE are associated with moderate or severe hypotension as a result of volume depletion; such hypotensive cases of HAPE should not be treated with diuretics. Similarly, the use of morphine sulfate to reduce preload is illogical, and its use in remote settings is justly controversial because narcotic-induced hypoventilation or apnea may ensue without the availability of resuscitative equipment. Nifedipine, and similarly tadalafil, have been shown in small trials to reduce the incidence of HAPE in susceptible individuals (those with a history of HAPE).45 The benefit observed in these small trials of select individuals supports the concept of pulmonary vasoconstriction as a participant in the development of HAPE. A single study has shown that dexamethasone reduces the incidence of HAPE,45 potentially by stabilizing endothelial function against inflammation. Nifedipine, inhaled nitric oxide, and tadalafil have been shown to afford acute improvement in the clinical profile of HAPE. Nifedipine has been reported to reduce pulmonary artery pressures by 25% to 55%, improve arterial saturation, reduce the alveolar-arterial pressure gradient, improve the radiographic score, and improve symptoms.39 Similar findings have been observed with tadalafil, another pulmonary vasodilator.45 Inhaled nitric oxide reduces the pulmonary artery pressure and improves O2 saturation in individuals with HAPE. Nitric oxide (40 ppm) has been shown to reduce pulmonary artery pressure by an average of 25 mm Hg.6 However, the combination of supplemental oxygen and nitric oxide is more effective than either alone in reducing pulmonary artery resistance. Compared with the values in ambient air, pulmonary resistance decreased by 23% with supplemental oxygen, by 36% with nitric oxide (15 ppm), and by 54% with nitric oxide plus oxygen (1:1). Similarly, the combination of supplemental oxygen and nitric oxide was superior in reducing the alveolar to arterial oxygen difference and increasing saturation. Bosentan (a nonselective endothelin receptor antagonist) has been shown in healthy individuals to reduce the increase
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Pulmonary artery pressure increased by more than 40%, and _ O2max) decreased by 12% maximal oxygen consumption (V acutely but normalized after 5 days of acclimatization. Unpredictably, a patient who had a stable anginal syndrome at low altitude experienced a myocardial infarction on exertion during the study at moderate altitude. Although these findings constitute a small body of data, they underscore the unpredictability of coronary disease in the ambient milieu of hypobaric hypoxia and an increased sympathetic activation at altitude. Ascent to altitude by those with a low threshold to ischemia at low altitude appears unwise. Altitude-related myocardial infarction has been described in an individual without apparent atherosclerosis. A notable case occurred in a 28-year-old elite athlete who experienced a prodrome of angina on effort at high altitude47 and then an acute ST-segment-elevation inferior wall infarction. Subsequent coronary angiography was normal, and thus the mechanism of altitude-related infarction remains unclear. In susceptible younger individuals, it may involve hyperventilation-induced spasm of the coronary arteries, whereas in older individuals with CAD, the mechanism may be sympathetic activation–mediated infarction. For individuals with recognized CAD who intend to ascend to altitude, several general recommendations can be made48: n a moderate or better functional capacity; n a more gradual and graded ascent than usual; n tight control of blood pressure; n avoidance of exertion while at altitude, especially for the first several days; n availability of or access to medical facilities (i.e., supplemental oxygen); and n ability of the patient to check the blood pressure and heart rate. Such considerations may reduce the incidence of ischemia but may not alter the incidence of infarction. For individuals with recognized CAD who recently have experienced unstable coronary syndromes or who have a low threshold to ischemia, ascent to or beyond moderate altitude is relatively contraindicated. Roach and colleagues49 observed that an older group of patients (59 to 83 years), most of whom had a history of CAD or hypertension, acclimatized generally well to an altitude of 2440 m (8000 feet) over 5 days, with a lower incidence of AMS than in younger individuals and without significant problems. However, the complex considerations that may surround older patients with respiratory distress at altitude were highlighted by Basnyat and associates,50 who reported a case of myocardial infarction in a previously well, 60-year-old man who developed pulmonary edema caused by myocardial infarction and not by HAPE.
hypertension on exposure to altitude. Because it generally is held that hypertension is recognized in only 50% of individuals who have it and only 50% of those with recognized hypertension have it well controlled, it is not surprising that many cases of hypertension are recognized for the first time or are exacerbated at altitude. It seems prudent to ensure that the blood pressure is well controlled before an individual ascends to altitude and to advise individuals with uncontrolled hypertension not to attempt such ascents.
Permanent Tissue Damage from Altitude and Frostbite Most altitude-related illness is acute and without residua in survivors. However, some evidence indicates that lasting tissue damage occurs. “Everest nails”51 (Fig. 141.4) and lingering subtle and pervasive neurologic deficits afflict those who travel to extreme altitude.2 Previous frostbite injury is a strong risk factor for repeat frostbite. Previously affected extremities are often bothersomely cold. Vascular function in previously frostbitten territory is abnormal, which may underlie the greatly impaired resistance to repeat injury.
Subacute and Chronic Altitude Illness Principally seen in the Andes, chronic altitude illness is a rare form of altitude illness that arises in a few individuals who live in the sparse permanent settlements at altitudes above 3050 m (10,000 feet). Bolivia has the largest number of extremely high permanent settlements, and these are among the best studied populations with true chronic (versus subacute) high altitude disorders.52 Cyanosis and right-sided heart failure as a result of pulmonary hypertension and polycythemia cause fatigue and dyspnea. The findings and complaints resolve with descent. The maximum altitude at which pregnancy can reliably be carried to term determines the maximum elevation of permanent habitation, and the stress of altitude-related hypoxia has been well characterized in infants (dyspnea, cyanosis, and edema).53 Indian soldiers, rotated through outposts at moderate to high altitudes, have been observed to develop dyspnea, cough, and peripheral edema, consistent with right-sided heart failure incited by hypoxic altitude stress.54 The bovine disorder “brisket disease,” an altitude-dependent edema in cows caused by right ventricular dysfunction, behaves similarly.55
Hypertension
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Many individuals experience an increase in blood pressure when ascending to altitude. The mechanism for this is not well understood, but it generally is held to pertain to the sympathetic activation that occurs with exposure to hypoxic conditions. Many individuals with hypertension expose themselves to altitude during recreational pursuits such as skiing and hiking. Such individuals, even those receiving antihypertensive treatment, are more likely to have uncontrolled
Figure 141.4 “Everest nails” in a 40-year-old man who climbed Cho Oyu (8254 m [27,063 feet]) in the Everest region. White bands are seen on all nail beds; the bands’ width and distance from the base plate are proportional to the time spent at high altitude and to the time since exposure to high altitude.
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chapter
Alternative Cardiovascular Medical Therapies William J. Kostuk
Definition n
Alternative medicine for cardiovascular disease is in high demand by health consumers.
n
Popular forms of therapy are chelation therapy, antioxidant vitamin supplementation, and herbal therapies.
Key Features n
The major concern is the lack of any scientific evidence for clinical benefit.
n
Randomized trials have shown no beneficial effect of vitamin E in preventing cardiovascular disease.
n
A large, randomized trial to assess chelation therapy will complete enrollment in 2009.
Clinical implications n
Currently, these alternative therapies cannot be recommended either to prevent or to treat atherosclerotic disease.
Complementary or alternative medicine is in demand by health consumers throughout the developed world. These therapies, which can be defined as “medical interventions that are not taught widely in Western medical schools or generally available at major hospitals,”1 have an impact on all medical specialties, including cardiovascular medicine. The major difference between alternative medicine and conventional medicine is the lack of scientific evaluation. Moreover, the proponents of alternative medicine do not see any need for such evaluation and rely instead on the testimonials and anecdotes of patients. These therapies are widely available to the general public through all means of communication, including the Internet, which is becoming a popular and primary source of information for many people. Given that people in the United States spend approximately $21 billion on these therapies each year, there must be reasons patients seek out and use such remedies, either in addition to or instead of conventional medicine. Chelation therapy, high-dose vitamins, and herbal therapies are among the myriad alternative measures that are being popularized for the treatment of cardiovascular disorders.2
REASONS PATIENTS SEEK ALTERNATIVE THERAPIES During the past decade, a general shift has occurred toward nonconventional or alternative approaches to health care in many disease processes. Some think that these alternative
approaches are safer and better than so-called Western medicine. However, despite the great popularity of various supplements, general agreement on their benefits is lacking. Myths and false information abound both in print and on the Internet. In the United States, more visits are made to alternative practitioners than to primary care physicians.1 In Europe and Australia, up to 50% of the population uses alternative therapies.3,4 Most patients do not tell their physicians that they are consulting alternative medical practitioners. If the scientific message is, “Alternative therapies do not work,” why do so many people, physicians included, use them? The diverse reasons patients seek alternative therapies are summarized in Table 142.1.5
CHELATION THERAPY The term chelate, coined by the analytic chemist G. T. Morgan in 1920, has its origin in the Greek chele (meaning claw), which refers to the claw-like chemical structure of the compound. In chelation, a metallic ion is firmly bound into a ring within the chelating molecule. The use of natural chelators has a long history in medicine. In 1917, sodium tartrate was used in the treatment of antimony poisoning; in 1938, fruit juices were prescribed for nickel-induced eczema, primarily because of the citrate and tartrate in the fruit juices. Synthetic chelators are abundant and serve as analytic and research tools in chemistry. Chelation therapy was applied to humans during the World War II, when the chelating agent dimercaprol (also known as British antilewisite or BAL) was developed and used to treat arsenic poisoning caused by the war gas lewisite. In 1938, ethylenediamine tetraacetic acid (EDTA) was developed and used by chemists. EDTA is a water-soluble chemical that forms soluble complexes with bivalent and trivalent cations such as calcium, magnesium, iron, mercury, copper, aluminum, copper and nickel, cobalt, zinc, cadmium, and magnesium. In the late 1940s, EDTA was used to treat industrial workers with lead poisoning. When injected into the blood, EDTA binds the heavy metal, which subsequently is excreted in the urine; this has remained the treatment of choice for lead poisoning.6 EDTA also was investigated for use in the treatment of hypercalcemia and radiation poisoning caused by plutonium. In the 1960s, it was used in the treatment of digitalis toxicity, until it was supplanted by digitalis-specific antibodies.
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142
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REASONS PATIENTS EXPLORE ALTERNATIVE THERAPIES
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n n n n n
The patient wants to promote good health and prevent disease. Conventional therapies have been exhausted. Conventional therapy is ineffective or risky. No conventional therapy is available. Conventional therapy is perceived to be emotionally or spiritually without benefit.
Table 142.1 Reasons patients explore alternative therapies.
Rationale for Use in Cardiovascular Disease After EDTA was found to be effective in chelating and removing toxic metals from the blood, some investigators in the early 1950s postulated that atherosclerotic vessels could be “softened” if the calcium in the walls was removed.7 During the past four decades, numerous theoretical mechanisms have evolved to justify the use of EDTA chelation in patients with atherosclerotic disease. These include8 n the simple removal of calcium from the atherosclerotic lesions; n an effect on endothelial enzymatic function, such that the availability of calcium or some other metallic ion is altered; n an anticoagulant effect, resulting from a decrease in platelet stickiness; n improved arterial elasticity, resulting from a reduction in metallic cross-linkages in arterial walls; n vasodilatory effects, resulting from calcium channel blocker–like activity; and n prevention of free radical production and thus lipid peroxidation. None of these proposed mechanisms has been validated.
Procedure for Chelation Therapy
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The American College of Advancement in Medicine (ACAM) was founded in 1973 for the study of complementary and alternative medical therapies. A major focus of ACAM is the promotion of chelation therapy. ACAM’s procedure for chelation therapy calls for intravenous infusion of approximately 500 mL of a solution that contains the ingredients listed in Table 142.2.9 The solution is infused slowly over 3 to 4 hours one to three times a week. Renal function is checked before each infusion. In addition to the infusions, patients are prescribed supplemental nutrients (vitamins and minerals) and lifestyle modification, including stress reduction, avoidance of caffeine, limitation of alcohol intake, cessation of smoking, exercise, and nutritional counseling. The number of treatments required for patients with symptomatic disease ranges from 20 to 50 separate infusions, depending on the patient’s health status; the average number required for “optimal benefit” is 30 treatments. Some patients eventually receive more than 100 chelation infusions over several years. The protocol states that “full benefit does not normally occur for up to 3 months after a series is completed” and that “follow-up treatments may be given once or twice monthly for long-term maintenance, to sustain improvement, and to prevent recurrence of symptoms.” The cost is $80 to $125 per treatment.
CHELATION INFUSION MIXTURE n
Sterile water
440 mL
n
EDTA (150 mg/mL)
50 mg/kg lean body weight
n
Sodium bicarbonate
(50 mmol per 50 mL)
n
Vitamin C
3.0 g
n
Magnesium sulfate
500 mg/mL
n
Heparin
2500 U
n
Folic acid
2.5 mg
n
Pyridoxine (vitamin B6)
100 mg
n
Hydroxycobalamin (vitamin B12)
1000 U
n
B-complex-100
1 mg
n
Lidocaine (2%)
200 mg
EDTA, ethylenediamine tetra-acetic acid.
Table 142.2 Chelation infusion mixture.
Purported Indications Chelation therapy is promoted and practiced throughout the world as an alternative form of medical therapy for the treatment of atherosclerotic disease. Unfortunately, the claims for the efficacy of chelation therapy for atherosclerotic vascular disease have been based on uncontrolled studies. These studies have involved small numbers of participants, the diagnostic and evaluation criteria were largely subjective, and controls were not used. The effects of other medications were not given, and follow-up periods were short. Most of these reports have been confined to the holistic literature. The proponents of chelation therapy state that “more than 75% of chelation patients have improved dramatically.”10 However, this statement is based on personal testimonials and not on scientific evidence. Until recently, no randomized, placebocontrolled, double-blind trials of chelation therapy had been conducted that might provide any support for this statement. The possibility that EDTA could be used as a treatment for atherosclerotic disease was suggested by Clarke and colleagues7 in 1955. These investigators studied the effect of EDTA on serum calcium in patients. A patient with bilateral nephrocalcinosis showed radiographic improvement in kidney stones, which implied direct evidence of removal of metastatic calcium. The authors speculated on the possible inter-relationship of calcium and atherosclerotic plaque.7 They subsequently reported that anginal symptoms improved in 19 of 20 patients with coronary and peripheral arterial disease.11 Kitchell and colleagues12 initially reported subjective improvement of anginal symptoms in nine of 10 patients. A subsequent follow-up study of 28 patients who received EDTA for treatment of angina showed that after 18 months, seven (25%) were dead; the condition of two (7%) was worse; the condition of six (21%) was unchanged; and the condition of the remaining 13 (46%) had improved. The authors concluded that “chelation as used in this study did not benefit patients more than commonly used therapeutic methods. It is not a useful clinical tool in the treatment of coronary artery disease at the present time.”12 No reports appeared in the medical literature of EDTA chelation therapy regarding cardiovascular disease until 2002, when Knudtson and others13 reported a double-blind,
TRIAL TO ASSESS CHELATION THERAPY (TACT) 1. To enroll 1950 patients (nonsmokers > 3 months) > 50 years with previous myocardial infarction > 6 weeks 2. Randomized (factorial 2 2) to: n Chelation therapy or placebo n High-dose vitamin supplements or placebo 3. Infusions: n Weekly 30 n Bimonthly 10 4. Average follow-up 3.5 years 5. Primary endpoint composite of: n Major vascular events: n Myocardial infarction n Stroke n Admission to hospital for angina n Coronary revascularization n Death
Table 142.3 Trial to Assess Chelation Therapy (TACT).
about the study is available at www.clinicaltrials.gov/ct/ show/NCT00044213or. The evidence from randomized, placebo-controlled, double-blind trials for EDTA treatment for patients with peripheral vascular disease has been reviewed.14 Studies were identified using computerized literature searches (MEDLINE 1966-1996; CISCOM 1996, a database specializing in complementary/alternative medicine; bibliographies of relevant papers) and suggestions from six leading experts and national societies. Studies were selected if they were randomized, placebo-controlled, double-blind trials of intravenous chelation therapy for peripheral arterial occlusive disease. Outcomes included walking distances, ankle and arm blood pressures, transcutaneous oxygen tension, and the results of angiography. Four papers reported on three trials that involved patients with intermittent claudication. None of the studies found between-group differences for patients receiving chelation therapy and those receiving placebo. A small trial of 10 men reported no between-group differences in walking distance or ankle and arm blood pressures for patients who received 10 intravenous injections of EDTA (totaling 1.5 g), compared with patients who received placebo. Nevertheless, the authors concluded that “EDTA had a significant impact in causing the improvements seen in the patient’s clinical status.”15 A trial of 153 patients allocated to 20 treatments of either disodium EDTA (3 g) or isotonic saline over 5 to 9 weeks found no between-group differences in the outcome parameters (walking distance, ankle/brachial index, or subjective evaluation) at the end of treatment or after 6 months.16 A subgroup of 30 patients from this trial underwent digital angiography before and after treatment. Most of the angiograms were unchanged; only two were improved, one in the placebo group and one in the treatment group.17 A study of 32 patients allocated to 20 infusions of EDTA (n ¼ 15) or saline (n ¼ 17) over 10 weeks likewise found no difference for walking distances or ankle and arm blood pressures at the 3-month follow-up. The proportion of patients who improved was similar in each group (60% for the EDTA group versus 59% for the saline group).18 Compared with this paucity of controlled clinical trials for chelation therapy, case report series are abundant. A retrospective review of 2870 patients treated with EDTA showed “marked improvement” in 76.9%; “good improvement” occurred in 17% of treated patients with ischemic heart disease. In treated patients with peripheral vascular disease and intermittent claudication, marked improvement occurred in 91% and good improvement in 8%.19 There was no comparison group. The claims of improvement for chelation therapy are not limited to the treatment or prevention of atherosclerosis. Proponents claim that chelation is effective against arthritis, multiple sclerosis, psoriasis, Alzheimer’s disease, and problems with vision, hearing, smell, and sexual potency.10 None of these claimed benefits has ever been demonstrated. Because no evidence showing that treatment has modified the disease process is available, the “benefits” described clearly are the result of other factors. These include not only a placebo effect, but also the compassionate care given to the patient’s problems and the encouragement given to them to
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randomized, placebo-controlled study conducted from January 1996 to January 2000. In this study, 84 individuals with documented disease (coronary angiography and/or a myocardial infarction with stable angina and evidence of ischemia on treadmill testing) received an infusion of weight-adjusted (40 mg/kg) EDTA (n ¼ 41) or a placebo (n ¼ 43). Infusions were given over 3 hours twice weekly for 15 weeks and then monthly for an additional 3 months, a total of 33 treatments. Patients in both groups took multivitamins in accordance with the ACAM protocol. The primary endpoint in this study was the change in time to ischemia (1 mm of ST-segment depression) at the 27-week evaluation. Thirty-nine patients in each group completed the procedure; one patient in the EDTA group was withdrawn because of an increase in serum creatinine. At 27 weeks, exercise time to ischemia improved significantly in both groups (by 54 and 63 seconds in the placebo and EDTA groups, respectively), but no significant difference was seen between the times to ischemia in the two groups. Exercise capacity and quality of life scores improved in a similar fashion in both groups. The improvement is related not only to the placebo and training effects commonly seen in studies of patients with angina, but also to the optimal risk reduction therapy in both groups. The authors concluded that “the use of chelation therapy to increase ischemic threshold and improve quality of life cannot be supported for patients with ischemic heart disease.” They also stated that larger trials with a broader range of patients would be required to assess the impact of EDTA therapy. The National Institutes of Health currently is supporting a large, randomized trial of chelation therapy to assess clinical outcomes in individuals with coronary artery disease. This study, Trial to Assess Chelation Therapy (TACT), is supported jointly by the National Center for Complementary and Alternative Medicine and the National Heart, Lung and Blood Institute. TACT commenced enrollment in September 2003, and completion is expected by July 2009. The planned enrollment is 1950 patients age 50 years or older who had had a heart attack at least 6 weeks earlier. Centers across the United States and Canada are involved. This study is large enough to determine whether chelation therapy has any benefit (Table 142.3) More information
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cope with their symptoms and to changes in lifestyle. These lifestyle and diet changes (i.e., smoking cessation, regular exercise, proper diet, and weight loss) are extremely valuable for improving the quality of life and the patient’s sense of well-being.
Complications EDTA is not a benign drug, and it has been associated with serious adverse effects. These are most likely to occur if EDTA is infused either too rapidly or in too large a dose. In such instances, profound hypocalcemia and nephrotoxicity with renal failure have occurred. Other adverse effects are minor discomfort at the injection site, vasculitis, hypotension, hypoglycemia, and prolongation of the prothrombin time. Perhaps the most serious adverse effect, and the one of greatest concern, is that chelation therapy, which is unproven, may prevent patients from receiving the benefits of effective methods of treatment, or at least delay them. Also, the repeated and prolonged course of chelation therapy leads to needless expense.
Conclusions Without scientific evidence to support either the efficacy or safety of chelation therapy in treating atherosclerosis, its use is discouraged. Absolutely no proof indicates that this therapy either relieves symptoms or alters the atherosclerotic process. Important toxicity may include hypocalcemia, renal injury, and thrombophlebitis. At worst, there is a significant risk to patients in believing chelation therapy to be an accepted treatment for vascular disease and thus perhaps depriving themselves of the well-established benefits of recognized modes of therapy, including lifestyle modification, medications, and surgical procedures. In 1998, ACAM agreed to settle charges by the U.S. Federal Trade Commission (FTC) that it made unsubstantiated and false advertising claims that chelation therapy is effective in treating atherosclerosis or any other circulatory disorder.
ANTIOXIDANT VITAMINS The link between increased total cholesterol and atherosclerosis is well established. The oxidation of low-density lipoprotein (LDL) cholesterol, particularly by macrophages, is thought to play a significant role in the formation of atherosclerotic plaques. Oxidized LDL-cholesterol also is thought to play a part in the precipitation of clinical events such as plaque rupture and thrombosis. This has stimulated interest in the role of antioxidants that may prevent or retard the process. The major lipid-soluble antioxidant vitamins are vitamin E (alpha-tocopherol) and beta-carotene, a precursor of vitamin A. The major water-soluble antioxidant vitamin is vitamin C.
Indications
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Evidence for the antioxidant vitamin–cardiovascular disease hypothesis has accumulated from several lines of research. Laboratory research has identified biochemical properties of the antioxidant vitamins that could explain their possible role in inhibiting and delaying coronary atherosclerosis.20
Supplemental concentrations of vitamin E inhibit platelet function.21 In addition, endothelial-dependent vasodilatation, although improved with cholesterol reduction, is further enhanced when antioxidant therapy (probucol) is added to an agent that lowers LDL-cholesterol.22 Also, antioxidants may modify smooth muscle proliferation.23
Observational Studies Epidemiologic studies have provided support for the antioxidant vitamin–cardiovascular disease hypothesis by showing that individuals who consume large amounts of antioxidant vitamins through diet or supplements, or those with high concentrations of these nutrients in their blood, have reduced morbidity and mortality from coronary artery disease. Descriptive studies that examine the characteristics of a population and its associated disease rates have shown an inverse relationship between consumption of fresh fruit and vegetables and rates of cardiovascular disease.24 Case-control studies support an association between lower plasma concentrations of vitamin E in individuals with angina compared with controls,25 which suggests that this antioxidant might reduce the risk of cardiovascular disease. In the past decade, large prospective cohort studies, such as the Nurses Health Study26 and the Health Professionals Study,27 showed a 31% to 40% risk reduction for nonfatal myocardial infarction and death from cardiovascular disease among individuals whose vitamin E intake was in the upper quintile during follow-up for 4 to 8 years. This benefit was greatest in those who took vitamin E supplements (more than 100 IU/day) for at least 2 years. In these same studies, a high intake of vitamin C or beta-carotene was not associated with a lower risk of coronary artery disease. A smaller prospective cohort study in Finland, which involved a follow-up for a mean of 14 years, showed a significant reduction in cardiovascular death only in women who were in the highest tertile of vitamin E intake (Table 142.4).28 Muntwyler and coworkers29 obtained data on the use of vitamin E, vitamin C, and multivitamin supplements by means of a self-administered questionnaire given to the 83,693 male physicians participating in the Physicians Health Study in the United States. They found that 29% of the men (24,270) were current users of one or more of these supplements, most commonly a multivitamin (in 24.6% of the cohort). During a mean follow-up of 5.5 years (and after adjusting for several cardiovascular risk factors, including hypertension, hypercholesterolemia, current and past smoking, alcohol intake, physical activity, and body mass index), Muntwyler’s researchers found that the use of supplements was not associated with any decrease in total cardiovascular or coronary heart disease mortality.29 In a study of 34,486 postmenopausal women with no cardiovascular disease who were followed for 7 years, Kushi and colleagues30 observed that vitamin E supplementation did not provide any benefit in reducing death from coronary disease. However, they did observe an inverse association of vitamin E intake from food and coronary deaths. The women in the highest quintile of vitamin E intake from food had less than half the risk of women in the lowest quintile (relative risk [RR], 0.42 versus 1.0). The reason for the lack of association with supplementation is not clear.30 It is important
CARDIOVASCULAR ENDPOINTS AND VITAMIN E TREATMENT
95% CI
Nurses Health Study26
87,245
0.66
0.50-0.87
Health Professionals27
39,910
0.63
0.47-0.84
Finland men
2748
0.42
0.66-1.11
Finland women28
2348
0.14
0.35-0.88
34,486
0.96
0.82-1.51
Study Observation Studies
28
Postmenopausal women30 Randomized Trials ATBC31 CHAOS33
29,133
0.96
0.9-1.03
2002
0.60
0.40-0.89
GISSI39
11,324
0.98
0.87-1.10
HOPE38
9541
1.04
0.94-1.15
20,536
1.00
0.94-1.06
HPS40,41 37
Su.Vi.Max WACS42
13,017
0.97
0.77-1.20
8171
0.94
0.85-1.04
CI, confidence interval; ATBC, alpha-tocopherol, beta-carotene.
Table 142.4 Cardiovascular endpoints and vitamin E treatment.
to emphasize that observational studies do not prove cause and effect; that is, they are unable to exclude the possibility that individuals who consume antioxidant-rich diets or who take vitamin supplements also share important lifestyle or dietary practices that actually account for their lower disease rates. Because of these uncertainties, the only definitive way to determine whether antioxidants have any part to play in reducing cardiovascular risk is through large-scale, randomized clinical trials.
Randomized Trials The large-scale, randomized trials of antioxidants have shown mixed results in terms of reduction in cardiovascular events (see Table 142.4). Several of these trials were designed specifically to address outcome from cancer and not from cardiovascular disease. In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC), middleaged Finnish smokers were treated daily with beta-carotene, vitamin E, both, or neither for 5 to 8 years. Neither vitamin E nor beta-carotene provided any benefit for mortality from cardiovascular disease. However, in this trial, the dose of vitamin E (50 mg) was below the protective range suggested by the epidemiologic studies.31 Also in this study, no beneficial effect was seen from supplemental vitamin E or betacarotene in the male smokers who had had a previous myocardial infarction upon entry. In fact, more deaths occurred in the beta-carotene and vitamin E groups.32 Among 22,000 physicians, no difference was seen in cardiovascular death rates between those who took beta-carotene and those who did not.33 In the Cambridge Heart Antioxidants Study (CHAOS), patients with angiographically documented coronary artery disease were randomly allocated to groups to receive daily treatment with vitamin E (400 to 800 IU) or placebo. During the median follow-up of 510 days, a 77% reduction in
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n
Risk Reduction
nonfatal myocardial infarction (14% compared with 41%) was seen in the group receiving vitamin E. However, a nonsignificant, slight excess of cardiovascular deaths was noted in the vitamin E group (27 compared with 23 in the placebo group).34 In a double-blind, primary prevention trial, smokers, former smokers, and workers exposed to asbestos were randomly allocated to receive daily beta-carotene (30 mg) and vitamin A (25,000 IU) or placebo. After an average of 4 years of supplementation, the combination of beta-carotene and vitamin A showed no protective benefit and may have had an adverse effect on the incidence of lung cancer and cardiovascular death; this led to premature termination of the study.35 The results of a small, randomized, double-blind, placebocontrolled trial of probucol, beta-carotene, and vitamins C and E are of interest. Probucol, a lipid-soluble, cholesterollowering drug with potent antioxidant properties, was administered alone or together with the vitamins in patients undergoing coronary angioplasty. Therapy was commenced 4 weeks before angioplasty and continued for 6 months after it. Follow-up angiograms showed a smaller reduction in luminal diameter in the patients who had received probucol; no significant difference was seen in those who did or did not receive vitamins. Moreover, the rates of repeat angioplasty were lowest (at 11%) in the probucol group, compared with 16% in the combined treatment group, 24% in the multivitamin group, and 27% in the placebo group.23 Several large-scale, randomized trials are in progress or have recently been completed. The Women’s Health Study (WHS), which examines primary prevention of coronary artery disease, involves more than 40,000 healthy postmenopausal nurses.36 In this randomized, double-blind, placebocontrolled trial using a 2 2 factorial design, women age 45 or older received vitamin E (600 IU every other day), or placebo and aspirin (100 mg every other day), or placebo. Randomization, which began in February 1993 and ended in January 1996, was stratified on 5-year age groups. The primary endpoint is the reduction of vascular events and a decrease in the incidence of total malignant neoplasms of epithelial cell origin. The study has been extended through March 2009. Additional observational follow-up is available at http://clinicaltrials.gov/ct/show/NCT00000479. The Supplementation en Vitamines et Mineraux Antioxydants study, which commenced in 1994, involved 13,017 men and women age 35 to 60. The participants were randomly allocated to a single capsule of a combination of vitamin C, vitamin E, beta-carotene, and minerals (selenium and zinc) or a placebo. After a median follow-up of 7.5 years, no difference was seen between the groups for incidence of ischemic heart disease (2.1% versus 2.1%), cancer (4.1% versus 4.5%), or all-cause mortality (1.2% versus 1.5%). However, the total cancer incidence and all-cause mortality were lower in the men.37 The Heart Outcomes Prevention Evaluation (HOPE) enrolled 9541 women and men age 55 or older who were at high risk for cardiovascular events because of cardiovascular disease or diabetes and one other risk factor. In this simple, double-blind, 2 2 factorial design trial, patients were randomly assigned to groups to receive the angiotensin-converting enzyme (ACE) inhibitor ramipril (up to
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10 mg/day), or vitamin E (400 IU/day), or placebo.38 The primary endpoint was the combination of cardiovascular death, myocardial infarction, or stroke. The trial (ramipril/ placebo arm) was stopped early after 4.5 years by the independent data and safety monitor board when it was determined that individual endpoints clearly were reduced by ramipril (by 13.9%, compared with 17.5% for placebo). In contrast to the excellent results achieved with ramipril, the results from the vitamin E arm of the HOPE study were disappointing. Active vitamin E treatment showed a neutral effect across the range of cardiovascular outcomes (16% for vitamin E compared with 15.4% for placebo) (Fig. 142.1). In the randomized, open-label Gruppo Italiano per lo Studio della Sopravuivenza nell’ Infarto Miocardico Prevenzione study (GISSI) involving 11,324 patients who had recently suffered myocardial infarction, the investigators compared the effects of an n-3 polyunsaturated fatty acid (PUFA; 1 g/day), vitamin E (300 mg/day), both supplements, and no supplements, on the combined primary endpoints of death, nonfatal myocardial infarction, and stroke over 3.5 years. Intention-to-treat analyses were completed by factorial design (two way) and treatment group (four way). Treatment with an n-3 PUFA, but not with vitamin E,
SURVIVAL RATES FROM STUDY OF EFFECTS OF RAMIPRIL VERSUS PLACEBO AND VITAMIN E VERSUS PLACEBO
Ramipril versus placebo Kaplan–Meier rates
0.20 Ramipril
0.15
Placebo
0.10 RR = 0.78 (95% CI, 0.70 to 0.86)
0.05
P < 0.001
0 0
500
1000
1500
Follow-up time (days)
Vitamin E versus placebo Kaplan–Meier rates
0.20 Vitamin E
0.15
Placebo 0.10 RR = 1.05 (95% CI, 0.95 to 1.16)
0.05
P = 0.33
0 0
500
1000
1500
Follow-up time (days)
1858
Figure 142.1 Survival rates from study of effects of ramipril versus placebo and vitamin E versus placebo. RR, relative risk; CI, confidence interval.
significantly reduced the relative risk of the primary endpoint by two-way and four-way analysis (10% and 15%, respectively). By four-way analysis, benefit was attributed to relative decreases in overall mortality and cardiovascular mortality (20% and 30%, respectively). This study, therefore, demonstrated a modest benefit from n-3 PUFAs, but no benefit from vitamin E, for the secondary prevention of cardiovascular events after myocardial infarction.39 The landmark Heart Protection Study (HPS) assessed the long-term effects of treatment with statins (hydroxymethyl glutaryl [HMG]-CoA reductase inhibitors) and antioxidant vitamin supplementation in 20,536 individuals age 40 to 8040,41 who had coronary artery disease (previous myocardial infarction or angina), other occlusive vascular disease, or diabetes, and in men older than age 65 who had hypertension that was being treated. In a factorial 2 2 design, patients were randomly allocated to groups to receive simvastatin (40 mg daily), combination vitamins (600 mg of vitamin E, 250 mg of vitamin C, and 20 mg of betacarotene), both, or neither. After an average of 5.5 years of follow-up, vitamin supplementation did not reduce the risk of death, myocardial infarction, strokes, or cancer. Participants assigned to simvastatin had significantly lower mortality (12.9%) than those given placebo (14.7%). The coronary death rate was 18% lower with simvastatin (5.7% compared with 6.9%). After the first year, statin treatment provided significant protection against major vascular events (i.e., nonfatal infarctions, stroke, and coronary or noncoronary revascularization), which were 24% lower with simvastatin (19.8% compared with 25.2%) (Fig. 142.2). The Women’s Antioxidant Cardiovascular Study (WACS) assessed the effects of ascorbic acid (500 mg/day), vitamin E (600 IU every other day), and beta carotene (50 mg every other day) on the prevention of cardiovascular events. The study involved 8171 female health professionals age 40 or older who had a history of cardiovascular disease (CVD) or three or more risk factors. Follow-up, for a mean of 9.4 years, lasted from 1995-1996 to 2005. In the study, 1450 women experienced one or more CVD outcomes, but no overall effects of ascorbic acid, vitamin E, or beta carotene were seen on cardiovascular events among women at high risk for CVD.42 The Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFACS), a randomized trial of the roles of folic acid and B vitamins in the prevention of cardiovascular (CV) events, involved 5442 women age 40 or older who had either preexisting heart disease or at least three major risk factors. This trial was a subset of the larger WACS trial. The participants received folic acid (2.5 mg/day), vitamin B6 (50 mg/day), vitamin B12 (1 mg/day), or placebo. Over the 7.3 years of follow-up, 796 women (14.6%) experienced a CV event; no significant difference was seen between the groups. Furthermore, supplementation was ineffective at preventing CV events in the women with CV disease (AHA Scientific Sessions Nov 2006). These studies further underscore the importance of randomized controlled trials to test hypotheses generated by experimental and observational data. A recent study adds further interest to the issue of vitamins and heart disease. In a study of 1739 children of the Framingham Heart Study participants (average age, 59), researchers observed that those with low blood levels of
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Simvastatin therapy or placebo Proportion with event (%)
Proportion with event (%)
30 P 4%) n Thoracic n Vascular
until the condition had been stabilized. Historical information may be of value, such as previous cardiac catheterization results; percutaneous interventions or bypass surgery; stress test results; or echocardiographic findings. All these considerations usually are sufficient in patients with a high likelihood of or known CAD to characterize the disease as mild, moderate, or severe. If uncertainty still exists, then further testing may be necessary.
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Imaging also can function as an ischemia detection method. It usually is accomplished by echocardiography or nuclear perfusion scintigraphy. Because dobutamine is an exercise mimic, echocardiography usually is used to detect wall motion abnormality. Myocardial perfusion imaging usually reveals differences in perfusion more reliably with vasodilator drugs. However, both vasodilators and dobutamine have been used with echocardiography and perfusion imaging with relatively good results. The current practice in the United States is to use dobutamine echocardiography and either dipyridamole or adenosine nuclear perfusion imaging.
Indications for Testing Because cardiac catheterization and revascularization are not usually performed just to improve surgical risk, stress testing usually is done only if the patient has an active cardiac problem that requires therapy or if such testing will change the management strategy.10,11 Either surgical or percutaneous revascularization delays noncardiac surgery; the former for healing and the latter because of the need for aggressive antiplatelet therapy. Although surgery can be accomplished while the patient is taking aspirin and clopidogrel, the risk of bleeding is increased such that surgeons delay all but life-saving surgery. Occasionally the diagnosis of CAD or defining its severity changes the management strategy. For example, when the decision about noncardiac organ transplantation is borderline, knowledge of the presence of severe CAD could tip the decision. The use of prophylactic beta blockers also might be affected, but in borderline cases this therapy usually is used, because the risk of adverse events from beta blockers is low. Assessment of left ventricular function can be valuable in selected patients and usually is accomplished with echocardiography. The discovery of wall motion abnormalities may help clarify the significance of nonspecific ECG findings. Also, patients with unexplained dyspnea or a change in status of chronic heart failure may benefit from knowledge of left ventricular function. However, routine assessment of left ventricular function has not been shown to be useful.
STRATEGY
1866
The complexity of preoperative evaluation of the cardiac patient for noncardiac surgery has occasioned the publication of several algorithms to aid the process. Most were derived retrospectively, and some have been prospectively tested. The American College of Cardiology and the American Heart Association produced a guideline and algorithm on this topic by committee.12 It relies heavily on clinical predictors, an assessment of the patient’s ability to exercise, and test results. It also considers the urgency and type of surgery. Although comprehensive, the algorithm is very complex, which limits its usefulness. Despite the attractiveness of some of these algorithms, they do not cover all patients and all situations. Highly skilled anesthesia care also can help to get high-risk patients through surgery without complications. In addition, the cost of risk-stratifying strategies must be considered in relation to benefit. If a patient with known coronary disease and recent revascularization is asymptomatic and exercises every day, little will improve the individual’s risk for surgery.13
PREOPERATIVE RISK REDUCTION Once risk stratification is accomplished, the consultant advises the surgeon and anesthesiologist of the risk of cardiac events. The surgeon then assesses the risk to benefit ratio of surgery, and a decision is made to cancel surgery, to go ahead with the operation, or to try to modify the risk. Risk modification can be as simple as controlling blood pressure, heart failure, or angina by adjusting the patient’s medical regimen. On the other hand, it can be as aggressive as coronary artery bypass surgery before noncardiac surgery. If surgery is performed, the consultant’s role continues in the management of the patient to reduce the risk of perioperative morbidity and mortality. This may include the choice of anesthesia, the surgical approach, specific monitoring, perioperative prophylactic therapy, and postoperative rehabilitation.
Ischemic Heart Disease Considerable information exists concerning the use of prophylactic beta blockers for higher risk patients undergoing major noncardiac surgery. Although early studies showed significant reductions in perioperative events, several recent randomized trials have shown no benefit.14,15 Examination of these data suggest that these drugs are beneficial in high-risk patients, especially those with ischemic heart disease, undergoing high-risk noncardiac surgery.16,17 In lower risk patients or those undergoing low-risk surgery, the risks of beta blockers probably outweigh any potential benefits. If beta blockers are given, data suggest that long-acting agents are better than short-acting ones and that titration of dose to a resting heart rate less than 70 beats per minute (bpm) is important. Also, beta blockers should be continued for at least 1 week postoperatively and longer in selected cases when recovery takes longer. In addition, patients already taking a beta blocker for clear indications should be kept on it for surgery. The use of other drugs prophylactically in the perioperative period is less well established. a2-Agonists, such as clonidine, have been shown in several trials to reduce the incidence of myocardial infarction and death.18 These drugs may be most useful when the preoperative patient has hypertension. Intravenous nitrates have not been shown to influence outcomes favorably. Calcium channel blockers have been shown to reduce perioperative ischemia and supraventricular arrhythmias but not death or infarction.19 Statins may be beneficial, based on observational studies and one small, randomized trial, but they cannot be routinely recommended at this time.20-22 Despite the attractiveness of angioplasty, especially for patients with one- or two-vessel disease, no prospective, randomized trials have supported the efficacy of this approach for reducing preoperative risk in patients undergoing noncardiac surgery. However, retrospective observational studies do suggest a benefit.13 Currently, the indications for angioplasty are similar to the indications if surgery were not being considered. Whether stents would improve the results obtained is unknown. The major issue with stents is the timing of surgery after stent placement because of the need for intensive antiplatelet therapy for weeks to months after placement of the stent. Patients who have undergone percutaneous coronary procedures before surgery present special challenges.23 Balloon
Valvular Heart Disease Of the valvular lesions, stenosis carries a higher risk than regurgitant lesions. Because mitral stenosis is unusual in developed countries, where more surgery is done, aortic stenosis is the most common lesion of concern. In a recent study, more than 5000 patients with aortic stenosis were compared with more than 10,000 controls matched for age and type of surgery.24 The rate of acute myocardial infarction was 2% in the control group versus 4% in the aortic stenosis patients. After correcting for heart failure and coronary artery disease, which frequently are associated with aortic stenosis, aortic stenosis was associated with a 55% higher incidence of perioperative myocardial infarction even in low-risk surgeries. However, death rates were not significantly different. The data were not stratified by severity of aortic stenosis, and other outcomes, such as heart failure, were not reported. Nevertheless, aortic stenosis modestly increases the rate of perioperative myocardial infarction.25,26 Whether prophylactic pharmacologic therapy would reduce this risk is not known, but many prophylactic drugs for the perioperative period lower blood pressure, which could be dangerous in patients with severe aortic stenosis. Very few data are available on the advisability of performing valvular surgery to improve preoperative risk. If the criteria are met for valvular surgery and the noncardiac surgery can be delayed, it would make sense to do the valvular surgery first. Hemodynamic derangements during surgery that reduce blood pressure or fluid levels can cause a cardiac arrest, and significant aortic stenosis makes resuscitation extremely difficult. Therefore, patients with severe aortic stenosis should avoid noncardiac surgery, or the stenosis should be addressed before noncardiac surgery, if possible. Those who refuse valvular surgery or are not candidates for aortic valve replacement can undergo noncardiac surgery, but the perioperative major cardiac event rate is 10% or higher in these patients. Also, percutaneous aortic balloon valvuloplasty can be considered as a bridge to noncardiac surgery when comorbidities that prevent valvular surgery may
be corrected by the noncardiac surgery. Balloon valvuloplasty is an even better option for patients with severe mitral stenosis who need major noncardiac surgery because, unlike aortic valvuloplasty, it may have lasting benefit. Regurgitant lesions are better tolerated than stenosis even if they are severe. Reduced left ventricular filling pressure is almost never an issue, even with bleeding and reduced intravascular fluid, because the regurgitation provides adequate filling for the left ventricle. Valve regurgitation patients are at higher risk of increases in blood pressure during surgery, which can increase the amount of regurgitation and result in congestive heart failure. However, elevated blood pressure is readily controlled during surgery. Patients with heart failure caused by valvular disease usually have aggressive treatment that reduces or controls the heart failure and makes surgery more feasible. Patients who require chronic anticoagulation for cardiovascular disease present special problems in management. If surgery can be safely accomplished with the patient taking anticoagulants or with a reduced international normalized ratio (INR; 1.8 to 2.5), there is no major issue; however, if anticoagulation therapy has to be stopped, management depends on the risk of thrombosis. In patients with mechanical prosthetic valves, the risk of valve thrombosis increases rapidly after 48 hours off anticoagulation. These patients must have a heparin bridge until surgery, then 48 hours off heparin, and then resumption of heparin, followed by warfarin when safe. Patients with a history of deep venous thrombosis, atrial fibrillation, or left ventricular aneurysm probably can tolerate being off anticoagulation for 7 to 10 days with a low risk of thrombotic events, but the more conditions the patient has, the greater the risk.
Heart Failure A history of congestive heart failure is important in most preoperative risk algorithms for predicting major cardiac events. However, in patients with clinically stable heart failure who are undergoing elective surgery, the risk may not be as high as previously reported. The 1-month mortality is higher than in non–heart failure populations, but the absolute risk is 1% to 2%.27 These patients need more care postoperatively; therefore, the length of stay is about 1 day longer on average, and 1-month readmission rates are twice that of non–heart failure patients. There are several reasons for these more encouraging recent experiences. Many patients today have heart failure caused by diastolic dysfunction rather than systolic dysfunction, and the former have a lower risk of perioperative mortality. Also, elective surgery allows time for optimizing the patient’s clinical status. Furthermore, advances in anesthesia care and less invasive and traumatic surgery put less stress on the dysfunctional heart. For these reasons, a history of heart failure should not automatically exclude a patient from needed surgery.
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143 SECONDARY HEART DISEASE: CONSULT ISSUES: Perioperative Evaluation and Management of the Cardiac Patient
angioplasty causes endothelial injury at the site that takes 2 to 4 weeks to heal, and aspirin therapy is important during this time. The peak incidence of restenosis after balloon angioplasty is 8 to 12 weeks. Therefore, the ideal timing of noncardiac surgery would be 1 month after angioplasty. If bare metal stents are placed, the peak incidence of in-stent thrombosis is during the first 2 weeks, and 4 to 6 weeks are required for complete endothelialization. Restenosis is rare before 12 weeks. Also, a thienopyridine usually is administered for the first 4 weeks after placement of a bare metal stent. Therefore, the ideal time for noncardiac surgery after bare metal stent replacement is 6 to 12 weeks after stenting. The thienopyridine can be stopped after 4 weeks, which allows time for it to clear the system before surgery. Because drug-eluting stents require longer to endothelialize, patients need to take thienopyridines for a longer period. Premature cessation of aspirin and thienopyridines may result in acute stent thrombosis if endothelialization is not complete. Also, each brand of drug-eluting stent is different; therefore, the manufacturer’s information should be consulted. However, after 1 year with any drug-eluting stent, stopping thienopyridine therapy and proceeding with noncardiac surgery is relatively safe.
Arrhythmias and Electrophysiology Devices For patients with supraventricular arrhythmias, consideration should be given to ablation, cardioversion, or rate control, as appropriate for the type of arrhythmia. In patients with intermittent atrial arrhythmias, no indication exists for prophylactic digitalization as a preventive measure, and
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most supraventricular arrhythmias can be dealt with effectively in the perioperative setting. Patients in chronic atrial fibrillation who are taking anticoagulants present a special problem. Although few data exist on how to manage noncardiac surgery in such patients, it would seem prudent to switch them to heparin preoperatively and then to reverse the heparin for the surgery and the immediate postsurgical period, when bleeding is most likely to occur. The risk of stroke is less than 5% a year in such patients who are not taking anticoagulation drugs, and the advisability of switching patients preoperatively to heparin for stroke prevention is problematic, especially if surgery can be accomplished with the patient taking warfarin or during a brief period of lower INR values. Ventricular arrhythmias usually are not a problem unless they induce a hemodynamic abnormality in the patient. Prophylactic therapy usually is not indicated, because ventricular arrhythmias during surgery can be readily treated with intravenous lidocaine (lignocaine) or procainamide. The indications for temporary pacing for patients undergoing noncardiac surgery are similar to the indications for permanent pacing; namely, advanced atrioventricular block and severe bradycardia.9 Therefore, most patients should have permanent pacers placed before surgery. In addition, the availability of transthoracic pacing has made the use of prophylactic temporary pacing much less important. Intraventricular conduction defects and bifascicular block, with or without first-degree atrioventricular block, should not be taken as indications for temporary pacing if the patient has no symptoms of syncope or documented episodes of advanced block. Patients with implanted electrophysiologic devices may experience device malfunction during electrocautery. If the patient is pacemaker dependent, the pacemaker should be reprogrammed to an asynchronous mode, or a magnet should be placed over it during surgery. Patients with implantable defibrillators may experience unwanted shocks if the electrocautery discharges are interpreted as tachycardias. Therefore, the tachycardia treatment function should be shut off just before surgery and a defibrillator should be available in the operating room. If defibrillation is necessary, the paddles should be placed anteroposteriorly away from the device. After surgery, full functionality of the device should be restored.
PERIOPERATIVE MYOCARDIAL INFARCTION
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Troponin elevation is now considered the cornerstone of myocardial infarction diagnosis; however, it must be accompanied by two of the following: typical chest pain, ECG changes, or imaging evidence of infarction. Because anesthesia and postoperative pain medications may blunt or abrogate chest pain, ECG changes or cardiac imaging become much more important in the diagnosis of myocardial infarctions. If troponins are measured in all postoperative patients, numerous false-positive myocardial infarctions will be chased in patients who do not have ECG or imaging abnormalities consistent with infarction. Therefore, troponin should be measured only if hemodynamic abnormalities are present or infarction is suspected for other reasons, such as ventricular arrhythmias. If troponin measurement is done, an ECG also should be done. If the troponin result is positive and
the ECG is nonspecific, imaging is necessary. If the ECG shows ST elevation, an echocardiogram should be done immediately to confirm an evolving infarction. Generally, two types of myocardial injury occur perioperatively: supply-demand mismatch ischemic events and plaque rupture coronary artery thrombosis events. The latter usually show ECG ST-segment elevation or significant new wall motion abnormalities and should be treated as any ST-elevation myocardial infarction. Preference should be given to invasive management, because thrombolysis may be problematic in a postoperative patient. The supplydemand events, or “demand MIs,” frequently are associated with small elevations of troponin; minor, nonspecific ECG changes; and normal wall motion on echocardiography. These patients can be observed for hemodynamic or arrhythmic events and not treated prophylactically. If all goes well, the prudent course is to perform an outpatient stress test after the patient has recovered from surgery, because many of these patients have underlying ischemic heart disease.
SUMMARY Cardiac events are a significant cause of morbidity and mortality during major noncardiac surgery. Therefore, risk stratification of preoperative patients is important to identify those at high risk of such an event. These high-risk patients should not have surgery, or the surgery should be delayed until the risk can be reduced, providing it is not emergency life-saving surgery. Clinical indices of risk and algorithms have been developed, but they are complex and not easily remembered. Simple, more intuitive approaches are preferable, but they require considerable experience and judgment. One such approach recently was described by Goldman (Table 143.5). Patients with no history of heart disease, who do not have any symptoms, and who are fully active, need no further evaluation, not even an ECG. Patients with stable, known CAD or who have a high likelihood of coronary disease based on risk factors (e.g., a vascular surgery patient) and who are functional class I need a resting ECG and careful perioperative management. High-risk patients, such as those with a very recent myocardial infarction, overt heart failure, or advanced arrhythmias, who are functional class III or IV, need a full cardiac evaluation and appropriate therapy. This could include cardiac catheterization and coronary revascularization in some cases, because this therapy is necessary for optimal management of the heart disease. Invasive procedures solely for the purpose of lessening the risk of surgery are rarely justified. The situation becomes more difficult in patients with known CAD or diabetes; those older than 75 years; and those undergoing vascular surgery whose functional class is II or III or unknown. Noninvasive testing probably can stratify these patients into a lower risk group (the majority) or a high-risk group (few); however, even in these patients, the risk of perioperative myocardial infarction is 1% to 2%, and mortality is less frequent. Nevertheless, the risk of perioperative myocardial infarction probably can be reduced to less than 1% in these patients by appropriate interventions, such as beta blockers. For these reasons, this selective testing and intervention approach has become the accepted method for the management of the perioperative cardiac patient.
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SIMPLIFIED APPROACH TO PREOPERATIVE CARDIAC EVALUATION AND MANAGEMENT Cardiac Event Risk* (%)
8
Recommended Tests
No history or symptoms of CAD Fully active
None
55 yr
Education
Postgraduate degree
Less education
Clinical status
None or mild
Significant
Clarification of medical status
Number of cardiac events
One
Numerous
Clarification of medical status
Family attitudes
Supportive
Not supportive, overprotective, or believes that work caused the event
Early family involvement in discussions about returning to work
Involved in rehabilitation
May sabotage efforts regarding return to work
Family awareness of patient’s improvement in rehabilitation
Labor market
Previous job still available or other jobs available
Job market poor
Early vocational intervention (community agency)
Career stage
Advancement or maintenance
Retirement stage
Job satisfaction
High
Low
Clarification of job-interest mismatch
Work stress
Manageable
High; believed that “stress caused cardiovascular problems”
Stress management strategies
Type of work
White collar, self-employed
“Blue collar”
Time off work
Working at time of event
Off work before the event; has not worked for 6 months
Financial situation
Needs work for income
Sufficient alternative funds
Employer aspects
Job modification possible; contact maintained with employees
No job modification possible; no contact while off work
Trial of altered job requirements
Coworkers’ attitudes
Supportive, encouraging, and help to reduce work stressors
Minimal assistance; resentful
Advocacy for worker in discussions with employer and coworkers
Left ventricular impairment
Social issues
Employment aspects
Early vocational intervention
144 SECONDARY HEART DISEASE: CONSULT ISSUES: Employment and Insurability
Individual factors
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More Likely to Return to Work
Factor
SECTION
Table 144.2 Factors that influence return to work and possible interventions.
Societal Issues Societal issues are important in determining return to work.19,20 For most patients, the family can provide a positive or negative influence with respect to returning to work. If the family believes that the “stress” of the job caused the cardiac event or that the job places the patient at risk, efforts to delay returning to work may ensue. Women generally have less social support, which may inhibit return to work.21 Obviously, the local labor market helps to dictate job availability.
Employment Aspects The influence of employment-related factors in determining return to work is well recognized.22,23 Work or unemployment becomes an integral part of a person’s life, and the patient’s pre-event working status, therefore, is an important determinant of return to work. The individual’s career stage
also helps determine return to work options, both for the patient and for the employer. The career stages are career advancement (workers consider career a top priority), maintenance/stabilization, and retirement. More recently, the concept of retirement is changing as the baby boomer generation rewrites the expectations of the various stages of life. Bolles and Nelson24 state that “retirement implies a kind of parole from a thing called work, which is assumed to be onerous and tedious. It implies ‘disengagement’ from both work and life, as one patiently, or impatiently, waits to die.” Thus, a certain percentage of workers may continue to work at their full job or at modified jobs, or they may engage in a new career. “White collar” or self-employed patients who had a high level of job satisfaction and manageable levels of stress are likely to return to work. Conversely, those with “blue collar” jobs who perceive their jobs to have high degrees of stress and low job satisfaction are unlikely to
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return to work. Financial incentives or disincentives for returning to work are related to the availability of sick leave, disability, or pension plans. The characteristics of the job and the attitude of the employer, coworkers and, in some instances, the union can influence the possibility of job availability and the ease of returning to work.
Multivariate Analyses
Smith and O’Rourke25 assessed 151 patients after myocardial infarction and found that 72% returned to work. Univariate analyses showed that education, the energy demands of employment, the severity of the myocardial infarction, the patient’s perception of his health status, financial incentives, socioeconomic status, social status, locus of control, satisfaction with work, and early entry into the job force all were associated with returning to work.
MULTIVARIATE ANALYSIS OF PREDICTORS OF RETURN TO WORK
Study
Possible Related Factors
Smith and O’Rourke25
Years of education Physical requirements of job Severity of myocardial infarction General health rating index
Mark and colleagues26
Functional capacity
Self-efficacy
Age
Career stage, financial disincentives
Mittag and coworkers27
SamkangeZeeb and others28
Mark and colleagues26
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Predictive Factors (from multivariate analysis)
Socioeconomic class, “white collar” job “Blue collar” job, high job stress
Black race
Socioeconomic status
Congestive heart failure
Self-efficacy, job requirements
Age
May reflect situation in the labor market, employer attitudes
Patient’s perception of cardiac disability
Self-efficacy
Physician’s perception of vocational disability by overall medical condition
Self-efficacy
Age Profession
Career stage
Positive expectations concerning return to work Level of depression
Self-efficacy
Predictive factor
Predictive value (%)
Demographic and socioeconomic factors
45
Physical and emotional measures Clinical variables
27 20
Table 144.3 Multivariate analysis of predictors of return to work.
A multivariate analysis indicated that the most important predictor for return to work was a higher level of education, followed by decreased energy demands of the job, less severe myocardial infarction, and a favorable general health rating index. Mark and colleagues26 correlated various factors at angiography with work status 1 year later. Functional capacity, as reported subjectively by the Duke Activity Survey, was the most important predictor, followed by older age, black race, presence of congestive heart failure, lower education level, presence of extracardiac vascular disease, poorer psychological status, and lower job classification. Mittag and associates27 evaluated 132 male patients participating in a cardiac rehabilitation program. The predictive variables for work return at 1 year were derived from the perspectives of both patient and physician. The physicians derived their prognosis from medical variables (cardiac status and comorbidity), whereas the patient’s perspective concerned his or her overall health status, the former job status, job satisfaction, and negative incentives for return for work. A multivariate analysis found three variables that predicted return to work in 85% of cases: age, the patient’s perception of the degree of disability from cardiac problems, and the physician’s views of the extent of disability derived from the overall medical situation. As with other studies, the cardiac status had little relevance with regard to the return to work status. Samkange-Zeeb and coworkers28 reported that return to work rates in Germany varied from 43% to 67%. A risk tool was developed in hopes of identifying individuals at risk of not returning to work. The screening instrument had a positive predictive value (PPV) of 33%. In other words, it predicted the non–return to work (non-RTW) of 33% of the participants starting the rehabilitation program. It had a negative predictive value (NPV) of 93%; that is, it had excellent discriminating properties for identifying individuals not at risk of early retirement; therefore, intervention programs were not required. The significant factors in the multiple regression analysis included greater age, profession, positive expectations concerning return to work, and level of depression. These four prospective studies have slightly different indicators in terms of predictors of return to work. In general, they corroborate categories of predictive information recognized by Mark and colleagues,26 which indicate that demographic and socioeconomic characteristics provide 45% of the total, followed by physical and emotional measures (27%), and clinical variables (20%).
WORK PERFORMANCE Although consideration of strategies for work return and identification of predictive variables are important, equal attention is required for the quality of work return and work retention. Ellis and associates29 defined work performance as “the physical, psychological and social functioning of an individual while at work.” In a cross-sectional study, these researchers used a mail survey to evaluate 490 patients previously diagnosed with an acute coronary syndrome. They were evaluated over a 3-year period after the index event. More than 84% of the patients had worked longer than 1 year since the most recent cardiac event.
Assessment for Licensing to Drive or Fly Heart disease always has been associated with an unpredictable aspect, and this has challenged the authorities responsible for the public safety of roads and airways. Concern about sudden incapacitation haunts cardiac patients and their families and physicians, in addition to transportation policy workers. About 33% of myocardial infarctions are fatal, and 50% of patients who suffer a myocardial infarction die suddenly before reaching the hospital. The challenge is to identify these patients before they can put others in harm’s way by operating a moving vehicle on the ground or in the air.
Case Presentation Lee Wulff was a great guru of Atlantic salmon fishing. In fact, a famous salmon fly bears his name: the Royal Wulff. In his 80s, he still enjoyed flying around the Adirondack countryside in his Piper Super Cub, which he had owned for 30 years. However, one day Wulff did not return home. He was found crumpled up with his Piper Cub in his beloved Adirondack woods. Should he have still been flying? Did he pose a risk to anyone but himself? How good is the mandatory annual medical examination in detecting heart disease? How accurate are existing techniques for assessing cardiac risk? What are the health and safety implications of a rapidly aging pilot population? These are questions that pertain to Lee Wulff and to anyone with a heart condition who assumes responsibility for heavy equipment that is set in motion in the public domain.
Other Cardiac Conditions: Implications for Licensing to Drive or Fly Although problems relating to ischemia are most likely to evoke concern for commercial drivers and pilots, other conditions such as cardiomyopathy, hypertension, arrhythmias, and valvular and congenital heart disease raise issues that demand evaluation. Treatment of hypertension with medications free of adverse side effects, such as hypotension, excessive somnolence, or untoward bradycardia, must be documented. A combination of potassium-sparing thiazide diuretics, beta
CARDIAC ARRHYTHMIAS AND FITNESS TO FLY Arrhythmia
Response
Premature atrial contractions or premature ventricular contractions
Report if symptomatic
Paroxysmal tachycardias
Report
Atrial flutter or atrial fibrillation
Report
Sinus node dysfunction
Report
Heart block and bundle branch block
Report if block is second or third degree
Pacemakers
Report
Cardioverter defibrillator
Unfit
Table 144.4 Cardiac arrhythmias and fitness to fly.
blockers, long-acting calcium channel blockers, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers often suffices. Cardiac arrhythmias cover a wide spectrum of risk, from the chronically benign to the capriciously malignant. The presence of structural heart disease and the likelihood of loss of consciousness dictate the degree of operator restriction (Table 144.4). Valvular and congenital heart disease must be assessed individually. Recipients of prosthetic valves require periodic review because of the risk of thromboembolism, valve failure, and anticoagulant-induced bleeding. Congenital heart disease usually is assessed at the time of the initial application for licensing, but it may present with symptoms that mandate a report. Patients with cardiomyopathy must meet minimal left ventricular functional criteria, usually an ejection fraction greater than 50%. They also must demonstrate that they do not have potentially incapacitating ventricular arrhythmia.
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Perceived work performance was evaluated using the Work Performance Scale (WPS) of the Functional Status Questionnaire.30 This particular cohort was primarily Caucasian, well educated, and had a higher socioeconomic status. About half the group rated their heart disease severity to be moderate to very severe. Findings showed that 84% of patients had a perceived high level of work performance. Symptom burden, perceived disease severity, age, time since the event, and physical function were most associated with work performance. Symptoms and physical parameters seem to have a stronger effect on perceived work performance than on predictors for work return. Similar findings by Drory and associates31 showed that early resumption of employment after an acute myocardial infarction is primarily a function of the sociodemographic and vocational characteristics of the person, as opposed to the specific medical condition. Long-term maintenance of work mainly is related to the medical condition.
Managing Risk: Identifying and Responding to Cardiac Patients Licensing restrictions generally are predicated on the cardiac patient’s perceived risk for sudden incapacitation and the consequences such incapacitation would have for the patient and others. The physician must balance the dual roles of advocate for the patient’s individual human rights and protector of the public from potential harm. The most common tasks are assessing risk and determining the appropriateness of commercial drivers and pilots returning to work after myocardial infarction. Bus drivers and pilots face the greatest hurdle.32 However, recent initiatives to abort evolving myocardial infarctions by prompt revascularization using thrombolytic agents or primary angioplasty have improved outcomes, with better ventricular function and less recurrent ischemia, leading to a more favorable prognosis. Generally, the more severe the functional class of cardiac impairment, the greater the restriction. For example, patients with a New York Heart Association class IV impairment are prohibited from all driving. Those who have stable angina or New York Heart Association class II or III functional impairment are restricted to driving a private vehicle. Asymptomatic patients who have good exercise tolerance may drive any type of vehicle.33 Patients with unstable angina or
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non-ST-elevation myocardial infarction (NSTEMI) may resume private driving as soon as 48 hours after successful coronary angioplasty; the requirement is 7 days for commercial drivers and 6 months for pilots in the absence of provocable ischemia by stress test. Details about specific guidelines for assessing fitness to drive must be obtained from publications such as Determining Medical Fitness to Operate Motor Vehicles.34 Guidelines for assessing cardiac patients with rhythm disturbances, valvular heart disease, or congenital heart disease are itemized in publications dedicated to this purpose.
Establishing the Acceptable Level of Risk Regulations that govern the operation of a vehicle or aircraft tend to reflect the concern of society for tolerating risk to an innocent third party. This often defies logic. Risk-adverse citizens concerned about the perils of fluorinated water and nuclear power generation are more sanguine about the inevitable health hazards of smoking and alcohol consumption. With respect to cardiac patients on the road, it has been suggested that the accepted level of risk from a sudden incident amounts to 1 in 20,000 fatalities or injuries per driver-year. This extremely low risk is achieved when the probability of sudden cardiac incapacitation at any time during the year is 1% or less for commercial drivers and 20% or less for private drivers.33 A mathematical function attempts to estimate the risk of harm that results from a cardiac patient being granted a driver’s license:
Risk of harm ¼ To V SCI Ac where To is the fraction of the day spent driving, V is the type of vehicle driven, SCI is the risk of a sudden cardiac incapacitation, and Ac is the probability that such an event will result in injury or fatality for a third party. Using this type of model, it has been estimated that fewer than 0.2% of all road accidents are caused by sudden driver illness. Although 5% of sudden cardiac deaths occur while the individual is driving, the risk to a third party is very small, with fewer than 2% of these incidents resulting in injury or death for bystanders.35 Generally accepted guidelines permit a driver of a heavy vehicle to return to work 3 months after an acute myocardial infarction, provided that New York Heart Association functional class I activity has been achieved, with a negative stress test at 7 metabolic equivalent of task units (METs), and no disqualifying arrhythmias. Using the previous formula for calculating the risk of harm, such a driver would be associated with a risk of causing death or injury to others of approximately 1 in 20,000 over 1 year. This generally is acceptable. Interestingly, the expenditure to achieve public safety per quality-adjusted life-year saved far exceeds that deemed acceptable for more conventional medical treatment such as dialysis.
Fitness to Fly: the Pilot’s Position
1876
Greater rigor is brought to bear in assessing a pilot’s fitness to fly because of the dependence of passengers on the welfare of the pilot. A high degree of international coordination of fitness criteria has been achieved under the aegis of the
International Civil Aviation Organization and its affiliates. The pilot is responsible for grounding himself or herself, and the physician is responsible for reporting to an aviation medical adviser any medical condition that may compromise flight safety. Heart problems are the second most common cause of incapacitation in flight. Commercial airline travel remains exceedingly safe, with less than 1 fatality per 1 million passengers each year35; this amounts to fewer than 25% of the traffic fatalities in the United Kingdom alone. An inverse relationship exists between the size of an aircraft and the accident rate. Private pilots have fatal accidents 10 to 20 times more often than professional airline transport pilots. The likelihood of a serious accident resulting from sudden pilot incapacitation in the modern, highly automated, multicrew cockpit is virtually negligible. In more than 300 million flying hours, no fatalities to passengers in multicrew aircraft have occurred as a result of a pilot having a cardiovascular event. In most jurisdictions, a pilot’s license is not legal without an appropriate medical validation certificate. The frequency and standard of the aviation medical examination are determined by the type of license and the pilot’s age. The most consistent risk factor contributing to cardiac disqualification for medical validation to fly is advancing age. The cardiovascular mortality rate of a 65-year-old man is about 1% annually. This approximates to a rate of 1 event in 1 million flying hours. This 1% rule can be extrapolated to a medical-cause accident rate in multicrew operations of 1 incident in 100 million to 1 billion flying hours.35 However, in the single-crew commercial environment, the 1% per year risk is considered too high, necessitating a license restricted to flying with a copilot. Ironically, the benefits of medical screening are lost by middle age, as accumulating flying experience more than compensates for the increasing age-related medical hazard. This evokes an aphorism well known to all pilots: “There are old pilots and there are bold pilots, but there are no old, bold pilots.”
Assessing and Controlling Cardiovascular Risk in the Pilot In addition to the clinical history, physical examination, and compilation of cardiac risk factors, a routine resting electrocardiogram (ECG) is a required item of the pilot medical examination. Minor ST-segment and T-wave changes occur in 2% to 3% of pilots. Of these, fewer than 20% have an abnormal exercise ECG, and of these, only 33% have significant coronary disease at angiography.36 Consequently, in keeping with Bayesian theory, the pretest likelihood of coronary disease in an apparently healthy aircrew is so low that an exercise ECG is likely to yield a false-positive and misleading result. Stress testing remains useful when special scrutiny is required, such as among those with suspected angina, multiple risk factors, or known coronary disease after a myocardial infarction or revascularization. However, an exercise ECG is not part of the routine examination for aircrews. Establishing the level of risk and fitness to fly for those who have valvular or congenital heart disease, cardiomyopathy, dysrhythmias, or vascular disorders requires reference to a detailed manual of guidelines for assessing cardiovascular fitness to fly.
PREREQUISITES FOR PILOT RECERTIFICATION AFTER A CORONARY EVENT n
n n n
Table 144.5 Prerequisites for pilot recertification after a coronary event.
Pilot Recertification after a Coronary Event Unstable angina and acute myocardial infarction need not be the death knell for a pilot’s flying career. Timely thrombolytic treatment or primary angioplasty quickly performed during a myocardial infarction can preserve substantial myocardium, resulting in a better ejection fraction and an improved prognosis. Revascularization by CABG surgery or coronary angioplasty and stenting can eliminate residual ischemia in many cases. A well-preserved left ventricle with an ejection fraction of at least 50% and an absence of ischemia on physiologic testing are two compelling recommendations that support unrestricted recertification after a suitable hiatus, usually 6 months.37 The interpretation of tests and written reports in support of pilot recertification (Table 144.5) requires deft judgment by the physician, who must find a balance between being the pilot’s advocate and being a protector of public safety. Licensing issues for driving a vehicle or flying a plane should leave an important element of discretion with respect to the way the plethora of transportation rules and regulations that govern operator fitness are applied.
INSURABILITY OF THE CARDIAC PATIENT In 2009, 1.2 million Americans will have a coronary attack; of these, more than one third will die. Heart attack, therefore, ranks as the United States’ single leading cause of death.7 Better prediction of outcome has enabled insurance companies to devise a more accurate risk assessment of applicants. This results in more equitable and less costly premiums for policy holders. Identification and control of risk factors such as hypertension, diabetes mellitus, hyperlipidemia, and smoking have improved access to insurance at more reasonable rates. The mortality rate from coronary heart disease has reduced by 50% between 1980 and 2000, and half of this decline has been attributed to better control of major risk factors.38 Risk can be usefully characterized by the mortality ratio, which is defined as the number of observed deaths over the number of expected deaths in a cohort of a certain age and gender within a defined period. A mortality ratio of 100% is standard, whereas 150% implies 50% more deaths than expected. Generally, companies do not insure anyone with a mortality ratio greater than 40% than expected. Actuarial tables relate mortality ratios to the number of expected deaths over an interval (e.g., 10 years) to determine the additional premium to be charged.
ASSESSMENT FOR RETURN TO WORK General Concepts The physician plays a major role in determining whether a patient can return to work. The focus of an occupational work evaluation is to determine whether the cardiovascular demands produced by physical, psychological, and environmental stressors exceed the threshold for a safe working capacity. Three factors must be considered: the capability of the patient to perform the job; the risk involved in performing the job; and the risk to society if the patient performs the job. Some patients should not return to work for medical or psychological reasons. Or, as Lewin39 eloquently states, “Return to work is not necessarily the optimal outcome and is a rather naı¨ve audit point; a contented pensioner may represent a better outcome than a frightened and unwilling company man.” If, however, returning to work appears feasible, a proactive approach is required to reduce the risk factors for nonreturn. Patients who have not returned to work within 6 months of a myocardial infarction or coronary bypass surgery are unlikely to do so.40 Conversely, if return to work is prescribed too early, before the patient is capable of managing the work demands, problems may occur (e.g., fatigue) that lead the patient to quit.
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n
Symptom: limited exercise electrocardiogram (ECG) to Bruce stage IV without ischemia; scintigraphy may be required to show absence of reversible ischemia Left ventricular ejection fraction 50% No significant arrhythmia by ambulatory monitoring No stenosis >30% in a vessel that is remote from the infarct-related artery Annual cardiologic follow-up with physiologic testing
Insurance underwriters rely on standard prognostic indicators when assessing an applicant’s insurability and calculating the premium. For example, poor left ventricular function or evidence of residual ischemia after a myocardial infarction signal a poor prognosis, and most insurance companies decline the risk in these cases. However, successful revascularization may improve the insurance rating, as may compliance with risk factor control and adherence to a prescribed rehabilitation program. In summary, insurance companies demand access to all relevant clinical and laboratory information about an applicant with heart disease. They then apply a risk stratification strategy to determine the cardiac prognosis and the implications for insurability. The Orwellian prospect of genetic profiling to estimate the risk of coronary heart disease is on the horizon. The ethical implications of this technology for the insurability of susceptible individuals will be the topic of a vigorous public policy debate in the years to come.
Assessment of the Job Physical Requirements The physician must have accurate information about the demands of the patient’s job. Job titles generally provide little insight into the requirements of a position and may be misleading. The tasks that are performed on the job can be categorized in terms of metabolic cost as METs and found in tables that describe occupational activities in METs. This allows the work tasks to be compared with the individual’s peak or symptom-limited functional capacity, as determined by a recent stress test. The current recommendation is that tasks performed regularly in an 8-hour working day should fall within the range of 25% to 40% of the maximum METs achieved on the stress test, and peak tasks performed occasionally should be no greater than the maximum METs.
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The patient may be unable to provide all the information that pertains to the job. Therefore, a visit to the individual’s work site facilitates a thorough assessment of the work environment, work culture, labor relations, and technologic processes.41 This assessment may be performed in some settings by the cardiac rehabilitation staff.
Environmental Factors Working conditions can include shift work, fumes, extremes of temperature, and low job control (Table 144.6). Shift work has been postulated to increase the risk of coronary heart disease42 and can add to energy demands, particularly if the shifts are irregular. Workplace fumes should be considered; for example, exposure to carbon monoxide can result in the formation of carboxyhemoglobin, which reduces the oxygencarrying capacity of the blood. Patients may experience angina with less effort when working in cold temperatures.15 Hard work with an isometric component performed in a cold environment increases the risk of cardiovascular complications.43,44 Working in hot conditions causes the heart rate and myocardial oxygen consumption to increase disproportionately to keep up with increasing metabolic demands.45 If low job control or an imbalance between personal efforts and rewards (or both) is a factor, the risk of coronary heart disease is increased.46 Earlier literature suggested that high job demands were damaging; however, recent findings indicate that low job control is a requisite cofactor. AboaEboule´ and coworkers47 demonstrated that the risk of a recurrent coronary event after a first MI was greater if the
individual experienced chronic job strain. Job strain was defined as high psychological demands and low decision latitude.
Employer Issues Employers must be reassured that a patient who has cardiovascular disease can resume work with a manageable risk of adverse sequelae. Froom and colleagues48 showed that individuals attempting to resume employment had a 1.2% risk of having an ischemic event at work. Employers usually resist modifying jobs; however, medical persuasion might allow a graduated return to full duties and hours of work. Continuing contact between the employer and employee can facilitate the patient’s return to work; failure of an employer to contact an employee is demoralizing and can inhibit return to work.49 Social support from supervisors tends to reduce the risk of early retirement caused by disability.50
Assessment of the Patient Exercise Capacity It is axiomatic that vocational tasks should not exceed the functional capacity of the patient or provoke untoward cardiovascular symptomatology (e.g., ischemia or arrhythmias). A patient’s current exercise capacity can be estimated by functional scales, such as the Duke Activity Scale.51 However, such functional scales may be misleading, because they do not ascertain peak capacity, blood pressure response, or signs or symptoms of ischemia. Some patients are evaluated while they are at work, undergoing Holter monitoring to
EFFECTS OF CHEMICAL AND PHYSICAL AGENTS ON THE CARDIOVASCULAR SYSTEM Agent
Mechanism
Effects
Carbon monoxide
Carboxyhemoglobin
Reduced tolerance to exercise Earlier-onset angina Increased vulnerability to cardiac arrhythmias
Cobalt
Nephrosclerosis
Dilated cardiomyopathy
Mercury
Arteriolar vasoconstriction
Hypertension
Metal and metalloids
Cadmium
Renal hypertension
Lead Nitrates
Hypertension Absorption through respiratory system and skin Excessive nitrate absorption Withdrawal
Vasodilatation, orthostatic hypotension Coronary vasospasm Sensitization to epinephrine (adrenaline)
Cardiac sensitization to epinephrine, decreased inotropism, suppressed sinus and atrioventricular (AV) nodes
Arrhythmias Arrhythmias
Shunting of blood from core to periphery
At >75 F (24 C), increased heart rate response of 1 beat per minute (bpm) per degree (C) increase in temperature; with exercise, a heart rate response of 2-4 bpm per degree (C) increase in temperature Possible arrhythmia
Organic solvents Freon Chlorinated hydrocarbons Heat
Loss of electrolytes (through sweating)
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Cold
Reflex vasoconstriction of the coronary arteries
Lowered ischemic threshold Decreased workload
Noise
Activation of the autonomic nervous system
Increased heart rate and blood pressure at all workloads
Table 144.6 Effects of chemical and physical agents on the cardiovascular system.
Other Medical Conditions Other medical problems may have an adverse effect on a successful return to work. Some conditions that predated the cardiac event may have changed. For example, a patient with chronic lung disease and mild shortness of breath may become more dyspneic, with superimposed left ventricular dysfunction. A number of musculoskeletal, neurologic, or psychological problems may result from CABG surgery.
Work Simulation The myocardial oxygen requirements for any task may be increased by factors unique to the job, such as superimposed mental stressors, environmental conditions, or mechanical factors. The estimated work capacity from the stress test (using the leg musculature) may not easily translate to arm work, which provokes greater myocardial oxygen demands. If necessary, simulated tasks can approximate actual working conditions and can include lifting, stacking, and carrying (Table 144.8). During the simulation, the myocardial oxygen demands can be estimated from the heart rate and blood pressure response, and any untoward aspects can be recorded. Work simulation may be appropriate for individuals with a reduced functional capacity (10%) should take aspirin, 75 to 162 mg PO daily, over no antithrombotic therapy or a vitamin K antagonist (grade 2A). 2. Patients at a particularly high risk of a coronary event, in whom the international normalized ratio (INR) can be monitored without difficulty, should be given a low dose of a vitamin K antagonist, with a target INR of 1.5 (grade 2A). From Harrington RA, Becker RC, Ezekowitz M, et al. Antithrombotic agents in coronary artery disease. Chest 2004;126:513S-548S. *American College of Chest Physicians (ACCP) guidelines for primary prevention of CAD.
Table 145.1B Recommendations for primary prevention of coronary artery disease.
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intracerebral bleeding), and chronic alcohol abuse. Aspirin increases operative and postoperative bleeding in patients who receive the very high doses of heparin that are required during open heart surgery. However, the benefits of the combination of aspirin and heparin outweigh the risk in treatment of acute coronary syndromes.8 Hemorrhagic complications during intravenous heparin infusion are managed by stopping the infusion. The half-life of the intravenous therapeutic dose of heparin is approximately 30 to 60 minutes. With cessation of therapy, the anticoagulant effect is rapidly lost. In the case of a heparin overdose or life-threatening bleeding, the heparin effect may need to be reversed more rapidly with protamine sulfate. The dose of protamine sulfate is determined by the concentration of circulating heparin, which in turn depends on the dose of heparin administered and the time elapsed since the last heparin dose. The full neutralizing dose is 1 mg of protamine sulfate for every 100 U of heparin; the dose must be reduced to one half at 1 hour and to one quarter at 2 hours after stopping the heparin. The maximum dose should not exceed 50 mg. Caution must be exercised, because an overdose of protamine sulfate induces bleeding and paradoxically increases the activated clotting time (ACT). Also, the benefits of protamine use should be carefully weighed against
RECOMMENDATIONS FOR ANTITHROMBOTIC THERAPY IN PATIENTS WITH NON-ST-ELEVATION MYOCARDIAL INFARCTION AND ACUTE CORONARY SYNDROME* 1. Aspirin in initial dose of 160 to 325 mg, then 75 to 162 mg orally daily indefinitely (grade 1A). 2. Patients with aspirin-induced bleeding should receive lower doses of aspirin: 20,000 U every 24 hour) for longer than 1 to 3 months. Adverse cutaneous reactions to heparin include three distinct types of skin lesions: urticarial lesions, erythematous papules and plaques, and skin necrosis. Urticarial lesions occur at the site of subcutaneous injection and may be caused by a contaminant in the heparin preparation. Changing to a different salt or heparin of a different animal origin may be beneficial. Skin necrosis is the most serious complication of heparin. A less severe form presents as erythematous papules and plaques. Skin necrosis usually occurs as a complication of subcutaneous heparin, but it also has been observed in association with the intravenous route of administration. These lesions usually develop after 5 days or more of therapy. Skin necrosis seems to be unrelated to the source of the heparin; therefore, treatment with alternative antithrombotic agents, such as danaparoid, r-hirudin, or argatroban, is indicated. Other reported complications include generalized hypersensitivity
RECOMMENDATIONS FOR ANTICOAGULATION WITH PROSTHETIC HEART VALVES* Mechanical Heart Valves 1. Patients with mechanical valves must receive a vitamin K antagonist for anticoagulation. Unfractionated heparin (UFH) should be used concomitantly until the international normalized ratio (INR) is therapeutic for 2 consecutive days.
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145 SECONDARY HEART DISEASE: CONSULT ISSUES: Anticoagulation in Heart Disease
1. Patients with acute ST-elevation myocardial infarction (STEMI), irrespective of fibrinolytic therapy, should receive aspirin, 160 to 325 mg PO, followed by indefinite therapy with 75 to 162 mg PO orally daily. 2. Patients allergic to aspirin should receive clopidogrel at a loading dose of 75 mg and then a maintenance dose of 75 mg daily (grade 2C). 3. Intravenous heparin bolus, followed by a drip to target a partial thromboplastin time (PTT) of 50 to 75 sec (grade 2A). 4. Patients with normal renal function younger than age 75: low-molecular-weight heparin (LMWH) is administered subcutaneously with tenecteplase intravenously for 7 days (grade 2B). 5. Glycoprotien (Gp) IIb/IIIa inhibitors are not recommended with thrombolysis. 6. Direct thrombin inhibitors are not recommended with thrombolysis.
lepirudin (recombinant hirudin), or argatroban, should be started if continued anticoagulation is needed or if HIT-associated thrombosis develops.8-10 The platelet count usually returns to baseline levels within 4 days of stopping heparin. Warfarin should not be used alone while HIT-induced thrombosis is treated because of the risk of warfarin-associated venous thrombosis and limb gangrene. Although LMWHs are contraindicated in the treatment of HIT because of cross-reactivity, danaparoid has been used successfully for this indication.9,10 (NOTE: Danaparoid is not available in the United States.)
St. Jude valve in the aortic position: target INR ¼ 2.5. Tilting disk valve and bileaflet mechanical valves in the mitral position: target INR ¼ 3 (range, 2.5-3.5). n Cage-disk or ball-cage valves: target INR ¼ 3, in combination with 75 to 100 mg of aspirin daily. n Carbomedics bileaflet valve or Medtronic Hall tilting disk mechanical valves in the aortic position, normal left atrial (LA) size and sinus rhythm: target INR ¼ 2.5. n Mechanical valves and additional risk factors (e.g., atrial fibrillation, myocardial infarction, LA enlargement, low ejection fraction): target INR ¼ 3, in combination with low-dose aspirin. 2. If a patient with mechanical heart valves suffers systemic embolism despite a therapeutic INR, a combination of low-dose aspirin and an INR of 3 is recommended. n n
Bioprosthetic Heart Valves First 3 Months 1. 2. 3. 4.
Bioprosthetic Bioprosthetic Bioprosthetic Bioprosthetic
valves valves valves valves
in the mitral position: vitamin K antagonist, with target INR of 2.5, for the first 3 months. in the aortic position: vitamin K antagonist, with a target INR of 2.5, or aspirin for the first 3 months. and a history of systemic embolism: vitamin K antagonist for 3 to 12 months. and left atrial thrombus at surgery: vitamin K antagonist life long or until thrombus disappears.
Long-Term Treatment 1. Bioprosthetic valves and atrial fibrillation: long-term anticoagulation with a vitamin K antagonist. 2. Bioprosthetic valves, patient in sinus rhythm: may be maintained on long-term aspirin. From Salem DN, Stein PD, Ahmad AA, et al. Antithrombotic therapy in patients with valvular heart disease: native and prosthetic. Chest 2004;126:457S-482S. *American College of Chest Physicians (ACCP) guidelines for anticoagulation in patients with prosthetic heart valves.
Table 145.4 Recommendations for anticoagulation with prosthetic heart valves.
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GUIDELINES FOR ANTICOAGULATION IN PATIENTS WITH ATRIAL FIBRILLATION*
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Age (yr)
Risk Factors{
Recommendations
>75
Present/absent
Warfarin (target INR, 2-3)
65-75 20.0), vitamin K1 in a dose of 10 mg should be given by slow intravenous (IV) infusion (e.g., over 20 to 30 min) and the INR checked every 6 hours. It may be necessary to repeat vitamin K1 every 12 hours and supplement with plasma transfusion or prothrombin complex concentrate, depending on the urgency of the situation. 5. In case of life-threatening bleeding or serious warfarin overdose, replacement with prothrombin complex concentrate is indicated, supplemented with IV vitamin K1 (10 mg), which should be repeated as necessary, depending on the INR. 6. If continued warfarin therapy is indicated after administration of high doses of vitamin K1, heparin can be given until the effects of vitamin K1 have been reversed and the patient becomes responsive to warfarin. Modified from Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. Pharmacology and management of vitamin K antagonists. Chest 2004;126:204S-233S.
Table 145.9 Recommendations for management of patients with a high international normalized ratio (INR).
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the protein C level before the reduction in the levels of factors II, IX, and X, and it has been shown to be free of the recurrence of skin necrosis.48
Embryopathy Warfarin is contraindicated in the first trimester of pregnancy. If possible, it should be avoided throughout pregnancy. Warfarin can cross the placenta. When given during pregnancy, it has been known to produce a characteristic embryopathy, central nervous system abnormalities, or fetal bleeding.49 Warfarin inhibits the action of vitamin K on osteoblasts and interferes with the carboxylation of Gla proteins (osteocalcin) synthesized in bone. This could lead to bone abnormalities in neonates of women treated with warfarin during pregnancy (see Chapter 136). Heparin and LMWHs are the preferred anticoagulants in pregnancy. However, in patients at very high risk of thrombosis or in certain cases in which heparin is contraindicated, warfarin use during pregnancy may be justified. Convincing evidence indicates that warfarin therapy in a nursing mother does not induce an anticoagulant effect in the breast-fed infant; therefore, breast-feeding is not contraindicated.50
ORAL ANTICOAGULATION IN SELECTED CARDIAC CONDITIONS Chronic Stable Coronary Artery Disease Aspirin is the drug of choice for primary prevention of CAD. In patients at high risk who are intolerant to aspirin, clopidogrel may be used. Warfarin also is effective in some subgroups of patients, as was shown in one trial.51 In patients with chronic stable CAD, aspirin is the drug of choice for secondary prevention. Coumadin is not recommended except in very high risk patients whose INR can be followed closely. Warfarin remains a viable option in patients intolerant to aspirin. A hypercoagulable state and risk of thrombosis persist for up to 6 months after MI, with the highest risk of reinfarction and death within 1 month. Aspirin consistently has reduced the risk of MI, death, and stroke and is a standard of care for secondary prophylaxis of CAD. Analysis of pooled data compared the efficacy of oral anticoagulation of different intensity versus aspirin or placebo or a combination of warfarin and aspirin. Warfarin alone or a combination therapy of low-intensity INR (
