Cardiac Mapping

Cardiac Mapping Second Edition Edited by Mohammad Shenasa, MD Attending Physician Department of Cardiovascular Services O'Connor Hospital; Heart and Rhythm Medical Group San Jose, California

Martin Borggrefe, MD Professor of Medicine (Cardiology) Head, Department of Cardiology, Angiology and Pneumology Klinikum Mannheim GmbH Universitatsklinikum Fakultat fur Klinische Medizin Mannheim der Universitat Heidelberg Mannheim, Germany Gunter Breithardt, MD Professor of Medicine (Cardiology) Head, Department of Cardiology and Angiology and Institute of Arteriosclerosis Research Hospital of the Westfalische Wilhelms-Universitat Munster Munster, Germany

Futura, an imprint of Blackwell Publishing

© 2003 by Futura, an imprint of Blackwell Publishing Blackwell Publishing, Inc./Futura Division, 3 West Main Street, Elmsford, New York 10523, USA Blackwell Publishing, Inc., 350 Main Street, Maiden, Massachusetts 02148-5018, USA Blackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ Blackwell Science Asia Pty Ltd, 550 Swanston Street, Carlton South, Victoria 3053, Australia Blackwell Verlag GmbH, Kurfurstendamm 57, 10707 Berlin, Germany All rights reserved. No part of this publication may be reproduced in any form or by any electronic or mechanical means, including information storage and retrieval systems, without permission in writing from the publisher, except by a reviewer who may quote brief passages in a review. 03 04 05 06 5 4 3 2 1 ISBN: 0-87993-404-2 Library of Congress Cataloging-in-Publication Data Cardiac mapping / edited by Mohammad Shenasa, Martin Borggrefe, Gunter Breithardt.—2nd ed. p. ; cm. Includes bibliographical references and index. ISBN 0-87993-404-2 (alk. paper) 1. Arrhythmia. 2. Electrocardiography. I. Shenasa, Mohammad. II. Borggrefe, Martin. III. Breithardt, Gunter. [DNLM: 1. Electrocardiography. 2. Electrophysiology. 3. Heart Diseases—physiopathology. WG 140 C267 2003] RC685.A65 C287 2003 616.1'28—dc21 2002014632

A catalogue record for this title is available from the British Library Acquisitions: Steven Korn Production: Joanna Levine Typesetter: International Typesetting and Composition, in New Delhi, India Printed and bound by Walsworth Publishing Company, in Marceline, MO USA For further information on Blackwell Publishing, visit our website: www.futuraco.com

This book is dedicated to those who paved the "roads of cardiac mapping" To all who taught us: our mentors, colleagues, students, and patients We also dedicate this book to our wives, children, and parents for their continuous lifetime support and love

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Acknowledgments

We are grateful to our friends and colleagues for their excellent state-of-theart contribution to the second edition of Cardiac Mapping. We deeply appreciate Ms. Maryam Shenasa for her superb assistance during the preparation of this

work. Our special thanks to Joanna Levine for her tireless efforts in editorial assistance, and to Steve Korn and Jacques Strauss of Blackwell Publishing's Futura Division for their support and advice in completing this project.

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Contributors

Maria Alcaraz, MD Chief, Radiology Service, Hospital Santa Cristina, Madrid, Spain

Jacques Billette, MD, PhD Professor of Physiology, Department de Physiologie, Universite de Montreal, Montreal, Quebec, Canada

Maurits Allessie, MD, PhD Professor of Physiology, Head, Department of Physiology, University of Limburg, Maastricht, The Netherlands

Susan M. Blanchard, PhD Professor of Biological and Agricultural Engineering, North Carolina State University, Raleigh, NC

Thabet Al-Sheikh, MD Consulting Electrophysiologist, Cardiology Consultants, Pensacola, FL

Lucas Boersma, MD Department of Physiology, University of Limburg, Maastricht, The Netherlands

Gregory T. Altemose, MD Consulting Electrophysiologist, Mount Carmel Health System, Columbus, OH

Martin Borggrefe, MD Professor of Medicine (Cardiology), Head, Department of Cardiology, Angiology and Pneumology, Klinikum Mannheim GmbH, Universitatsklinikum, Fakultat fur Klinische Medizin Mannheim der Universitat Heidelberg, Mannheim, Germany

Shlomo A. Ben-Haim, MD, DSc Professor of Medicine, Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel Edward J. Berbari, PhD Professor of Electrical Engineering and Medicine, Director of Biomedical Engineering, Biomedical Engineering Program, Indiana University Purdue University Indianapolis, Indianapolis, IN

Gunter Breithardt, MD, FACC, FESC Professor of Medicine (Cardiology), Head, Department of Cardiology and Angiology and Institute of Arteriosclerosis Research, Hospital of the Westfalische Wilhelms-Universitat Miinster, Munster, Germany

Martin Biermann, MD Josep Brugada, MD, PhD Department of Cardiology and AngiAssociate Professor of Medicine, Arrhythmia Section, Cardiovascular ology, Hospital of the Westfalische Wilhelms-UniversitatTMunster,TER, Institute, Hospital Clinic, University Munster, Germany of Barcelona, Barcelona, Spain vII

viii CARDIAC MAPPING Riccardo Cappato, MD Chief, Center of Clinical Arrhythmia and Electrophysiology, Instituto Policlinico San Donato, San Donato Milanese, Milan, Italy

Andre d'Avila, MD Clinical Arrhythmias and Pacemaker Unit, Heart Institute (InCor)— University of Sao Paulo Medical School, Sao Paulo, Brazil

Corrado Carbucicchio, MD Centro Cardiologico Fondazione Monzino IRCCS, Instituto di Cardiologia dell'Universita, Milan, Italy

Jacques M.T. de Bakker, PhD Professor of Experimental Electrophysiology, Department of Experimental Cardiology, University of Amsterdam, Amsterdam, The Netherlands; Department of Cardiology, University of Utrecht, Utrecht, The Netherlands

Rene Cardinal, PhD Professor of Pharmacology, Department of Pharmacology, Universite de Montreal and Research Center, Hopital du Sacre-Coeur de Montreal, Montreal, Quebec, Canada Edward B. Caref, PhD Research Associate, Cardiology Research Program, NY Harbor VA Health Care Center, Brooklyn Campus, Brooklyn, NY Xu Chen, MD Kardiologisk Laboratorium, Department of Medicine, Rigshospitalet Blegdamsvej, Copenhagen, Denmark Kee-Joon Choi, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France

Paolo Delia Bella, MD Centro Cardiologico Fondazione Monzino IRCCS, Instituto di Cardiologia deH'Universita, Milan, Italy Igor R. Efimov, PhD Elmer L. Lindseth Associate Professor of Biomedical Engineering, Case Western Reserve University, Cleveland, OH Nabil El-Sherif, MD Professor of Medicine and Physiology and Director of Cardiac Electrophysiology Program, State University of New York, Downstate Medical Center; Chief, Cardiology Division, NY Harbor VA Health Care Center, Brooklyn Campus, Brooklyn, NY

Jacques Clementy, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France

Sabine Ernst, MD II Medizinische Abteilung, Allg. Krankenhaus St. Georg, Hamburg, Germany

Francisco G. Cosio, MD, FESC, FACC Chief, Cardiology Service, Hospital Universitario de Getafe, Madrid, Spain

Gaetano Fassini, MD Centro Cardiologico Fondazione Monzino IRCCS, Instituto di Cardiologia dell'Universita, Milan, Italy

D. Wyn Davies, MD Consultant Cardiologist, St. Mary's Hospital and Imperial College School of Medicine, London, UK

Vladimir G. Fast, PhD Assistant Professor, Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL

CONTRIBUTORS ix Peter L. Friedman, MD, PhD Associate Professor of Medicine, Harvard Medical School, Boston, MA; Director, Clinical Cardiac Electrophysiology Laboratory, Cape Cod Hospital, Hyannis, MA; Physician, Brigham and Women's Hospital, Boston, MA Paola Galimberti, MD Centro Cardiologico Fondazione Monzino IRCCS, Instituto di Cardiologia dell'Universita, Milan, Italy Hasan Garan, MD Professor of Medicine, Columbia University College of Physicians and Surgeons; Director of Cardiac Electrophysiology, Columbia Presbyterian Medical Center, New York, NY Stephane Garrigue, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France Antonio Goicolea, MD, FESC Cardiac Electrophysiology Laboratory, Clinica Nuestra Senora de America, Madrid, Spain Michel Haissaguerre, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France Helena Hanninen, MD Division of Cardiology, Department of Medicine, and BioMag Laboratory, Helsinki University Central Hospital, Helsinki, Finland

Gerhard Hindricks, MD University of Leipzig Heart Center, Co-director, Department of Electrophysiology, Leipzig, Germany Meleze Hocini, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France Raymond E. Ideker, MD, PhD Jeanne V. Marks Professor of Medicine, Professor of Physiology, Professor of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL Pierre Jais, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France Michiel J. Janse, MD Professor of Experimental Cardiology, Editor-in-Chief, Cardiovascular Research, University of Amsterdam, Amsterdam, The Netherlands Robert Johna, MD Department of Cardiology and Angiology and Institute of Arteriosclerosis Research, Hospital of the Westfalische Wilhelms-Universitat Miinster, Miinster, Germany Eric E. Johnson, MD Cardiology, Stern Cardiovascular Center, Memphis, TN Mark E. Josephson, MD Chief, Cardiovascular Division, Beth Israel Deaconess Medical Center; Professor of Medicine, Harvard Medical School, Boston, MA

Wilhelm Haverkamp, MD Department of Cardiology and Angiology and Institute of Arteriosclerosis Research, Hospital of the Westfalische Wilhelms-Universitat Minister, Minister, Germany

Alan Kadish, MD Professor and Senior Associate Chief, Division of Cardiology, Northwestern University, Chicago, IL

Francois Helie, MSc Graduate Student, Department of Pharmacology, Universite de Montreal, Montreal, Quebec, Canada

Wilhelm Kaltenbrunner, MD The Ludwig Boltzmann Arrhythmia Research Institute, Wilhelminenspital, Vienna, Austria

x CARDIAC MAPPING Karim Khalife, BSc Department de Physiologie, Universite de Montreal, Montreal, Quebec, Canada Andre G. Kleber, MD Professor of Physiology, Department of Physiology, University of Bern, Bern, Switzerland Petri Korhonen, MD Division of Cardiology, Department of Medicine, and BioMag Laboratory, Helsinki University Central Hospital, Helsinki, Finland Hans Kottkamp, MD University of Leipzig Heart Center, Co-director, Department of Electrophysiology, Leipzig, Germany Karl-Heinz Kuck, MD Chief, II Medizinische Abteilung, Allg. Krankenhaus St. Georg, Hamburg, Germany Kenneth R. Laurita, PhD Assistant Professor of Medicine and Biomedical Engineering, Heart and Vascular Research Center, MetroHealth Campus, Case Western University, Cleveland, OH Michael D. Lesh, MD Section of Cardiac Electrophysiology, Department of Medicine, University of California, San Francisco, San Francisco, CA

Laurent Made, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France Markku Makijarvi, MD Assistant Professor of Medicine, Division of Cardiology, Department of Medicine, and BioMag Laboratory, Helsinki University Central Hospital, Helsinki, Finland John M. Miller, MD Professor of Medicine, Indiana University School of Medicine, Krannert Institute of Cardiology, Director, Clinical Cardiac Electrophysiology, Indianapolis, IN Maria Antonia Montero, MD Cardiology Service, Complejo Hospitalario de Ciudad Real, Ciudad Real, Spain Juha Montonen, Dr.Tech. BioMag Laboratory, Helsinki University Central Hospital; Laboratory of Biomedical Engineering, Helsinki University of Technology, Helsinki, Finland Reginald Nadeau, MD Centre de Recherche, Hopital du Sacre-Cceur de Montreal; Faculty of Medicine, Universite de Montreal, and Institut de Genie Biomedical, Ecole Polytechnique de Montreal, Montreal, Quebec, Canada

Jukka Nenonen, Dr.Tech. Academy Research Fellow, BioMag Laboratory, Helsinki University Central Hospital; Laboratory of Biomedical Engineering, Helsinki UniPeter Loh, MD versity of Technology, Helsinki, Hospital of the Westfalische WilhelmsFinland Universitat Munster, Department of Cardiology and Angiology and Insti- Ambrosio Nunez, MD Cardiology Service, Hospital Unitute of Arteriosclerosis Research, versitario de Getafe, Madrid, Spain Munster, Germany

Li-Jen Lin, MD Department of Internal Medicine, National Cheng-Kung University Hospital, Tainan, Taiwan

CONTRIBUTORS xi Jeffrey E. Olgin, MD Associate Professor of Medicine, Indiana University School of Medicine, Krannert Institute of Cardiology, Indianapolis, IN

Franz X. Roithinger, MD Electrophysiology Research Group, Department of Cardiology, University Hospital Innsbruck, Innsbruck, Austria

Feifan Ouyang, MD Medizinische Abteilung, Allg. Krankenhaus St. Georg, Hamburg, Germany

David S. Rosenbaum, MD Director, Heart and Vascular Research Center, Associate Professor of Medicine, Biomedical Engineering, and Physiology and Biophysics, MetroHealth Campus, Case Western Reserve University, Cleveland, OH

Pierre L. Page, MD Professor of Surgery, Department of Surgery, Universite de Montreal; Research Center and Staff Surgeon, Division of Cardiac Surgery, Hopital du Sacre-Coeur de Montreal and Institut de Cardiologie de Montreal, Montreal, Quebec, Canada Agustin Pastor, MD Cardiology Service, Hospital Universitario de Getafe, Madrid, Spain Nicholas S. Peters, MD Professor of Cardiac Electrophysiology, Department of Cardiology, St. Mary's Hospital and Imperial College School of Medicine, London, UK Florence Raybaud, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France

Pierre Savard, PhD Centre de Recherche, Hopital du Sacre-Coeur de Montreal; Faculty of Medicine, Universite de Montreal, and Institut de Genie Biomedical, Ecole Polytechnique de Montreal, Montreal, Quebec, Canada Mauricio Scanavacca, MD Unit of Cardiac Arrhythmia, Clinical Arrhythmias and Pacemaker Unit, Heart Institute (InCor) - University of Sao Paulo Medical School, Sao Paulo, Brazil Christophe Scavee, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France

Mark Restivo, PhD Richard Schilling, MD Senior Scientist, Cardiology St. Bartholomew's and Queen Mary's Research Program, NY Harbor VA University, London, UK Health Care Center, Brooklyn Campus; Assistant Professor of Med- Wolfgang Schoels, MD Department of Cardiology, Univericine, State University of New York, sity of Heidelberg, Heidelberg, Downstate Medical Center, Brooklyn, NY Germany Stefania Riva, MD Centro Cardiologico Fondazione Monzino IRCCS, Instituto di Cardiologia dell'Universita, Milan, Italy Pierre Rocque, BSc Research Assistant, Research Center, Hopital du Sacre-Coeur de Montreal, Montreal, Quebec, Canada

Dipen C. Shah, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France Hossein Shenasa MD, MSc, FACC Attending Physician, Department of Cardiovascular Services, O'Connor Hospital; Heart and Rhythm Medical Group, San Jose, CA

xii

CARDIAC MAPPING

Jafar Shenasa, MSc Department of Cardiovascular Services, O'Connor Hospital; Heart and Rhythm Medical Group, San Jose, CA Mohammad Shenasa, MD, FESC, FACC Attending Physician, Department of Cardiovascular Services, O'Connor Hospital; Heart and Rhythm Medical Group, San Jose, CA Haris J. Sih, PhD Research Scientist, Guidant Corporation, Cardiac Rhythm Management, St. Paul, MN Edward Simpson, MS Institute for Global Communications, San Francisco, CA Arne SippensGroenewegen, MD, PhD Arrhythmia Service, Thoracic Cardiovascular Institute, Section of Cardiology, College of Human Medicine, Michigan State University, East Lansing, MI Timothy W. Smith, D.Phil., MD Cardiovascular Division, BarnesJewish Hospital; Assistant Professor of Medicine, Washington University School of Medicine, St. Louis, MO William M. Smith, PhD Professor of Medicine, Professor of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL Eduardo A. Sosa, MD Director, Clinical Arrhythmias and Pacemaker Unit, Heart Institute (InCor) - University of Sao Paulo Medical School, Sao Paulo, Brazil Madison Spach, MD James B. Duke Professor of Pediatrics, Emeritus, Department of Pediatrics, Duke University Medical Center, Durham, NC

William Stevenson, MD Associate Professor of Medicine, Harvard Medical School; Director, Clinical Cardiac Electrophysiology Fellowship Program, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA Claudio Tondo, MD Centro Cardiologico Fondazione Monzino IRCCS, Instituto di Cardiologia dell'Universita, Milan, Italy Gioia Turitto, MD Associate Professor of Medicine, Director, Coronary Care Unit and Electrophysiology Laboratory, University Hospital, State University of New York, Downstate Medical Center, Brooklyn, NY Michel Vermeulen, B Pharm, MscA Research Assistant, Research Center, Hopital du Sacre-Coeur de Montreal, Montreal, Quebec, Canada Alain Vinet, PhD Associate Professor, Institute of Biomedical Engineering, Universite de Montreal and Research Center, Hopital du Sacre-Coeur de Montreal, Montreal, Quebec, Canada Jun Wang, MD, PhD Department de Physiologie, Universite de Montreal, Montreal, Quebec, Canada Rukshen Weerasooriya, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France Stephan Willems, MD Medizinische Klinik und Poliklinik, Abteilung fur Kardiologie, Universitats-Krankenhaus Eppendorf, Hamburg, Germany Andrew L. Wit, PhD Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY

CONTRIBUTORS xiii Patrick Wolf, PhD Associate Professor of Biomedical Engineering, Duke University, Durham, NC Teiichi Yamane, MD Hopital Cardiologique du HautLeveque, Bordeaux-Pessac, France

Douglas Zipes, MD Distinguished Professor of Medicine, Pharmacology, and Toxicology; Director, Division of Cardiology and Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN

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Preface

The first edition of Cardiac Mapping stood out as the only textbook in the field with outstanding contributions from world-renowned authors. The book was well received and indeed sold out. Since the release of the first edition, there have been areas of significant progress and even major breakthroughs in the field of cardiac mapping and catheter ablation of arrhythmias. In particular, the technical advancements in noncontact and nonfluoroscopic mapping improved our understanding of the mechanism and thus the appropriate treatment of many arrhythmias, particularly atrial and ventricular fibrillation. The second edition offers a

xv

unique source for the latest developments in cardiac mapping of arrhythmias. This new edition of Cardiac Mapping provides an important resource for the interventional electrophysiologist, rhythmologist, and those who are interested in understanding the mechanism of cardiac arrhythmias. As the field of interventional electrophysiology continues to evolve, cardiac mapping will remain an integral part of the science and practice of electrophysiology. The Editors San Jose, CA, Mannheim and Munster, Germany

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Preface to the First Edition

Cardiac mapping has always been an integral part of both experimental and clinical electrophysiology. Indeed, Sir Thomas Lewis systematically investigated the activation sequence of the dog ventricle as early as 1915. The detailed activation map from that experiment is shown in Figure 1. Since then, cardiac mapping has evolved from single sequential probe mapping to very sophisticated computerized three-dimensional mapping. By the time cardiac mapping began being used in the surgical management of ventricular as well as supraventricular

tachycardias, a large body of literature had already been collected. Despite this significant progress, a collective textbook that attempted to discuss all aspects of cardiac mapping did not exist. When we first considered working on such a project, we were not sure if our friends and colleagues who had paved the road to this point would think it necessary to join us in this effort, especially in this era of implantable devices. We were surprised and encouraged by their unanimous positive support to go ahead with this text. (Many of the contributors have

Figure 1

XVII

xviii CArDIAC MAPPING already asked about the second revised edition!) The contributors unanimously agreed to prepare manuscripts that discussed their latest work and that would subsequently be published in this, the only comprehensive book to present the state of the art on all aspects of cardiac mapping from computer simulation to online clinical application. Thus, we would like to thank all the contributors for presenting

their best work here. Without them, this book would not have been possible. A unique feature of this book is that chapters are followed by critical editorial comments by the pioneer of that specific area, so that the state of the art is discussed. We hope this book will serve as impetus to stimulate new ideas for cardiac mapping in the future. The Editors

Contents

Dedication Acknowledgments Contributors Preface Preface to the First Edition

iii v vii xv xvii

Part 1. Historical Perspectives Chapter 1. Historical Notes on the Mapping of Arrhythmias: The Contributions of George Ralph Mines Michiel J. Janse, MD 3 Part 2. Methodological and Technical Considerations Chapter 2. The Interpretation of Cardiac Electrograms Martin Biermann, MD, Mohammad Shenasa, MD, Martin Borggrefe, MD, Gerhard Hindricks, MD, Wilhelm Haverkamp, MD, and Gunter Breithardt, MD

15

Chapter 3. Methodology of Cardiac Mapping Haris J. Sih, PhD and Edward J. Berbari, PhD

41

Chapter 4. Noncontact Endocardial Mapping Richard Schilling, MD, Nicholas S. Peters, MD, Alan Kadish, MD, and D. Wyn Davies, MD

59

Chapter 5. Principles of Nonfluoroscopic Mapping: Nonfluoroscopic Electroanatomical and Electromechanical Cardiac Mapping Shlomo A. Ben-Haim, MD, DSc

103

Chapter 6. Principles of Magnetocardiographic Mapping Jukka Nenonen, Dr. Tech., Juha Montonen, Dr. Tech., and Markku Makijarvi, MD

119

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xx CARDIAC MAPPING Chapter 7. Fast Fluorescent Mapping of Electrical Activity in the Heart: Practical Guide to Experimental Design and Applications Igor R. Efimov, PhD, Martin Biermann, MD, and Douglas Zipes, MD 131 Chapter 8. Precision and Reproducibility of Cardiac Mapping Martin Biermann, MD, Martin Borggrefe, MD, Robert Johna, MD, Wilhelm Haverkamp, MD, Mohammad Shenasa, MD, and Gunter Breithardt, MD

157

Chapter 9. The Ideal Cardiac Mapping System Raymond E. Ideker, MD, PhD, Patrick D. Wolf, PhD, Edward Simpson, MS, Eric E. Johnson, MD, Susan M. Blanchard, PhD, and William M. Smith, PhD

187

Part 3. Mapping in Experimental Models of Cardiac Arrhythmias Chapter 10. The Role of Myocardial Architecture and Anisotropy as a Cause of Ventricular Arrhythmias in Pathological States Nicholas S. Peters, MD and Andrew L. Wit, PhD

197

Chapter 11. The Figure-of-Eight Model of Reentrant Ventricular Arrhythmias Nabil El-Sherif, MD, Edward B. Caref, PhD, and Mark Restivo, PhD 237 Chapter 12. Demonstration of Microreentry Hasan Garan, MD

275

Chapter 13. Optical Mapping of the Effects of Defibrillation Shocks in Cell Monolayers Vladimir G. Fast, PhD and Andre G. Kleber, MD

291

Chapter 14. Effects of Pharmacological Interventions on Reentry Around a Ring of Anisotropic Myocardium: A Study with High-Resolution Epicardial Mapping Josep Brugada, MD, PhD, Lucas Boersma, MD, and Maurits Allessie, MD, PhD 311 Chapter 15. Microscopic Discontinuities as a Basis for Reentrant Arrhythmias Madison S. Spach, MD 323 Chapter 16. Mapping in Explanted Hearts Jacques M.T. de Bakker, PhD and Michiel J. Janse, MD

341

Chapter 17. Efferent Autonomic Innervation of the Atrium: Assessment by Isointegral Mapping Pierre L. Page, MD and Rene Cardinal, PhD

363

Chapter 18. Mapping of Atrial Flutter Wolfgang Schoels, MD and Nabil El-Sherif, MD

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CONTENTS xxi Chapter 19. Mapping of Normal and Arrhythmogenic Activation of the Rabbit Atrioventricular Node Jacques Billette, MD, PhD, Jun Wang, MD, PhD, Karim Khalife, BSc, and Li-Jen Lin, MD 383 Chapter 20. Mapping of the AV Node in the Experimental Setting Peter Loh, MD, Jacques M.T. de Bakker, PhD, Meleze Hocini, MD, and Michiel J. Janse, MD

403

Part 4. Noninvasive Methods of Cardiac Mapping Chapter 21. Mapping of Atrial Arrhythmias: Role of P Wave Morphology Arne SippensGroenewegen, MD, PhD, Franz X. Roithinger, MD, and Michael D. Lesh, MD

429

Chapter 22. Surface Electrocardiographic Mapping of Ventricular Tachycardia: Correlation with Electrophysiological Mapping John M. Miller, MD, Jeffrey E. Olgin, MD, Thabet Al-Sheikh, MD, and Gregory T. Altemose, MD 455 Chapter 23. Body Surface Potential Mapping for the Localization of Ventricular Preexcitation Sites and Ventricular Tachycardia Breakthroughs Reginald Nadeau, MD and Pierre Savard, PhD 467 Chapter 24. Clinical Application of Magnetocardiographic Mapping Markku Makijarvi, MD, Helena Hanninen, MD, Petri Korhonen, MD, Juha Montonen, Dr.Tech., and Jukka Nenonen, Dr.Tech

483

Part 5. Mapping of Supraventricular Tachyarrhythmias Chapter 25. Endocardial Catheter Mapping in Patients with Wolff-Parkinson-White Syndrome: Implications for Radiofrequency Ablation Karl-Heinz Kuck, MD and Riccardo Cappato, MD

497

Chapter 26. Endocardial Catheter Mapping in Patients with Mahaim and Other Variants of Preexcitation Hans Kottkamp, MD and Gerhard Hindricks, MD

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Chapter 27. Endocardial Catheter Mapping of Atrial Flutter Francisco G. Cosio, MD, Antonio Goicolea, MD, Agustin Pastor, MD, Ambrosio Nunez, MD, Maria Antonia Montero, MD, and Maria Alcaraz, MD

537

xxii CARDIAC MAPPING Chapter 28. Catheter Ablation of Atrial Fibrillation in Humans: Initiation and Maintenance Michel Haissaguerre, MD, Pierre Jais, MD, Dipen C. Shah, MD, Meleze Hocini, MD, Laurent Made, MD, Rukshen Weerasooriya, MD, Teiichi Yamane, MD, Kee-Joon Choi, MD, Christophe Scavee, MD, Florence Raybaud, MD, Stephane Garrigue, MD, and Jacques Clementy, MD 561 Chapter 29. Mapping of Atrial Fibrillation: Clinical Observations Riccardo Cappato, MD, Sabine Ernst, MD, Feifan Ouyang, MD, and Karl-Heinz Kuck, MD

577

Part 6. Mapping of Ventricular Tachyarrhythmias Chapter 30. Substrate Mapping for Ablation of Ventricular Tachycardia in Coronary Artery Disease Timothy W. Smith, D.Phil., MD and Mark E. Josephson, MD

595

Chapter 31. Intraoperative Mapping of Ventricular Tachycardia in Patients with Myocardial Infarction: New Insights into Mechanisms and Electroanatomical Correlations in Septal Tachycardias Pierre L. Page, MD, Wilhelm Kaltenbrunner, MD, and Rene Cardinal, PhD . . . .605 Chapter 32. Dynamic Analysis of Postinfarction Monomorphic and Polymorphic Ventricular Tachycardias Rene Cardinal, PhD, Alain Vinet, PhD, Francois Helie, MSc, Michel Vermeulen, B Pharm, MScA, Pierre Rocque, BSc, and Pierre L. Page, MD 619 Chapter 33. Mapping of Unstable Ventricular Tachycardia William Stevenson, MD and Peter L. Friedman, MD, PhD

635

Chapter 34. Subthreshold Electrical Stimulation: A Novel Technique in Localization and Identification of Target Sites During Catheter Ablation of Cardiac Arrhythmias Mohammad Shenasa, MD, Stephan Willems, MD, Gerhard Hindricks, MD, Jafar Shenasa, MSc, Xu Chen, MD, Hossein Shenasa, MD, MSc, Martin Borggrefe, MD, and Giinter Breithardt, MD

649

Part 7. New Frontiers Chapter 35. Transcoronary Venous Mapping of Ventricular Tachycardia Paolo Delia Bella, MD, Claudio Tondo, MD, Corrado Carbucicchio, MD, Stefania Riva, MD, Gaetano Fassini, MD, and Paola Galimberti, MD

667

Chapter 36. Transthoracic Epicardial Mapping and Ablation Technique EduardoA. Sosa, MD, Mauricio Scanavacca, MD, and Andre d'Avila, MD . . . .681

CONTENTS xxiii Chapter 37. Nonfluoroscopic Mapping of Supraventricular Tachycardia Gerhard Hindricks, MD and Hans Kottkamp, MD

693

Chapter 38. Optical Mapping of Cellular Repolarization in the Intact Heart Kenneth R. Laurita, PhD and David S. Rosenbaum, MD

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Chapter 39. Techniques for Mapping Ventricular Fibrillation and Defibrillation William M. Smith, PhD and Raymond E. Ideker, MD, PhD 729 Chapter 40. Disorders of Cardiac Repolarization and Arrhythmogenesis in the Long QT Syndrome Nabil El-Sherif, MD and Gioia Turitto, MD

747

Index

775

Color Appendix

Al

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t Historical Perspectives

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Chapter 1

Historical Notes on the Mapping of Arrhythmias: The Contributions of George Ralph Mines Michiel J. Janse, MD

and we started to talk about Mines, who at that time was known to only a few people. We founded the G.R. Mines Club, In the first edition of Cardiac Map- whose other members included Maurits A. ping I provided some historical notes on Allessie, Felix I.M. Bonke, Frans J.L. van the early history of mapping of reentrant Capelle, and Robert H. Anderson, and arrhythmias and on the interpretation of Professor Rytand sent me some very extracellular waveforms.1 Rather than interesting correspondence, parts of which repeating these notes, I would like to I quote in this chapter. He wrote to me on elaborate on the role of George Ralph October 19, 1973: "As Founder and PresMines in our understanding of circus ident of the G.R. Mines Club, you should movement reentry, and to introduce some have copies, at the least, of these letters." Although Professor Rytand has by now, "personal" history as well. In the summer of 1973, David A. in his own words, joined "that Great ReRytand, Bloomfield Professor of Medicine entry in the Sky," I feel that he would at Stanford University, visited our depart- not have objected to my quoting certain ment in the Wilhelmina Gasthuis. Pro- passages. Anyone who ever met Dave fessor Durrer telephoned me, asking to Rytand will understand that he used show Professor Rytand ("you know, the terms such as Founder and President in flutterologist") around. I had read his bril- a very tongue-in-cheek manner. He was a liant review on the early history of delightful person with a great sense of arrhythmia research2 (the title suggests humor and the total opposite of a pompous that it only deals with atrial flutter, professor. In his review he discussed A.G. Mayer's which was the subject of Rytand's own research, but it covers a much wider field) experiments, in which circus movement The Early History of Circus Movement: In Search of a Film

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; ®2003.

3

4 CARDIAC MAPPING was described in ring-like preparations from the muscular tissue of the subumbrella of the scyphomedusa Cassiopeia. "In one record specimen the pulsation persisted for 11 days during which it traveled 457 miles."2 In April 1964, Rytand wrote to Sir Henry Dale: "During a recent sabbatical leave as visiting Professor of Physiology with Dr. S.M. Tenney at Dartmouth College, we were able to make some motion pictures of circus movement in Cassiopea Xamachana, repeating A.G. Mayer's classic observations. It occurred to me to try and find the similar films made by George Ralph Mines 50 years ago, and I learned that you had been on their trail ahead of me." In his reply, Sir Henry denies "any knowledge, or interest of mine, in these, or any other films made by Mines"; however, he passes the request to "The one of my friends still living, who was a partial contemporary at least of Mines at Cambridge, E.D. Adrian, now of course Lord Adrian and Master of Trinity College, Cambridge." In June 1964, Sir Henry writes that through Lord Adrian he has "come across what may be a trail; and although my own rather deep immersion in other, and what seemed more urgent, demands, has prevented me from following it as actively as I should have wished, I have not yet given up all hope," and he provides Professor Rytand with the address of Mrs. Dorothy Thacker, "who at that time was Miss Dorothy Dale (not related to me as far as I know, except by name)," and who "worked with Mines at the time when he described the circus movement." "Mrs. Thacker informs me that she thinks that such a film was taken when she was working with Mines at the Marine Biological Station at Plymouth, and that the circus phenomenon was demonstrated on a ring, cut from the auricles of a skate or ray." Sir Henry mentions that he will write to Dr. F.S. Russell, CBE, FRS, the Secretary of the Marine Biological Association and

Director of the Plymouth Laboratory, but in a later letter he writes that Dr. Russell could not find any record of a film taken there by Mines. Meanwhile, Professor Rytand had contacted Mrs. Thacker, and a lengthy correspondence (hand-written on her part) develops. She confirms that she had the "pleasure and privilege of working with him at Cambridge from 1911 onwards, and at the Marine Biological Laboratory, Plymouth. He was full of ideas and enthusiasm, a clever and ingenious experimentator. Apart from music—he was an excellent pianist—physiology was his overwhelming interest." With respect to the film of "circus rhythm" she writes that she "knew nothing of what happened to his records when Mines left Cambridge in the summer of 1914 to become Professor of Physiology at McGill University, Montreal." She gives a list of Mines' publications, of which the last entry is, "1913. IXieme Congres International des Physiologistes a Groningue - le 2-6 sept. 1913. A short communication about circus rhythm 'with demonstration, projection and cinematografic projection.'" She never indicates that she ever saw the film or that she was present when it was made. "I can only think it might have been taken to Montreal. If so, its fate is probably unknown." Thus ends the trail of the film. However, she sent Professor Rytand some very interesting documents: copies of pages 372 and 383 of Mines' 1913 paper in the Journal of Physiology.3 On page 372 Mines described circus movement in a ring-like preparation of a tortoise heart. In the paper, he provides no mechanical or electrographic records of what he saw and described. In his handwriting, he made the following note: "Later I took electrograms of this expt." On page 383 he wrote: "Repeated this experiment about 6 times on auricle rings from Acanthias vulgaris at Roscoff in Sept. 1913. The best test for a circulating excitation is to cut through the ring at one point. Cinematographed the

HISTORICAL NOTES: GEORGE RALPH MINES 5 ring ext. At Toronto, March 1914, before seeing Garrey's paper, I obtain circulating excitations in rings from excised heart of dog (rt. ventricle), [over] In these preparations the contraction wave coursed round rapidly about once a second. It was instantly stopped by section of the ring." (See Figure 1.) Professor Rytand published these pages in his review "by permission of the Editorial Board of the Journal of Physiology (London) from a reprint presented by Lord Adrian to the Library at the Cambridge 372

0. R. MINKS.

To test the hypothesis, I devised another experiment, which I carried out on the heart of a tortoise. The heart was excised and the sinus venosus cut away. A longitudinal incision was then made extending through the anterior and posterior walls of the auricle and ventricle, so that the heart was converted into a ring, as shown in Fig. 23. The auricles were connected with the ventricle in two places, and Fig. 23. across each of these junctions it was found that excitation could pass. The experiment was made at a temperature of 21°C. On stimulating any part of the heart there was, after a slight pause, contraction in each of the other parts. After stimulating several times, the following condition appeared. The four portions of the heart marked V1, V2, A1, A2, contracted in the order given, with distinct pauses between the successive portions. This cycle of events was repeated over and over again without any further external stimulation. When V, became excited the excitation spread to V2 but not back to A, which was still refractory. From V2 it spread to A1, from A, to A2, now recovered from its refractory state, and then again from A2 to V1. While the cycle was being regularly repeated, the application of an external stimulus to either of the chambers, if out of phase with the cycle, stopped the contractions, showing that they were not originated by an automatic rhythm in any part of the preparation, but were due to a wave of excitation passing slowly round and round the ring of tissue. * It seems then that the reciprocating rhythm may reasonably be regarded as due to a circulating excitation. The circumstances under which the phenomenon made its appearance were such as to produce the favourable conditions of slow conduction and short refractory period. By its continuance the circulating rhythm would tend to maintain these conditions. The conditions are easily upset by the occurrence of an extra systole and they may be re-established by other extra systoles. I venture to suggest that a circulating excitation of this type may be responsible for some cases of paroxysmal tachycardia as observed clinically. The to-and-fro character of the movement in the cases of reciprocating rhythm which I have described recalled in a curious way the appearances sometimes seen in fibrillation of the mammalian heart, with the difference that in fibrillation, different portions of the muscle in a single chamber, instead of separate chambers of the heart, appear to exhibit reciprocating rhythm.

Physiological Laboratory. Mrs. Dorothy Thacker and Prof. Sir Bryan Matthews most kindly made this figure available."2 The Garrey paper to which Mines referred was the 1914 paper on the nature of fibrillation,4 in which Garrey used the term circus contractions. As was the case with Mines, no mechanical or electrographic tracings were presented, only the description of what the author had observed with his own eyes. Still, on the basis of Mines' addenda, we may consider him to be the first arrhythmia mapper. CONTRACTION

OF HEART.

383

ADDENDUM. On circulating excitations in the musculature of a tingle chamber. Since the above paper was sent to press I have made further observations on circulating rhythm, which may be briefly noted here. The experiments were carried out at the Plymouth Marine Laboratory on ring preparations cut from the auricles of large rays. In such preparations a single stimulus applied to any point in the ring starts a wave in each direction. The waves meet on the opposite side of the ring and die out Bat by the application of several stimuli in succession it is sometimes possible to start a wave in one direction while the tissue on the other side of the point stimulated is still refractory. Such a wave runs round the ring sufficiently slowly for the refractory phase to have passed off in each part of the ring when the wave approaches it Thus the wave circulates and may continue to do so for fifty revolutions or more. Usually an interpolated extra stimulus stops the wave at once. The preparation may then remain quiescent or it may start beating with a slow spontaneous rhythm. In the latter case the totally different characters of the spontaneous rhythm and the ulating excitation are very striking.

Erratum. In L 3, p. 232 of my paper in vol. XLVI. of the Journal "the muscle u longer, has " should read " the muscle, Do longer has."

Figure 1. Pages 372 and 383 and its reverse of the article on dynamic equilibrium in the heart by Mines3 with footnotes in his handwriting (see text). These figures were given to the author by the late Professor D.A. Rytand and are reprinted with permission from the Annals of Internal Medicine.

6 CARDIAC MAPPING Mrs. Thacker also sent Professor Rytand 2 photographs of Mines, one of which a snapshot probably taken by herself in the summer of 1911 at Plymouth (Figure 2). It is with some trepidation that I publish this snapshot here, because Mrs. Thacker was rather upset when she learned that Professor Rytand was making copies of the photographs. The more official photograph of Mines was published2 and permission to do so was obtained by Professor Rytand from the photographic studio where it was taken. Whom to ask for permission? Anyway, the harm is already done, because the picture was published in Cardiovascular Research in 19925 by Michael R. Rosen,

who got it from me, who got it from Rytand, who got it from Mrs. Thacker.

Mines' Contributions Throughout the years, 2 causes of tachycardia have been considered: enhanced impulse formation and reentrant excitation. In 1887, McWilliam6 suggested for the first time that disturbances in impulse propagation could be responsible for tachyarrhythmias: "Apart from the possibility of rapid spontaneous discharges of energy by the muscular fibres, there seems to be another probable cause for continued and rapid movement. The peristaltic contraction

Figure 2. George Ralph Mines: a photograph probably taken by Mrs. Dorothy Thacker (at that time Dorothy Dale) in the Marine Biological Laboratory, Plymouth, in the summer of 1911. Professor D.A. Rytand made this picture available to the author.

HISTORICAL NOTES: GEORGE RALPH MINES travelling along such a structure as that of the ventricular wall must reach adjacent bundles at different points in time, and since these bundles are connected with one another by anastomosing branches the contraction would naturally be propagated from one contracting fibre to another over which the contraction wave had already passed... Hence the movement would tend to go on until the excitability of the muscular tissue had been lowered, so that it failed to respond with a rapid series of contractions."6 It is clear that Mc William envisaged the possibility that myocardial fibers could be reexcited as soon as their refractory period had ended by an irregularly propagating impulse, and he therefore may be considered a founding father of reentrant excitation. Yet it was the work of Mines and of Garrey some 30 years later that firmly established the role of reentry as a mechanism for arrhythmias. Both investigators, working independently, were inspired by Mayer's work. Garrey's contributions include the demonstration that fibrillation does not result from a single, rapidly firing focus and that a minimal tissue mass is required for fibrillation.4 Here, we shall concentrate on the work of Mines. Apart from a brief biographical sketch by Rytand,2 the most complete biography of Mines can be found in a recent paper by De Silva.7 Briefly, Mines was born in Bath, England, on May 13, 1886. He entered Sidney Sussex College, Cambridge University at the age of 19. In 1911 he was appointed Assistant Demonstrator in the Physiological Laboratory at Cambridge. As already mentioned, he did important work in the Marine Biological Laboratory in Plymouth (summer of 1912, together with Dorothy Dale) and in Roscoff, France, in August and September 1913 (see Figure 1). In 1914, at the age of 28, he was offered the position of Professor and Chair of Physiology at McGill University in Montreal, Canada. On the

7

evening of Saturday, November 7, 1914, the night janitor found Mines lying unconscious in his laboratory. Mines died shortly thereafter, presumably as a result of self-experimentation.7 The accomplishments of such a young man are truly astonishing. In his 1913 and 1914 papers,3,8 Mines formulated the essential characteristics of reentry: 1. For the initiation of reentry, an area of unidirectional block must be present (Garrey4 also emphasized this point, as was acknowledged by Mines.8) In the 1914 paper, he describes an experiment on an isolated auricular preparation from a large dog-fish (Acanthian), slit up in such a way as to form a ring. The ring was spread on a glass plate and serum was poured on. The preparation remained quiescent. "Pricking with a needle point provokes a strong contraction. Wave runs round ring in each direction; the waves meet on the opposite side of the ring and die out. Repeated the stimulus at diminishing intervals and after several attempts started a wave in one direction and not in the other. The wave ran all the way round the ring and then continued to circulate going round about twice a second. After this had continued for two minutes extra stimuli were thrown in. After several attempts the wave was stopped."8 Thus, not only was unidirectional block found to be essential, the principle of antitachycardia pacing was described as well. 2. Mines described the relationship between refractory period duration and conduction velocity, as shown in Figure 3, and can thus be considered the first to formulate the "wavelength" concept. In the 1913 paper he wrote: "With increasing

8 CARDIAC MAPPING

Figure 3. Mines' diagram to explain that reentry will occur if conduction is slowed and the refractory period duration is decreased. A stimulated impulse leaves in its wake absolutely refractory tissue (black area) and relatively refractory tissue (stippled area). In both A and B, the impulse conducts in one direction only. In A, because of fast conduction and a long refractory period, the tissue is still absolutely refractory when the impulse has returned to its site of origin. In B, because of slow conduction and a short refractory period, the tissue has recovered excitability by the time the impulse has reached the site of origin, and the impulse continues to circulate.

frequency of stimulation, each wave of excitation in the heart muscle is propagated more slowly but lasts a shorter time at any point in the muscle. The wave of excitation becomes slower and shorter. Similarly the refractory phase (towards strong induction shocks) is shortened."3 3. Mines realized that establishing the activation sequence during a reentrant rhythm is not sufficient to prove reentry. "Ordinary graphic records either mechanical or electrical are of no value in attesting the occurrence of a true circulating excitation in rings of this kind, since the records show merely a rhythmic series of waves and do not discriminate between a spontaneous series of beats and a wave of excitation which continues to circulate because it always finds excitable tissue ahead of it. The only method of recording the phenomenon which I have found of any use is cinematography."8 If only the film could have been

found! "The chief error to be guarded against is that of mistaking a series of automatic beats originating in one point in the ring and travelling round it in one direction only owing to complete block close to the point of origin of the rhythm on one side of this point... Severance of the ring will obviously prevent the possibility of circulating excitations but will not upset the course of a series of rhythmic spontaneous excitations unless by a rare chance the section should pass through the point actually initiating the spontaneous rhythm."8 Thus, Mines set the stage for catheter ablation of reentrant rhythm. 4. Mines discovered the vulnerable period for fibrillation. It is remarkable that Mines and Garrey almost simultaneously described fibrillation in terms of reentry. "Garrey arrives independently at a closely similar conclusion to that which I expressed in a recent paper, namely, that fibrillation is due to waves

HISTORICAL NOTES: GEORGE RALPH MINES 9 travelling in closed circuits in the syncytium."8 Mines then describes his experiment showing that fibrillation can be induced by a single induction shock: "The point of interest is that the stimulus employed would never cause fibrillation unless it was set in at a certain clinical instant." He shows that a stimulus falling in the refractory period has no effect, "a stimulus coming a little later in the cycle sets up fibrillation" and a stimulus applied "later than the critical instant for the production of fibrillation merely induces an extrasystole..." "In the production of fibrillation just described, the stimulus apparently arrives at some part of the ventricular muscle just at the end of the refractory phase and probably before the refractory phase has ended in some other regions of the muscle. If this is so, we have again a difference in conditions of different regions of the muscle as a basis for the inauguration of the state of fibrillation." "... Suppose that at the time when excitation is set up in A, B is in the refractory state. It cannot then be excited by A. But the excited state set up in A will persist for a considerable time, and the refractory state will disappear from B before the excited state has ceased in A. The question is: Is it ever possible that under these circumstances A will excite B?" It would be 74 years before Chen and colleagues9 answered this question. As described in detail by Acierno,10 around 1920 a considerable number of people were accidentally electrocuted because more and more electrical devices were installed in households. This prompted electric companies such as Con Edison to provide grants to investigate the effects of electrical currents on human beings. This

led to the (re) discovery of the vulnerable period by Wiggers and Wegria in 1940.11 In that paper Mines is not mentioned, but in another paper by Wiggers in 1940, a brief allusion to Mines is made.12 As also noted by De Silva,7 the extensive and otherwise admirable book The History of Cardiology by L.J. Acierno10 makes no note of Mines' contributions. Fortunately, this is not the case in Luderitz' book History of the Disorders of Cardiac Rhythm.13 Some of the most astonishing paragraphs in the 1913 and 1914 papers describe in detail the mechanisms of 2 arrhythmias that at that time were clinically unknown: atrioventricular (AV) reentrant tachycardia in the WolffParkinson-White (WPW) syndrome and AV nodal reentry. As described in detail by Rosen,5 none of the relevant papers on the WPW syndrome from 1930 to 1967 mention Mines. "As for Mines, who predicted and described it all, his name is known only to those who are aficionados of electrophysiological history (e.g., Rytand)."5 In 1913, after describing circulating excitation in a ring-like preparation of a tortoise heart, Mines wrote: "I venture to suggest that a circulating excitation of this type may be responsible for some cases of paroxysmal tachycardia as observed clinically."3 One year later he repeated this suggestion "... in the light of the new histological demonstration by Stanley Kent ... that an extensive muscular connection is to be found at the right-hand margin of the heart at the junction of the right auricle and right ventricle: Supposing that for some reason an impulse from the auricle reached the main A-V bundle but failed to reach this 'right lateral' connexion. It is possible then that the ventricle would excite the ventricular end of this right lateral connexion, not finding it as refractory as it normally would at such a time. The wave spreading then to the auricle might be expected

10 CARDIAC MAPPING to circulate around the path indicated."8 This was written 16 years before Wolff, Parkinson, and White14 described the clinical syndrome that now bears their name, 18 years before Holzmann and Scherf15 ascribed the abnormal ECG in these patients to preexcitation of the ventricles via an accessory AV bundle, and 53 years before the first studies in patients employing intraoperative mapping and programmed stimulation proved Mines' predictions to be correct.16–18 As already mentioned, Mines' name cannot be found in the bibliography of any of these papers. It is ironic that what Kent described is not at all the usual accessory AV connection, found in the WPW syndrome, as discussed in detail by Anderson and Becker.19 They stated that "... there are indeed good scientific reasons for discontinuing the use of 'Kent bundle' ... the most important being that Kent did not describe connections in terms of morphology we know today... If an eponym is really necessary, then let us call them nodes of Kent."19 From Mines' point of view, the important point was of course that a human heart had been described with multiple connections between atria and ventricles. For AV nodal reentry, the story is different. In the 1913 paper Mines describes what he called reciprocating rhythm. This was based on observations in 3 experiments on the "auricle-ventricle preparation of the heart of the electric ray, and in one experiment on the ventricle-bulbus preparation from the frog..." "After the application of rhythmic stimuli at some particular rate, the cessation of the stimuli was followed by a quick reciprocating movement of auricle and ventricle or of ventricle and bulbus. The appearance of the heart gave the impression that the beats of the ventricle were caused by those of the auricle or bulbus, while these in turn were caused by the ventricle." His explanation is as follows: "The connexion between the auricle and ventricle is never

a single muscle fibre but always a number of fibres, and although these are ordinarily in physiological continuity, yet it is quite conceivable that exceptionally, as after too rapid stimulation, different parts of the bundle should lose their intimate connexion... A slight difference in the rate of recovery of the two divisions of the A-V connexion might determine that an extrasystole of the ventricle ... should spread up to the auricle by that part of the A-V connexion having the quicker recovery process and not by the other part. In such a case, when the auricle became excited by this impulse, the other portion of the A-V connexion would be ready to take up the transmission again back to the ventricle. Provided the transmission in each direction was slow, the chamber at either end would be ready to respond (its refractory phase being short) and thus the condition once established would tend to continue, unless upset by the interpolation of a premature systole."3 I can remember my excitement when I gave a talk in the Hopital Lariboisiere in 1970, describing experiments in isolated rabbit hearts employing multiple microelectrode recordings where we induced and terminated AV nodal reentrant tachycardia by extrasystoles, and meeting Philippe Coumel, Alexandre Fabiato, and Robert Slama, who had treated patients with AV nodal reentry by a pacemaker that could be turned on when a tachycardia occurred and would terminate the arrhythmia when the stimuli would be timed just right. I am pleased to say that both our publications gave full credit to Mines,20,21 as did an earlier paper on AV nodal reentry by Moe and Mendez.22 I have no idea why Mines' name is not associated with the preexcitation syndrome, and why he is given proper recognition in papers on AV nodal reentry. It is remarkable that in the wonderful book by Pick and Langendorf, Interpretation of Complex Arrhythmias,23

HISTORICAL NOTES: GEORGE RALPH MINES Mines' 1913 and 1914 papers are quoted in the chapter on "Reentrant Arrhythmias (Reciprocal Beating)," but not in the chapter entitled "The Preexcitation Syndrome." It is as Rosen5 wrote: "Mines is known only to those who are aficionados of electrophysiological history." One may add that anyone who reads Mines' original papers is likely to become an aficionado. References 1. Janse MJ. Some historical notes on the mapping of arrhythmias. In: Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping. Mount Kisco, NY: Futura Publishing Co.; 1993:3-10. 2. Rytand DA. The circus movement (entrapped circuit wave) hypothesis and atrial flutter. Ann Intern Med 1966;65: 125-159. 3. Mines GR. On dynamic equilibrium of the heart. J Physiol (Lond) 1913;46:349–382. 4. Garrey WE. The nature of fibrillar contract of the heart. Its relation to tissue mass and form. Am J Physiol 1914;33: 397-414. 5. Rosen MR. Did Wolff, Parkinson and White mind their Ps and Qs? Cardiovasc Res 1992;26:1164–1169. 6. Mc William JA. Fibrillar contraction of the heart. J Physiol 1887;8:296–310. 7. De Silva RA. George Ralph Mines, ventricular fibrillation and the discovery of the vulnerable period. J Am Coll Cardiol 1997;29:1397-1402. 8. Mines GR. On circulating excitations in heart muscles and their possible relation to tachycardia and fibrillation. Trans R Soc Can 1914;IV:43-52. 9. Chen P-S, Wolf DD, Dixon EG, et al. Mechanism of ventricular vulnerability to single premature stimuli in open-chested dogs. CircRes 1988;62:1191-1209. 10. Acierno LJ. The History of Cardiology. London, Casterton, New York: The Parthenon Publishing Group; 1994. 11. Wiggers CJ, Wegria R. Ventricular fibrillation due to single, localized induction and condenser shocks applied

11

during the vulnerable phase of ventricular systole. Am J Physiol 1940; 128: 500-505. 12. Wiggers CJ. The mechanism and nature of ventricular fibrillation. Am Heart J 1940;20:399–412. 13. Liideritz B. History of the Disorders of Cardiac Rhythm. Second Revised and Updated Printing. Armonk, NY: Futura Publishing Company; 1998. 14. Wolff L, Parkinson J, White PD. Bundlebranch block with short P-R interval in healthy young patients prone to paroxysmal tachycardia. Am Heart J 1930;5: 685-704. 15. Holzmann M, Scherf D. Ueber Elektrokardiogramme mit verkurzter VorhofKammer-Distanz und positiven P-Zacken. Z Klin Med 1932;121:404–423. 16. Durrer D, Roos JR. Epicardial excitation of the ventricles in a patient with a Wolff-Parkinson-White syndrome (type B). Circulation 1967;35:15–21. 17. Burchell HB, Frye RB, Anderson MW, McGoon DC. Atrioventricular and ventriculo-atrial excitation in Wolff-ParkinsonWhite syndrome (type B). Circulation 1967;36:663-672. 18. Durrer D, Schoo L, Schuilenburg RM, Wellens HJJ. The role of premature beats in the initiation and termination of supraventricular tachycardia in the WolffParkinson-White syndrome. Circulation 1967;36:644-662. 19. Anderson RH, Becker AE. Stanley Kent and accessory atrioventricular connections. JThorac Cardiovasc Surg 1981;81: 649–658. 20. Coumel P, Cabrol C, Fabiato A, et al. Tachycardie permanente par rythme reciproque. Arch Mal Coeur 1967;60:1830– 1864. 21. Janse MJ, van Capelle FJL, Freud GE, Durrer D. Circus movement within the AV node as a basis for supraventricular tachycardia as shown by multiple microelectrode recording in the isolated rabbit heart. Circ Res 1971;28:403–414. 22. Moe GK, Mendez C. The physiological basis of reciprocal rhythm. Prog Cardiovasc Dis 1966;8:461–482. 23. Pick A, Langendorf R. Interpretation of Complex Arrhythmias. Philadelphia: Lea & Febiger; 1979.

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Part 2 Methodological and Technical Considerations

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Chapter 2

The Interpretation of Cardiac Electrograms Martin Biermann, MD, Mohammad Shenasa, MD, Martin Borggrefe, MD, Gerhard Hindricks, MD, Wilhelm Haverkamp, MD, and Gunter Breithardt, MD

in relation to anatomical landmarks of the heart and represents the local activation As early as 1915, Lewis and Roth- of myocardium at each recording site by schild, who studied the cardiac activation a single figure, the time of activation.6,7 In sequence in the dog by recording poten- an isochronal map, only a single activatials directly from the heart, wrote: "It tion time can be represented at each site must be evident that it is a matter of first and all other information also contained concern of us, to ensure a correct inter- in the electrograms is discarded.6 In isochronal mapping, the interpretation of pretation of our curves."1 The term electrogram, as opposed to the excitation sequence of the heart rests the term electrocardiogram (ECG), denotes entirely on the individual activation times a recording of cardiac potentials from elec- assigned to each electrogram, which is why trodes directly in contact with the heart, a the correct interpretation of individual elecdefinition introduced by Samojloff in trograms is of crucial importance. Alterna1910.2–4 Electrograms form the raw data tive mapping methods, namely isopotential for cardiac mapping, which has been and isoderivative mapping,7 place emphadefined as "a method by which potentials sis on interpreting a sequence of maps, recorded directly from the surface of the rather than a set of individual electroheart are spatially depicted as a function grams,7 the correct interpretation of which of time in an integrated manner,"5 and is often difficult and at times uncertain. The objective of this chapter is to which is important as both a research tool review the interpretation of individual carand a method for guiding therapy. The most common method of cardiac diac electrograms in 2 parts: (1) in respect mapping is isochronal or activation map- to timing local activation, and (2) in respect ping. A cardiac isochronal map outlines to information contained in the morphothe locations of the various recording sites logies of electrograms. Throughout this Introduction

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; ®2003.

15

16 CARDIAC MAPPING chapter it is assumed that negativity of the exploring electrode results in a downward movement in the unipolar electrogram.8,9 The process of creating maps out of electrogram data6,10 is not discussed, and one word of warning by Durrer et al. will have to suffice:"... the presence of time relationships compatible with an excitatory wave progressing in a certain direction does not necessarily prove the existence of such an excitatory wave."11 Activation Detection in Cardiac Electrograms The correct assignment of activation times for electrograms from each recording site is the cornerstone of isochronal mapping. With the transmembrane potential (TMP) as a gold standard, local activation of myocardium at a recording site can be defined as "the time instant when the upslope of the intracellular action potential... is a maximum."6 General Principles Underlying Electrograms

from the recording site, and the reciprocal value of the square of the distance between the dipole layer and the recording site.14,16 Thus, the unipolar electrogram records a combination of local and distant electrical events with the contribution of distant events decreasing in proportion to the square of the distance from the exploring electrode.17 The bipolar electrogram is recorded as the potential difference between 2 closely spaced electrodes in direct contact with the heart; it can be calculated as the difference between the 2 unipolar electrograms at each of the 2 electrode sites.18 These 2 unipolar electrograms differ only in the detail of the local activity at the moment of local excitation, in which case a spike in the bipolar electrogram results,18 the amplitude of which is inversely proportional to the third power of the distance between recording site and dipole.19–21 If the activation front is perpendicular in relation to the electrode pair, the bipolar spike will be of maximum amplitude, while if it is parallel, both electrodes will record the same waveform at the same time and no spike will result.6,22 To compensate the directional sensitivity of bipolar electrodes, investigators have processed bipolar signals from multipolar electrodes in different ways,23,24 or have advocated using bipolar coaxial electrodes,6,25 introduced by Fattorusso et al.26,27 in 1949 for recording precordial ECGs. However, even coaxial bipolar electrodes cannot detect activation fronts parallel to the place of the electrode (Ideker RE, oral communication).

The unipolar electrogram is recorded as the potential difference between a single electrode in direct contact with the extracellular space of the heart, the socalled "exploring electrode," and an "indifferent electrode,"12 which is an electrode placed at a distance from the heart1 or Wilson's central terminal.12 The electrical field produced at the border between resting and excited myocardium can be described as dipole.13–15 During cardiac excitation, the approach of this dipole The History of Activation Detection toward an exploring electrode gives a posAlthough direct cardiac leads had been itive deflection and its passage gives a rapid deflection in the negative direction, recorded2,28–35 (though not by Rothberger with a final return to baseline.5 Depolar- and Winterberg36) and bipolar electrodes ization, too, causes a dipole, albeit of the had been developed22,37,38 before 1914, reverse polarity.14 The amplitude of the Lewis' fame to have performed the first unipolar electrogram is proportional to cardiac mapping in 191439 and 19151 is the area of the dipole layer as "viewed" justified by the scope of his investigations.

INTERPRETATION OF CARDIAC ELECTROGRAMS

17

When Lewis et al.39 examined the spread ventricular outflow tract (RVOT) and the of excitation in the atria of the canine heart, pulmonary artery. The deflection that they used bipolar electrodes, assuming on appeared in all 6 electrograms at practithe ground of various experiments that cally the same time was thought to repre"the prominent spike" in a bipolar lead sig- sent distance cardiac activity and was nified local activation of the myocardium called the extrinsic deflection.1 A second beneath the electrode. When, in their stud- kind of deflection that occurred only in ies on the ventricles, Lewis and Rothschild.1 the 4 leads overlying myocardium and at switched to unipolar leads, they once more progressively later time instants was conhad to solve the question of activation eluded to signal the time of local activation detection. They took a series of electro- and was called the intrinsic deflection.1 grams from 6 equidistant epicardial sites While, according to Lewis' tracings, this arranged in a straight line on the right was the nadir of the S wave1 (Table 1), Table 1 Activation Detection in Unipolar Electrograms Article 1

Lewis T, 1915 Barker PS, 1930102 Wilson FN, 193440 Harris AS, 194146 Wilson FN, 194441 Wilson FN, 194745 Sodi-Pallares D, 195047 Schaefer H, 195154 Veyrat R, 195352 Durrer D, 195455 Durrer D, 195756 Jouve A, I960103 Durrer D, 1961120 Schaefer H, 196214 Durrer D, 196411 Ideker RE, 197980 Smith WM, 1980170 Parson I, 1982171 Cardinal R, 198484 De Bakker JMT, 198478 Parson I, 1984172 Carson DL, 198686 Blanchard SM, 198787 Bonneau G, 198779 Masse s, 198876 Page PL, 198885 Ideker RE, 19896 Paul T, 199090 Pieper CF, 1991168 Pieper CF, 199181 Pieper CF, 199182

Algorithm

Threshold in mV/ms

Evidence

S* S* R* R* R* S* S* FD* FD* FD* FD* FD* FD* FD* FD* MD MD MD* MD MD MD* MD MD MD MD MD MD MD MD MD MD

— — — — — — — — — — — — — — —

E R T E T T E E E E E R E T R R N N E N N E E N E E R R R R R

-2.5 -2.0-5.0 -0.5

-2.5 — —

-0.3 -1.4 -0.5-0.2 -0.5 — — — — —

-2.0

Articles that specified criteria or algorithms for activation detection in unipolar electrograms: fast downstroke (FD), maximum downslope (MD), peak of the R wave (R) or nadir of the S wave (S). Also listed is the type of evidence presented in favor of the criteria: experiment (E), theory (T), references (R), or none (N). It is assumed that negativity of the exploring electrode produces a downward deflection in the unipolar electrogram. An Asterisk (*) marks analog mapping systems.

18 CARDIAC MAPPING Wilson et al.40,41 assumed on the basis of the dipole theory that the time of local activation beneath an epicardial electrode coincided with the peak of the R wave. Later, influenced by the experiments of Cole, Curtis, and Hodgkin,42–44 they identified local activation with the nadir of the S wave.45 Harris46 used a new approach in 1941. Having demonstrated that the closely paired terminals of a bipolar electrode record only local but not distant activity, Harris compared sequential unipolar and bipolar recordings from the same sites and came to the conclusion that the peak of the R wave was "the unipolar manifestation of an action current in the local surface area."46 The investigation by Sodi-Pallares et al.47 in 1950 was based on the same principles. While all these experiments had been performed with the time-honored string galvanometer,9,48,49 Schaefer,50,51 Veyrat,52 Durrer et al.,20 and Scher et al.53 introduced highly accurate cathode tube equipment into their laboratories. The first to make the discovery that the fast downstroke in a unipolar electrogram signifies the moment of local activation were Schaefer54 in 1951, Veyrat52 in 1953, and Durrer and Van der Tweel55 in 1954. Although Schaefer and Trautwein19 had been able to demonstrate that the time of the maximum upstroke of the monophasic action potential precisely coincides with the peak of a bipolar electrogram recorded simultaneously at the same site, Schaefer's experimental evidence concerning unipolar electrograms54 is incomplete. While Veyrat52 essentially applied Lewis' methods of 1915, Durrer and Van der Tweel's approach did not differ markedly from Harris' in 1941: the absence of a fast bipolar complex in leads from thickened epicardium showed "that the fast part of the differential electrocardiogram [=bipolar electrogram] originates from electrical processes directly under the electrode."55 Simultaneous recordings of unipolar and

bipolar electrograms then yielded the following result: "In all cases where a fast part of the intrinsic deflection could be detected, the top of the differential spike [in the bipolar electrogram] was found to coincide with it."55 Thus, the fast downstroke in a unipolar epicardial electrogram was found to represent local activation. Durrer and Van der Tweel56 were able to extend these findings to intramural electrograms by means of a tripolar intramural electrode. Unlike Durrer, Scher et al.16,53 exclusively used bipolar leads for timing local activity, choosing "the positive or negative maxima of the bipolar records"16 as a criterion (Table 2). Intracellular Leads Since the development of suitable microelectrodes,57,58 many investigators have taken intracellular recordings from myocardial fibers to investigate the temporal correlation between extracellular recordings and the TMP (Table 3). The early experiments by Woodbury et al.,59 Sano et al.,60 Hoffman and Cranefield,61 and Dower and Osbourne62 all had serious shortcomings.63 It is, however, interesting to note that the results of the experiments of Sano et al. in 1956, which, due to a methodological error,63 had found no strict temporal correlation between the steep downslope in the unipolar electrogram and the point of the steepest rise of the TMP,60 were addressed by Durrer as late as 1968.64 The first to prove by modern standards "that the steep negative-going downstroke of the local ECG coincides with the upstroke of the transmembrane potential curve of the underlying cell or cells.. ."65 were Dower and Geddes65 in 1960. In their tracings of the in vivo guinea pig heart, the difference between the 2 events is less than 1 ms.65 In 1972, Myerberg et al.66 took simultaneous intracellular and extracellular bipolar recordings from superfused preparations of the right bundle branch of 30 dogs.

INTERPRETATION OF CARDIAC ELECTROGRAMS

19

Table 2 Activation Detection in Bipolar Electrograms Article 22

Clement E, 1912 Erfmann W, 191337 Garten S, 191338 Lewis T, 191439 Harris, AS 1941 46 Schaefer H, 195119 Scher AM, 195353 Durrer D, 1 95455 Durrer D, 195756 Scher AM, 195716 Durrer D, 1961120 Schaefer H, 196214 Durrer D, 196411 Ostermeyer J, 197923 Abendroth RR, 1980108 Rosenfeldt FL, 1984173 Witkowski FX, 1984174 Kaplan DT, 198791 Blanchard SM, 198889 Simpson EV, 198877 Paul T, 199090 Rosenbaum DS, 1990175 Pieper CF, 199181 Pieper CF, 199182

Algorithm

Evid.

onset* onset* onset* peak* peak* peak* peak* peak* peak* MAA* peak* peak peak* MD* 45°* MAA* MAA MAS, morph peak morph MAS, peak, 45° MAS MAS, peak BSS, MAS, morph, peak

N N N E E E E E E N E T R R R N N E E N E N E E

Articles that specified criteria for activation detection in bipolar electrograms in intraoperative or experimental mapping: the baseline crossing with steepest slope (BSS), the maximum absolute amplitude |V|max (MAA), the maximum absolute slope |dV/dt|max (MAS), the major deflection in the rectified bipolar electrogram (MD), morphological algorithms (morph), the onset of the bipolar EG (onset), the maximum amplitude Vmax (peak), the first deflection from baseline steeper than 45° (45°). The type of the main evidence (Evid.) presented in favor of the criteria is also listed: experiment (E), theory (T), references (R), or none (N). An asterisk (*) denotes analog mapping systems.

Bipolar electrograms occurred less than 1 ms before or after the upstroke of the TMP. In case of increasingly premature stimuli, however, disparities up to 10 ms were possible, which the authors explained by the nonuniform arrival time of an impulse across the transverse axis of the Purkinje fiber. Furthermore, the bipolar electrograms usually became unmeasurable some time before conduction finally failed.66 Experiments by Spach et al.67 on dog Purkinje fibers in the same year showed that the maximum downslope of the local unipolar electrogram occurred within less than 0.2 ms from the maximum upslope of the TMP.

Downar et al.68 noted a similar correlation in the acutely ischemic porcine heart. As their and Akiyama's tracings69 from fibrillating hearts show, activity during ventricular fibrillation that is recorded by intracellular electrodes can go undetected in local unipolar electrograms. In 1985, Spach and Kootsey70 published the results of a theoretical model that predicted that "the negative peak of the derivative of the extracellular [unipolar] potential always occurred at the time of dV/dtmax of the transmembrane potential." In experiments on human atrial muscle, Spach and Dolber71 found time differences

20 CAEDIAC MAPPING Table 3 Correlation of Transmembrane Potentials and Local Electrograms Transmembrane Potentials from

Evidence

Article 59

Woodbury LA, 1950 Sano T, 195660 Sano T, 1958176 Dower GE, 195862 Dower GE, 196065 Hoffman BF, 196061 Dower GE, 196263 Myerburg RJ, 197266 Spach MS, 197267 Downar E, 197768 Kleber AG, 1978128 Cinca J, 1980129 Akiyama T, 198169 Spach MS, 1981177 Gardner PI, 1985164 Spach MS, 198570 Spach MS, 198671 Steinhaus BM, 198873 Steinhaus BM, 198974 Haws CW, 199072 Rudy Y, 199175

D, T D, T D, T D, T D, T D, T D, T D, T D, T D, T D D D D D M,T M, D, T M, T M, T M, D,T M, T

Frog Turtle Dog Guinea pig Guinea pig Dog, PM Guinea pig Dog, CS Dog, CS Pig, Al Pig, Al Pig, Al Dog, Al Dog Dog, CMI — Human atrium — — Dog —

Articles that examined the problem of activation detection in extracellular signals by correlating transmembrane potentials and local electrograms, presenting evidence in the form of diagrams with simultaneous recordings (D), theoretical models (M), or remarks in the text (T). Al = acute ischemia; CMI = chronic myocardial infarction; CS = conduction system; PM = papillary muscle.

of less than 50 us between dV/dtmax of the TMP and the maximum downslope of the local unipolar electrogram. The model of Haws and Lux72 made a similar prediction. Steinhaus' computer simulations73,74 in 1988 showed that under conditions of nonuniform coupling resistances and membrane properties, differences in excess of 1.8 ms can occur between the times of maximum negative slope in the unipolar electrogram and the maximum positive slope in the TMP. The criterion of maximum absolute amplitude of electrograms from bipolar electrodes with 0.1-mm interelectrode distance yielded comparable results and performed better during conditions with marked contribution from distant events.73,74 In 1991, Rudy and Quan75 proposed a model that incorporated gap junctions with varying degrees of resistances between cells. They found that in the middle and in the prejunctional area of the cells, the time of the

maximum downslope in the unipolar electrogram and the time of the dV/dtmax in the TMP coincided with a deviation of less than 100 (us. In the postjunctional area of poorly coupled cells, however, deviations of up to 370 (uswere possible.75 Based on this evidence, we may conelude that the time of the maximum downslope in a unipolar electrogram is a valid fiducial point for identifying times of local activation in unipolar electrograms even though error in excess of 1 ms may occur, Computer Algorithms With the advent of computerized multichannel mapping systems, it became necessary to develop computer algorithms for automatic activation detection, manual marking of electrograms being impractical under the severe time constraints imposed on intraoperative mapping studies.76,77

INTERPRETATION OF CARDIAC ELECTROGRAMS 21 Unipolar electrograms

Practically all algorithms for unipolar electrograms are based on the criterion of the "maximum downslope" or "largest negative slope" (Table 1). The typical unipolar activation algorithm is based on the following 2 principles: 1. The algorithm searches each electrogram for time instants in which the negative slope of the electrogram is larger than a threshold slope; these time instants are assumed to represent possible times of local activation. 2. If 2 or more time instants meet criterion 1 within a defined time window, the time instant with the largest negative slope is chosen as the time of local activation. Individual algorithms basically differ in their choice of the threshold value for criterion 1, the width of the time window for criterion 2, for which variable values78 or values of 40 ms76,79 and 50 ms80 have been used, and the way the slope of the electrogram is calculated (e.g., 2-point, 3-point, or 5-point algorithms).81,82 Some unipolar algorithms also provide a refractory period after each time instant for which an activation has been detected using criteria 1 and 2.76,79 A few algorithms use a relative slope threshold in relation to slopes measured in each electrogram analyzed.76 The main controversy concerning unipolar algorithms is the optimum value of the slope threshold, the problem being to reliably distinguish local activity (associated with a steep downslope) from distant activity without local activity (associated with a shallow downslope). Ideker et al.80 used a slope threshold of 5 mV/2 ms, referring to Durrer and Van der Tweel's 1957 mapping study in healthy dogs.56 Roberts et al.83 determined downslopes in unipolar epicardial

electrograms between 11 and 64 mV/2 ms in noninfarcted canine myocardium. In canine chronic myocardial infarction (MI), Cardinal et al.84 were able to observe "organized propagation of wavefronts" at slopes of -0.5 mV/ms. Regardless of slope, a QS complex recorded in epicardial sites overlying transmural infarcts was interpreted as a cavity complex representing no local activity.84,85 Carson et al.86 observed "organized propagation" at slopes of -0.3 mV/ms in acutely ischemic porcine hearts. In a canine model with right ventricular (RV) isolation procedure, Blanchard et al.87,88 were able to simulate various combinations of local and distant activity by sequential or independent pacing of the RV and the left ventricle (LV). A slope threshold of 1.4 mV could reliably distinguish between local plus distant activity and distant without local activity; however, considerable overlap is likely under conditions of ischemia, chronic MI, and ventricular fibrillation.87,88 Checking computer markings against manual markings of electrograms from patients with Wolff-Parkinson-White (WPW) syndrome and ventricular tachycardia (VT), Masse et al.76 found a slope threshold of –0.2 V/s to perform optimally. Thus, recommended slope thresholds for unipolar activation detection algorithms range from -0.2 to –2.5 mV/ms. Bipolar electrograms

There is considerably less agreement on the best computer algorithm for bipolar electrograms. Basically, the following types of algorithms exist for activation detection in bipolar electrograms (Table 2), the respective merits of which are discussed in the succeeding paragraphs: l. the maximum amplitude Vmax of the bipolar electrogram (peak) and the maximum absolute amplitude | V |

max;

22

CARDIAC MAPPING 2. the maximum absolute slope |dV/dt| max of the bipolar electrogram (MAS); 3. the first elevation of more than 45° from the baseline of the bipolar electrogram (45°); 4. the baseline crossing with the steepest slope (BSS); 5. "morphological"82 algorithms.

The peak algorithm: On the conditions that an excitation wave has a constant shape and propagates with a constant velocity—conditions not met on a microscopic level71 and in diseased tissue10—the bipolar electrogram from closely spaced terminals can be considered to approximate the first temporal derivative of the local unipolar electrogram.20,70 In this case, the peak of the bipolar signal would precisely coincide with the maximum downslope of the local unipolar electrogram, which gives the peak criterion some theoretical justification. The maximum absolute amplitude criterion as opposed to the peak criterion has the advantage that it is independent of the polarity of the bipolar electrodes. Recent experimental evidence in favor of the peak criterion came from Blanchard et al.,89 in whose model of the canine RV isolation procedure the peaks of the bipolar electrograms occurred within 5 ms of the maximum downslope of simultaneous unipolar electrograms in 94% of cases regardless of wavefront-to-fiber orientation. Paul et al.,90 who evaluated 3 bipolar algorithms during sinus mapping in dogs, found that bipolar activation times assigned by the peak criterion were closest to those measured in unipolar electrograms from the same sites with the maximum downslope algorithm. Pieper et al.81 found that the peak criterion gave more stable results than the MAS criterion. In another study by Pieper et al.,82 the peak algorithm showed the closest correspondence with manually determined

activation times among all nonmorphological algorithms. The peak criterion has the added advantage that it does not require calculations like MAS.90 The MAS algorithm: Kaplan et al.91 chose the MAS criterion as the nearest equivalent to the criterion of maximum downslope for unipolar electrograms. This is, however, not correct: as each steep slope of the bipolar electrogram coincides with the maximum downslope of either of the 2 component unipolar electrograms,5 the MAS criterion marks the moment of maximum downslope at either of the 2 electrode terminals but not between the terminals. Paul et al.90 found that the MAS criterion corresponded less well than the peak criterion to unipolar activation times based on the maximum downslope criterion. Pieper et al.81 reported similar findings. The 45° algorithm: Scherlag et al.92 used "the first rapid excursion from the isoelectrical line at an angle of 45° or greater" to mark the onset of the A wave in His bundle electrograms. Paul et al.90 found that the 45° criterion led to significantly earlier activation times compared to the unipolar maximum downslope and even to a different localization of the first epicardial breakthrough. The BSS algorithm: Josephson et al.,93 Cassidy et al.,94 and Vassallo et al.95 used the BSS criterion for endocardial catheter mapping with electrode catheters with 10-mm interelectrode distance; these have a wider field of view than bipolar electrodes for intraoperative mapping. In the context of intraoperative mapping, Pieper et al.82 found that the BSS algorithm showed a slightly poorer correspondence with manually determined activation times than the peak algorithm. Morphological algorithms: Kaplan et al.91 compared a morphological algorithm using lead-specific templates with the MAS algorithm and found that the morphological algorithm gave the more

INTERPRETATION OF CARDIAC ELECTROGRAMS consistent results. Simpson et al.77 developed a complex morphological algorithm that marked the point of symmetry in the bipolar waveform. Pieper et al.82 found that their morphological algorithm, which was based on principles similar to those of Simpson's, performed best in every category: of all algorithms tested, it produced the fewest outliers and showed the fewest differences between computer and manual markings. Based on this evidence, we may conclude that the best among the "simple" bipolar activation detection algorithms is the peak criterion, while morphological algorithms perform somewhat better under practical conditions. Still, much remains to be done in the field of activation detection, as Smith et al. stated in 1990: "Much work is required in this area in order to be able to detect and characterize local activations with high sensitivity, specificity, and temporal accuracy, especially in the fast, chaotic milieu of ventricular fibrillation."96

23

"intrinsic deflection" is defined as any fast downstroke in a unipolar electrogram that is interpreted to indicate local activation. Electrograms in the Normal Human Heart The first to map the activation of the in situ human heart were Barker et al.102 in 1930; these investigators upset contemporary views about the ECG patterns of the bundle branch blocks.64 By 1960, Jouve et al.103 were able to list 21 references of mapping studies in humans. Endocardial electrograms

According to the study on 7 Langendorff-perfused preparations of the human heart by Durrer et al.,104 endocardial activation of the ventricles synchronously starts at 3 sites in the LV 0 to 5 ms after the onset of the LV cavity complex (LV-CC): a central area in the interventricular septum, a paraseptal area Morphological Interpretation near the base of the anterior papillary muscle, and a paraseptal area near the of Cardiac Electrograms base of the posterior papillary muscle. The local activation time is but one The endocardial activation becomes conpiece of information contained in an elec- fluent after 30 ms and the posterobasal 104 94 trogram. In the morphology of a unipolar area is activated last. Cassidy et al. electrogram, the activity of the whole largely confirmed these results. Endoheart is encoded, which allows important cardial activation of the RV starts near conclusions under a number of physio- the insertion of the anterior papillary logical and pathological conditions, while muscle between 5 and 10 ms after the 104 the morphology of bipolar complexes may onset of the LV-CC. Unipolar endocardial electrograms contain valuable information about patfrom canine experiments show a QS morterns of local activation. The following phology with a rapid downstroke in the paragraphs concentrate on ventricular first part of the QRS complex.16,53,56,105 electrograms during sinus rhythm in the human heart. We exclude the subjects of Bipolar endocardial electrograms in the mapping of tachycardias, which has normal human LV from catheters with already been amply reviewed,24,97–100 and 10-mm interelectrode distance have of mapping of the atria,17 of the specialized amplitudes of greater than 3 mV and conduction system,17 and of repolariza- durations of less than 70 ms, and no split, 94 tion.72–74,101 For the purpose of this chapter, fractionated electrograms are found.

24 CARDIAC MAPPING Intramural electrograms

The excitation of the thick LV wall proceeds in an almost strictly endocardial to epicardial direction, whereas the activation of the thin RV wall spreads tangentially from the pretrabecular area until, after 60 to 70 ms, the pulmonary conus and posterobasal area are reached. The activation of the interventricular septum proceeds from left to right and in an apical-basal direction.104 Immediately after introduction of a needle electrode, unipolar intramural electrograms show no rapid deflections and an ST segment elevation due to local injury. After 2 to 3 minutes, the ST segment gradually becomes isoelectric and fast downstrokes in the electrogram appear.56 Unipolar intramural electrograms from the normal human heart show a gradual transition from the endocardial QS complex resembling the LVCC to the epicardial complex with a prominent R wave, the greatest increase of which often occurs in the outer layers of the LV wall.106 Bipolar electrograms in the inner layers of the wall are relatively small, sometimes notched, and generally positive, indicating spread of excitation in an epicardial direction. In the middle and outer layers, they are larger, smooth, and always positive.106

The most accurate descriptions of human unipolar epicardial electrograms are those by Jouve et al.103 and Roos et al.106 (Figure 1), other studies109–111 being methodically inferior.103 Unipolar electrograms over the pretrabecular region of the RV surface have an rS morphology.106 As the excitation spreads over the RV, the r wave increases slightly in duration and amplitude106 and rS or RS103 complexes are recorded, which predominantly reflect distant activity of the LV. Electrograms from the RVOT may have an rS (sometimes with notching or r and/or S), rSr', rsr'S', or, rarely, qRS morphology.17 Unipolar complexes over the interventricular septum may have an rS or (v)rS morphology, (v) standing for vibrated initial segment103 and denoting a broad-tipped positive complex with small amplitude (1 to 2 mV) and long duration (20 ms), which begins with the onset of the LV-CC.106

Epicardial electrograms

Epicardial activation of the ventricles begins in the pretrabecular area of the RV about 20 ms after the onset of the LV-CC5,104,107,108 and over the inferior RV.5,107 LV epicardial breakthrough takes place later over the middle portions of the left anterior and left posterior paraseptal regions5,104,107 and occasionally over the left anterior septum near the base.5,104,107 Latest epicardial activation occurs near the base of the posterior LV104,107,108 or of the RV.5,107

Figure 1. Unipolar epicardial electrograms during sinus rhythm in a 61-year-old male patient with normal 12-lead ECG; figures represent the local activation times in milliseconds following the onset of the left ventricular cavity complex. Reproduced from reference 106, with permission.

INTERPRETATION OF CARDIAC ELECTROGRAMS Unipolar complexes from the LV surface may show q waves, the beginning of which coincide with the LV-CC, with amplitudes of up to 3 mV.106 There are no q waves on the anterior RV and on the first 2 cm of the LV lateral to the left anterior descending artery (LAD).112 Q waves with a duration of up to 27 ms can be present or absent over the RVOT and "in a band of 2-4 cm in width located laterally on the left ventricle but parallel to the anterior descending coronary artery and also posteriorly along the course of the posterior descending branch of the right coronary aftery."112 Over the remaining lateral and posterior LV, Q waves with durations between 4 and 32 ms are regularly found.112 Electrograms over the atrioventricular sulcus show long Q waves as the cavity potential is viewed over the rim of the ventricular cavitites.112 At a distance from the anterior attachment of the interventricular septum, R waves increase in size with amplitudes of up to 20 mV over the lateral wall; they can vary very significantly in closely adjacent regions.106 S waves are deep over the anterior aspect of the LV from apex to base and diminish in

25

size in a lateral direction.106 Thus, typical LV epicardial morphologies would be an rS complex on the anterior wall, a qRS complex on the lateral wall, and a qRs complex on the posterior wall. A discussion of epicardial waveforms in RV hypertrophy, RV diastolic overload, and LV hypertrophy is provided by Kupersmith.17 Electrograms in Preexcitation Syndromes The first intraoperative mapping of a patient with WPW syndrome113 was performed by Durrer and Roos114 in 1967, and the first successful mapping-guided ablation by Cobb et al.115 in 1968. In WPW syndrome, the morphology of the earliest recorded unipolar epicardial electrograms may provide information about the location of the accessory pathway (Figure 2).5,100 While a QS morphology indicates epicardial location of the accessory pathway with spread of activation away from the exploring electrode in an epicardial-to-endocardial direction, an rS morphology signifies endocardial location of the accessory bundle.5,116 In case of

Figure 2. Surface ECGs and epicardial unipolar and bipolar electrograms at the earliest site of preexcitation in a patient with Wolff-Parkinson-White syndrome. Reproduced from reference 5, with permission.

26

CARDIAC MAPPING

free wall pathways, the earliest epicardial intrinsic deflection occurs before or simultaneously with the delta wave in the surface ECG.5 Electrogram criteria indicative of septal pathways are earliest ventricular activation over the anterior or posterior septum, an rS morphology, and an intrinsic deflection after the onset of the surface delta wave.5 Electrograms in Acute Myocardial Ischemia and Infarction Since the classic experiments of Johnston et al.117 in 1935, numerous investigators have studied the acute effects of coronary artery occlusion on electrograms in dogs118–126 and pigs.68,127–129 The following paragraphs focus mainly on the porcine

heart, which, in respect to coronary anatomy, resembles the human heart more closely than does the canine heart.130,131 Prinzmetal et al.121 distinguished 2 patterns of ischemia in unipolar epicardial electrograms: "severe acute ischemia," as in acute ligation of the LAD with "elevation of S-T segments, increase in amplitude of R waves (sometimes 'giant' R waves) and decrease in depth or disappearance of S waves," and "mild ischemia,"121 as in hemorrhagic shock, in which epicardial unipolar electrograms showed "numerous islands of S-T depression, often with loss of amplitude of the R wave and increased depth of the S wave." Downar et al.,68 Kleber et al.,128 and Cinca et al.129 gave a precise account of the electrogram changes after acute ligation of the LAD in the porcine heart (Figure 3).

Figure 3. Local transmembrane potentials (upper tracings) and unipolar electrograms (lower tracings) from the ischemic zone (left panel) and from the border zone (right panel) before (control) and 7.5, 14, 30, 42, and 60 minutes after acute left anterior descending coronary artery occlusion in the Langendorff-perfused porcine heart. Note that the monophasic complex at 7.5 minutes is associated with no local activation, while in the other tracings local activation coincides with a shallow intrinsic deflection after the peak of the R wave. Reproduced from reference 128, with permission.

INTERPRETATION OF CARDIAC ELECTROGRAMS

Unipolar electrograms in the ischemic zone show depression of the initially isoelectric TQ segment, caused by a decreased resting TMP of the ischemic myocardium, ST segment elevation due to a decreased amplitude of the action potential, and inversion of the T waves whenever the repolarization of the ischemic cells occurs later than that of the normal cells.128 The main negative deflection in the QRS complex decreases in magnitude and downslope velocity128 while the R wave becomes tall with a delayed intrinsic deflection after the peak of the R (Figure 3, 14),129 the tallness of the R waves being a consequence of the delayed activation because cancellation effects of earlier activated areas of the heart are absent.129 Cells in the ischemic zone then become unresponsive, and unipolar electrograms show monophasic complexes without intrinsic deflection (Figure 3, 7.5).128 When excitability of the ischemic cells transiently returns between 10 and 20 minutes after occlusion in in situ hearts,128 epicardial electrograms show the reappearance of a large intrinsic deflection with diminished TQ depression and ST elevation (electrogram at 42' in Figure 3).129 Unipolar intramural electrograms show essentially the same changes.128 Bipolar epicardial electrograms in canine acute MI show reduced amplitude and increased duration,120,122,124,125 both of which have also been described in human acute MI,122,123 delay or absence of activation,120,124 and, often, ST segment elevation.120,125 Bipolar intramural124 and endocardial126 electrograms show similar changes. Electrograms in Chronic MI Since the classic experiments by Wilson et al.132,133 in 1935, numerous investigators have examined electrogram morphologies in chronic LAD ligation in

27

dogs,11,84,85,112,120,122,134-139 while there are comparatively few studies on chronic MI in humans.112,122,123,137,138 Epicardial electrograms

Durrer et al. made the following generalizations about unipolar epicardial electrograms in canine chronic MI: "(1) The area with abnormal Q waves was always slightly larger than the infarcted area. (...) (2) The beginning of Q and the beginning of the left ventricular cavity potential were synchronous."11 In small canine subendocardial MIs, the only change in the unipolar epicardial QRS complex is deepening and broadening of the Q waves due to loss of depolarizing myocardium.11 In the case of larger subendocardial MIs in which a thin muscle layer overlies a scar devoid of muscle fibers, epicardial electrograms have a qR or QR morphology with a tall R wave and a delayed intrinsic deflection after the peak of the R (Figure 4).11 The tall R waves result from delayed activation of the muscle layer in a tangential direction at a time when the excitatory forces of the remainder of the ventricles are reduced or absent.11 Daniel et al.112 found good correlation between the canine model of subendocardial chronic MI and clinical findings in humans; the concurrence of abnormal Q waves and delayed epicardial activation times permitted the accurate localization of underlying MIs in human hearts.112,137,138 The characteristic unipolar morphology of transmural chronic MI, both in dogs11,20 and in humans,140 is a QS complex which is synchronous with the LV-CC and which may be fractionated.11,120 A smoothlimbed QS complex indicates the absence of local activity11,84,85 regardless of slope.85 Canine septal chronic MI shows a characteristic picture of abnormal Q waves in unipolar electrograms over the RV without delay in epicardial activation.112

28 CARDIAC MAPPING

Figure 4. Cross-section through chronic canine subendocardial infarction (light area) with unipolar epicardial electrograms before (control) and after left anterior descending coronary artery ligation. In the post myocardial infarction electrograms, note the abnormal Q waves, which occur over an area slightly larger than the infarct, the tall R waves, and the delayed intrinsic deflections. The figures indicate activation times in milliseconds. Reproduced from reference 138, with permission.

Page et al.,85 who compared unipolar and bipolar electrograms in canine chronic MI, proposed an interesting classification of unipolar epicardial electrograms in sinus rhythm: "Class A" electrograms were electrograms of rs morphology with an intrinsic deflection within the QRS wave, "Class B" electrograms were electrograms with a wide QS deflection corresponding to a cavity potential, and "Class C" electrograms were electrograms with a QS complex followed by a late intrinsic deflection. Areas of Class C electrograms extending across regions with Class B electrograms were predicative of the inducibility of VT, the Class C areas becoming the common

pathways of figure-of-8 VTs.85 Whether these findings apply to humans remains to be seen.141 Bipolar epicardial electrograms from infarcted areas in both dogs and in humans show reduced amplitude and increased duration and permit accurate localization of infarcts in both dogs122 and humans.122,123 Intramural electrograms

Unipolar complexes from intrainfarction terminals have a QS form.11 In canine subendocardial MI, unipolar electrograms from terminals between the scar and the epicardium have a Qr or Qrs

INTERPRETATION OF CARDIAC ELECTROGRAMS morphology with small r waves (called embryonic r waves), which gradually increase in size toward the epicardium with progressively later intrinsic deflections.11 Bipolar electrograms have a low voltage, are notched, and, by their polarity, indicate predominant outward spread of activation.11 Again, human clinical data and canine experimental data correlate well.112 Intramural unipolar electrograms from all layers of canine transmural MIs show a QS complex synchronous with the LV-CC,11 which results from the unopposed transmission of cavity potential through the ventricular scar.11,132,133 In a scar completely deprived of muscular tissue, the unipolar QS complexes are smooth and the bipolar complexes broad, smooth, and of small amplitude.11 If the scar contains viable muscle fibers, fractionated unipolar and bipolar electrograms can be recorded.11 A classification of canine heart tissue as normal or infarcted based on peak amplitude and maximum slope of intramural unipolar and bipolar electrograms has been proposed.139 Endocardial electrograms

In canine experiments, Purkinje spikes recorded by endocardial electrode terminals have been reported to fall within normal limits.11,112 In human chronic MI, the activation of the endocardial surface over the MI is delayed.95 Fractionated Electrograms Since Durrer et al.120 reported "small, fast deflections" some 75 ms after the beginning of the QRS complex in electrograms over a canine transmural infarct (Figure 5), similar potentials have been recorded in dogs with acute125,142 and chronic11,143,144 MI as well as in patients with chronic MI during intraoperative

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Figure 5. Durrer's original tracings of fractionated electrograms over a transmural canine infarct. Multiple small amplitude deflections occurring 75 ms after the beginning of the QRS complex are recorded in both the local bipolar (top) and unipolar (bottom) electrogram. Reproduced from reference 120, with permission.

mapping112,140,145-150 and endocardial catheter mapping147,151-154 and in patients with arrhythmogenic RV disease.155—157 Electrograms or potentials have been termed late or delayed if they show ventricular activity after the end of the surface QRS complex21,150,152or if they occur "later than normal"158 or are clearly separated from the normal myocardial activation pattern.140 They have been termed fractionated or fragmented if they show several low-amplitude deflections of typically less than 1 mV.158 Late or fractionated potentials can be recorded during sinus rhythm and VT. The term continuous electrical activity denotes a fractionated electrogram that lasts throughout the cycle during VT159 and which is assumed to represent a composite recording of the electrical activity of a reentry circuit.143,160

30 CARDIAC MAPPING The morphology of late potentials is dependent on the recording technique.21 Endocardial bipolar recordings from mapping catheters with 10-mm interelectrode distance show a QRS synchronous potential followed by multiple smaller potentials of amplitudes of less than 1 mV during the ST segment.21,159 Bipolar recordings based on 1-mm interelectrode distance during intraoperative mapping may show one of the following patterns: after QRS synchronous potential, which may be normal,145 small and broad,21 or absent,145 or a delayed sharp potential of high amplitude follows and is often succeeded by another of similar morphology but with different orientation, or the QRS synchronous signal is followed by multiple fragmented potentials.21,145 Unipolar electrograms may show 1 of 3 patterns: a single, rapid biphasic deflection of rs morphology following a wide QS potential, a double rs deflection, or fragmentation with multiple deflections.140 Although fractionated electrograms can be artifacts resulting from distant activation fronts,158 electrode motion,151,161 filter ringing,162 or other sources,18 most instances of late potentials represent true cardiac potentials.158,159,163 According to the experiments in canine chronic MI by Gardner et al.,164 fractionation of electrograms is caused by asynchronous excitation of different poorly interconnected viable muscle fibers separated by fibrosis; the small amplitude of fractionated electrograms is the consequence of the scarcity of myocardium next to the electrode, TMPs in these regions being normal.164 The clinical significance of late fractionated electrograms lies in the fact that they are markers for the electrical and morphological milieu required for VTs.158,165 Among patients with chronic MI, late fractionated electrograms have been recorded more frequently in those with VT than in those without VT.145–147 In patients with VT, however, neither fractionated nor late

electrograms are specific to the site of origin of VT148,149,152 nor are they present at all sites of origin.148,149,152 Artifacts Artifacts in electrograms can be produced at all the different levels of a modern mapping system: electrodes, amplifiers, filters,148,158,162 analog multiplexors,166 analog-to-digital converters,167,168 and the data storage and display system. As a treatise of the technical aspects of multichannel mapping systems169 is beyond the scope of this chapter, our discussion is restricted to artifacts occurring at the level of the electrodes. Local myocardial injury by electrodes results in ST segment elevation in the local unipolar electrogram.56 Polarization of electrodes can cause slow shifts of the baseline of the signals. Electrodes may record pacing artifacts or 50-Hz or 60-Hz noise. Motion artifacts, which are often rhythmic and repeating,158,161 can be sudden shifts of potential,56 which computer algorithms often misinterpret as activations,80 or may mimic fractionated electrograms.158,161 Poor contact between electrode and myocardium leads to wide complexes in bipolar electrograms with heavier weighing of far-field effects and increased 50-Hz or 60-Hz noise.82 Finally, while all noncoaxial bipolar electrodes ignore activation fronts parallel to the line between the electrode terminals,6,22 widely spaced bipolar electrodes may also record a symmetric complex of 2 deflections if a single small activation front passes by.21,82 Conclusion This chapter presents an overview of major aspects of the interpretation of human ventricular electrograms in sinus rhythm. Though most of what is presented is not new, this information is

INTERPRETATION OF CARDIAC ELECTROGRAMS scattered among many articles. With the exception of Kupersmith's review of intraoperative mapping from 1976,17 there seemed to be no single text that could serve as an introduction for newcomers to the method of cardiac mapping, while the historical basis from much of what is now accepted fact appeared to have been largely forgotten. Indeed, we hope that this chapter may be a due tribute to the pioneers of cardiac mapping without whom mapping would not be what it is now: the gold standard in cardiac electrophysiology. Summary Simultaneous recordings of the TMP and of the local electrogram and theoretical models with computer simulations have shown that the time of myocardial activation, defined as the time of the maximum upstroke in the TMP and the time of the maximum downstroke in the local unipolar electrogram, practically coincide with deviations of less than 1 ms in most, though not all, conditions. For activation detection in unipolar leads, there is universal agreement on computer algorithms using the criterion of "maximum downslope." The main controversy is about the optimum slope threshold for distinguishing local from distant activation, recommended thresholds ranging from -0.2 to -2.5 mV/ms. The advantage of bipolar leads lies in the distinction of local versus distant activity, their disadvantage is their directional sensitivity. Among the various algorithms for activation detection, morphological computer algorithms perform the best under practical conditions. Among the simple algorithms, the peak algorithm corresponds the closest with the times of the maximum downslope in simultaneous unipolar leads. During sinus rhythm in the normal heart, the typical unipolar RV epicardial

31

complex has an rS morphology predominantly reflecting activation of the LV. The typical epicardial complexes of the LV are an rS or qrS complex over an anterior wall, a qRS complex over the lateral wall, and a qRs complex over the posterior wall. Q waves of up to 32 ms are typical of the lateral and posterior LV wall. In WPW syndrome, a QS morphology of unipolar epicardial electrograms in the preexcited area indicates epicardial location of the accessory pathway and an rS morphology endocardial location. The characteristic changes of unipolar epicardial complexes during acute ischemia are a reduced amplitude of the initial negative deflection, a tall R wave with or without a shallow intrinsic deflection after the peak of the R, massive ST segment elevation, and TQ segment depression. Unipolar epicardial electrograms overlying subendocardial MI typically show an abnormally deep and long Q wave and a tall R wave with a delayed intrinsic deflection. The typical unipolar complex over a transmural MI is a QS complex, which is synchronous with the LV-CC and which may be smooth or fractionated. Fractionated electrograms consist of several low-amplitude deflections after the QRS complex. They are caused by asynchronous excitation of poorly interconnected muscle fibers and indicate that the electrophysiological milieu for ventricular arrhythmias to occur is present. References 1. Lewis T, Rothschild MA. The excitatory process in the dog's heart. Part II. The ventricles. Philos Trans R Soc Lond [Biol] 1915;206B: 181-226. 2. Samojloff A. Weitere Beiträge zur Elektrophysiologie des Herzens. Pflugers Arch 1910;135:417-468. 3. Lewis T. The Mechanism and Graphic Representation of the Heart Beat. 3rd ed. London: Shaw and Sons; 1925:55.

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4. Wenckebach KF, Winterberg H. Die unregelmäßige Herztätigkeit. Leipzig: Verlag von Wilhelm Engelmann; 1927: 44. 5. Gallagher JJ, Kasell J, Sealy WC, et al. Epicardial mapping in the Wolff-ParkinsonWhite syndrome. Circulation 1978;57: 854-866. 6. Ideker RE, Smith WM, Blanchard SM, et al. The assumptions of isochronal cardiac mapping. Pacing Clin Electrophysiol 1989;12:456–478. 7. Ershler PR, Lux RL. Derivative mapping in the study of activation sequence during ventricular tachyarrhythmias. IEEE Proc Comput Cardiol 1987;623624. 8. Barnes AR, Pardee HEB, White PD, et al. Standardization of precordial leads: Joint recommendations of the American Heart Association and the Cardiac Society of Great Britain and Ireland. Am Heart J 1938;15:107-108. 9. Burch GE, DePasquale NP. A History of Electrocardiography. Chicago: Year Book Medical Publishers; 1964. 10. Berbari EJ, Lander P, Sherlag BJ, et al. Ambiguities of epicardial mapping. J Electrocardiol 1991;24(Suppl): 16-20. 11. Durrer D, Van Lier AAW, Buller J. Epicardial and intramural excitation in chronic myocardial infarction. Am Heart J1964;68:765-776. 12. Wilson FN, Johnston FD, Macleod AG, et al. Electrocardiograms that represent the potential variations of a single electrode. Am Heart J 1934;9:447-458. 13. Wilson FN, Macleod AG, Barker PS. The Distribution of the Currents of Action and of Injury Displayed by Heart Muscle and Other Excitable Tissues. (University of Michigan Studies, Scientific Series. Vol. X.) Ann Arbor: University of Michigan Press; 1933. 14. Schaefer H, Haas HG. Electrocardiography. In: Hamilton WF, Dow P (eds): Handbook of Physiology. Section 2: Circulation. Vol. I. Washington, DC: American Physiological Society; 1962:323–415. 15. Scher AM. The sequence of ventricular excitation. Am J Cardiol 1964;14:287-293. 16. Scher AM, Young AC. Ventricular depolarization and the genesis of the QRS. Ann N YAcad Sci 1957;65:768-778. 17. Kupersmith J. Electrophysiologic mapping during open heart surgery. Prog Cardiovasc Dis 1976;19:167-202.

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of its uses and limitations. Circulation 1972;46:601-613. 93. Josephson ME, Horowitz LN, Spielman SR, et al. Role of catheter mapping in the preoperative evaluation of ventricular tachycardia. Am J Cardiol 1982;49: 207-220. 94. Cassidy DM, Vassallo JA, Marchlinski FE, et al. Endocardial mapping in humans in sinus rhythm with normal left ventricles: Activation patterns and characteristics of electrograms. Circulation 1984;70:37-42. 95. Vassallo JS, Cassidy DM, Marchlinksi FE, et al. Abnormalities of endocardial activation pattern in patients with previous healed myocardial infarction and ventricular tachycardia. Am J Cardiol 1986;58:479-484. 96. Smith WM, Wharton JM, Blanchard SM, et al. Direct cardiac mapping. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology: From Cell to Bedside. Philadelphia: W.B. Saunders Co.; 1990:849-858. 97. Downar E, Harris L, Mickleborough LL. Direct cardiac mapping of ventricular arrhythmias. Prog Cardiol 1987;1:273288. 98. Josephson ME, Miller JM, Hargrove WC III, et al. Intraoperative mapping of ventricular tachycardia associated with coronary artery disease. In: Aliot E, Lazzara R (eds): Ventricular Tachycardia: From Mechanism to Therapy. Boston: Martinus Nijhoff Publishers; 1987:411-436. 99. Tyagii S, Sharma AD, Guiraudon G, et al. Intraoperative cardiac mapping of preexcitation syndromes and ventricular tachycardia. J Electrophysiol 1989;3: 47-64. 100. Shenasa M, Cardinal R, Savard P, et al. Cardiac mapping. Part I. Wolff-ParkinsonWhite syndrome. Pacing Clin Electrophysiol 1990; 12:223-230. 101. Spach MS, Barr RC. Ventricular intramural and potential distributions during ventricular activation and repolarisation in the intact dog. Circ Res 1975;37:243257. 102. Barker PS, Macleod AG, Alexander J. The excitatory process observed in the exposed human heart. Am Heart J 1930; 5:720-742. 103. Jouve A, Corriol J, Torresani J, et al. Epicardial leads in man. Am Heart J 1960;59:856-868.

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137. Daniel TM, Cox JL, Sabiston DC Jr, et al. Epicardial and intramural mapping of activation of the human heart—a technique for localizing infarction and ischemia of the myocardium. Circulation 1969;39(Suppl III):III-66. Abstract. 138. Daniel TM, Boineau JP, Cox JL, et al. Mapping of epicardial and intramural activation of the heart: A technique for localization of chronic infarction during myocardial revascularisation. J Thorac Cardiovasc Surg 1970;60:704-709. 139. Claydon FJ, Pilkington TC, Ideker RE. Classification of heart tissue from bipolar and unipolar intramural potentials. IEEE Trans Biomed Eng 1985;32:513520. 140. Lacroix D, Savard P, Shenasa M, et al. Spatial domain analysis of late ventricular potentials: Intraoperative and thoracic correlations. Circ Res 1990;66:55-68. 141. Ideker RE, Tang ASL, Daubert JP. On the trail of ventricular tachycardia or the adventure of the unspeckled band. Pacing Clin Electrophysiol 1988;11:650-655. Editorial. 142. Boineau JP, Cox JL. Slow ventricular activation in acute myocardial infarction. A source of re-entrant premature ventricular contractions. Circulation 1973;48: 702-713. 143. El-Sherif N, Scherlag BJ, Lazzara R, et al. Re-entrant ventricular arrhythmias in the late myocardial infarction period. 1. Conduction characteristics in the infarction zone. Circulation 1977;55:686702. 144. Berbari EJ, Scherlag BJ, Hope RR, et al. Recording from the body surface of arrhythmogenic ventricular activity during the S-T segment. Am J Cardiol 1978;41:697-702. 145. Klein H, Karp RB, Kouchoukos NT, et al. Intraoperative electrophysiologic mapping of the ventricles during sinus rhythm in patients with a previous myocardial infarction: Identification of the electrophysiologic substrate of ventricular arrhythmias. Circulation 1982;66: 847-853. 146. Wiener I, Mindich B, Pitchon R. Determinants of ventricular tachycardia in patients with ventricular aneurysms: Results of intraoperative epicardial and endocardial mapping. Circulation 1982;65: 856-861.

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147. Simson MB, Untereker WJ, Spielman SR, et al. Relation between late potentials on the body surface and directly recorded fragmented electrograms in patients with ventricular tachycardia. AmJCardiol 1983;51:105-112. 148. Kienzle MG, Miller J, Falcone RA, et al. Intraoperative endocardial mapping during sinus rhythm: Relationship to the site of origin of ventricular tachycardia. Circulation 1984;70:957-965. 149. Vassallo JA, Cassidy DM, Simson MB, et al. Relation of late potentials to site of origin of ventricular tachycardia associated with coronary heart disease. Am J Cardiol 1985;55:985-989. 150. Schwarzmaier H-J, Karbenn U, Borggrefe M, et al. Relation between ventricular late endocardial activity during intraoperative endocardial mapping and lowamplitude signals within the terminal QRS complex on the signal-averaged surface electrocardiogram. Am J Cardiol 1990;66:308-314. 151. Waxman HL, Sung RJ. Significance of fragmented ventricular electrograms observed using intracardiac recording techniques in man. Circulation 1980;6: 1349-1356. 152. Cassidy DM, Vassallo JA, Buxton AE, et al. The value of catheter mapping during sinus rhythm to localize the site of origin of ventricular tachycardia. Circulation 1984;69:1103-1110. 153. Cassidy DM, Vassallo JA, Buxton AE, et al. Catheter mapping during sinus rhythm: Relation of local electrogram duration to ventricular cycle length. Am J Cardiol 1985;55:713-716. 154. Stevenson WG, Weiss JN, Wiener IW, et al. Fractionated endocardial electrograms are associated with slow conduction in humans: Evidence from pace-mapping. J Am Coll Cardiol 1989; 13:369-376. 155. Fontaine G, Frank R, Gallais-Hamonno F, et al. Electrocardiographie des potentiels tardifs du syndrome de post-excitation. Arch Mal Coeur 1978;71:854-864. 156. Marcus FI, Fontaine GH, Guiraudon GM, et al. Right ventricular dysplasia: A report of 24 adult cases. Circulation 1982;65:384-398. 157. Fontaine G, Frank R, Tonet JL, et al. The Mikamo lecture. Arrhythmogenic right ventricular dysplasia: A clinical model for the study of chronic ventricular tachycardia. Jpn Circ J 1984;48: 515-538.

158. Ideker RE, Mirvis DM, Smith WM. Late, fractionated potentials. Am J Cardiol 1985;55:1614-1621. Editorial. 159. Josephson ME, Wit AL. Fractionated electrical activity and continuous electrical activity: Fact or artifact? Circulation 1984;70:529-532. Editorial. 160. Josephson ME, Horowitz LN, Farshidi A. Continuous local electrical activity: A mechanism of recurrent ventricular tachycardia. Circulation 1978;57:659-665. 161. Ideker RE, Lofland GK, Bardy GH, et al. Late fractionated potentials and continuous electrical activity caused by electrode motion. Pacing Clin Electrophysiol 1983;6:908–914. 162. Simson MB. Use of signals in the terminal QRS complex to identify patients with ventricular tachycardia after myocardial infarction. Circulation 1981;64:235— 242. 163. Wit AL, Josephson ME. Fractionated electrograms and continuous activity: Fact or artifact. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology and Arrhythmias. Orlando: Grune & Stratton, Inc.; 1985:343-352. 164. Gardner PI, Ursell P, Fenoglio JJ Jr, et al. Electrophysiologic and anatomic basis for fractionated electrograms recorded from healed myocardial infarcts. Circulation 1985;72:596–611. 165. Breithardt G, Borggrefe M, MartinezRubio A, et al. Pathophysiological mechanisms of ventricular tachyarrhythmias. Eur Heart J 1989;10(Suppl E):9-18. 166. Hoeks APG, Schmitz GML, Allessie MA, et al. Multichannel storage and display system to record the electrical activity of the heart. Med Biol Eng Comput 1988; 26:434–438. 167. Barr RC, Spach MS. Sampling rates required for digital recording of intracellular and extracellular cardiac potentials. Circulation 1977;55:40–48. 168. Pieper CF, Lawrie G, Roberts R, et al. Bandwidth-induced errors in parameters used for automated activation time determination during computerized intraoperative cardiac mapping: Theoretical limits. Pacing Clin Electrophysiol 1991;14:214-226. 169. Ideker RE, Smith WM, Wolff P, et al. Simultaneous multichannel cardiac mapping system. Pacing Clin Electrophysiol 1987;10:281-292. 170. Smith WM, Ideker RE, Kinicki RE, et al. A computer system for the intraoperative

INTERPRETATION OF CARDIAC ELECTROGRAMS mapping of ventricular arrhythmias. Comput Biomed Res 1980;13:61-72. 171. Parson I, Mendler P, Downar E. On-line cardiac mapping: An analog approach using video and multiplexing techniques. Am J Physiol 1982;242:H526–H535. 172. Parson I, Downar E. Clinical instrumentation for the intra-operative mapping of ventricular arrhythmias. Pacing Clin Electrophysiol 1984;7:683-692. 173. Rosenfeldt FL, Harper RW, Wall RE, et al. A digital timing and display unit for intra operative mapping of cardiac arrhythmias.

Pacing Clin Electrophysiol 1984;7:985–992. 174. Witkowski FX, Corr PB. An automated simultaneous transmural cardiac mapping system. Am J Physiol 1984;247: H661-H668.

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175. Rosenbaum DS, Kaplan DT, Wilbur DJ, et al. The precision of electrophysiologi

cal mapping: Localizing depolarization

wave front from digital extracellular electrograms and the role of data sampling rate. J Cardiovasc Electrophysiol 1990;1:2-14. 176. Sano T, Tsuchiahashi H, Shimamoto T. Ventricular fibrillation studied by the microelectrode method. Circ Res 1958: 41-46. 177. Spach MS, Miller WTII, Geselowitz DB, et al. The discontinuous nature of propagation in normal canine cardiac muscle. Evidence for recurrent discontinuities of intracellular resistance that affect the membrane currents. Circ Res 1981;48: 39-54.

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Chapter 3 Methodology of Cardiac Mapping Haris J. Sih, PhD and Edward ]. Berbari, PhD

Cardiac mapping involves making some measurement of the heart in 3-dimensional space and then displaying that measurement on a similar 3-dimensional representation. That measurement could be of its mechanical function, electrical function, structure, or some combination of these. To add further complexity, the measurement itself could be a value (such as activation time) or an array (such as conduction velocity, with a magnitude and direction). In the current literature, cardiac mapping usually refers to measuring the electrical activity of the heart in 2 or 3 dimensions and displaying that activity on 2-dimensional representations. The electrical activity is often activation times or isopotentials that are measured directly from electrodes in contact with the tissue or are calculated from body surface electrodes or other electrodes that are not in contact with the tissue. This chapter provides a brief introduction into the techniques of this category of cardiac mapping, and then illustrates how we have dealt with some typical complications to this type of mapping in infarct regions and during atrial fibrillation.

Overview of Current Techniques Most electrical mapping of the heart is done with either unipolar or bipolar electrodes and with either simultaneous multielectrode arrays or sequential recordings from several electrodes on the distal end of a catheter. A unipolar (or single-ended) measurement is usually made relative to some distant, stable reference on the body, the exact position of which is generally not considered critical to the data acquisition. A bipolar (or differential) measurement is between 2 electrodes that are often closely (100). Endocardial map- Webster, Diamond Bar, CA) is essentially ping can be accomplished with basket a sequential mapping system with a catheters, which have electrodes placed sophisticated display.2,3 This system places on thin wire-like splines. When the catheter a catheter tip in an electromagnetic field is inserted into a vein or artery, the and then uses the field to register the splines are contracted to fit into the diam- 3-dimensional location and orientation of eter of the catheter. Once in the chamber the catheter simultaneously with the of interest, the splines are expanded like recorded electrical activity. This allows for the opening of an umbrella, and the elec- a 3-dimensional reconstruction of the endotrodes are exposed and are hopefully in cardial surface and the activation sequence contact with the tissue. While basket across that surface. While this system aids catheters allow for closed-chest, endocar in the visualization of activation, it is still dial recordings, they are limited by sev- limited by its sequential mapping capabileral factors, including the lack of control ities, making it an ineffective tool for mapover which electrodes are in contact with ping nonrepetitive arrhythmias. The EnSite™ system (Endocardial the tissue, unevenly spaced electrodes between splines, and the difficulty in pre- Solutions, Inc., St. Paul, MN) is a multielectrode recording system that records cise anatomical location of the splines.

METHODOLOGY OF CARDIAC MAPPING from 64 sites on a noncontact balloon catheter then reconstructs the endocardial recordings on an ellipsoid-like projection of the endocardium using inverse solution techniques.4 This system changes the definition of spatial resolution for cardiac maps, since "virtual" electrograms can be reconstructed from nearly anywhere on the endocardial projection. The EnSite system can reconstruct activation sequences on the endocardial projection for either repetitive or nonrepetitive arrhythmias. Whether this system can be used to study mechanisms of arrhythmias with high spatial frequency content remains to be determined. As digital hardware speeds have gone up and their prices have come down, the conceivable number of simultaneous channels that can be acquired has increased. However, data management issues, such as electrogram display/review, activation visualization, etc., are more problematic with ever-increasing numbers of channels. These issues are especially troublesome for studying activation in a complex substrate and for studying rapid and irregular rhythms. To illustrate these technical challenges, this chapter focuses on 2 specific areas of cardiac mapping: mapping late potentials and mapping atrial fibrillation. Introduction For studies of late potentials, our original interest in using cardiac mapping was to establish the fundamental bases of the late potentials seen on the body surface ECG.5 The goal was to characterize, in an animal model, the late potential generator, e.g., signal strength, position, and orientation, and to use this information to model and compare with the actual body surface recordings. This prompted a more accurate assessment of the implicit assumptions of cardiac mapping in order to improve the late potential model. Questions concerning the determination of activation time and contour generation became paramount, as

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did determining which conditions were implicitly and explicitly assumed. While several studies have been performed to correlate activation times to extracellular electrogram features, little has been studied about the mechanics of contour generation for activation maps. Some investigators use a visual approach and manually draw the maps. Others use "canned" contour programs available in scientific subroutine software libraries, and still others use custom-written software. Only a few references exist on the mechanics of contour generation as applied to cardiac activation.6–9 The field of cartography has evolved around, and is usually applied to, geophysical problems,10,11 but a number of newer methods have been used in recent years. It is difficult to determine the extent to which these newer methods have been used in either the published reports or from commercial vendors in cardiac applications. It is our belief that many conclusions about activation sequences have been deduced from poorly constructed contour maps. Some general issues have been discussed by Ideker et al.12 In essence, a fundamental assumption about the underlying structure of activation is implicitly or explicitly made without regard to problems concerning spatial sampling or the assumption of spatial continuity. However, there have been no formal attempts to define the spatial sampling necessary for cardiac activation maps. Spatial continuity is the 2-dimensional property similar to time domain continuity. Most linear mathematical approaches to signal processing require that there be no abrupt changes in the values of the measured quantity; that is, the time derivatives are not infinite. This is also true for the 2dimensional problem where the spatial derivatives are not infinite. In other words, no point in the spatial representation can be multivalued. Unfortunately, mapping in infarct regions almost assures

44 CARDIAC MAPPING discontinuous regions. The inhomogeneity in conduction properties is well known and the presence of dead tissue, i.e., nonconducting regions, must be accounted for in the contour generation process. In geophysical terms, such discontinuities are called faults, and generating contours around a fault region should be considered in cardiac map generation. For atrial fibrillation mapping, the goal has been to use cardiac maps to probe the mechanisms of atrial fibrillation. Some early examples of the successful application of multielectrode mapping to study atrial fibrillation were performed by Allessie et al.13,14 In these studies, the authors were able to verify a long-standing hypothesis on the multiple circulating wavelet behavior of atrial fibrillation.15 One of the greatest complications associated with activation mapping during atrial fibrillation is that the very nature of atrial fibrillation may preclude a succinct presentation of activation. Since a hallmark of atrial fibrillation is its nonrepetitive activation of the atria, categorizing activation can be difficult. Cox et al.16 provided one framework with which to conceptualize possible reentrant patterns during atrial fibrillation by describing the locations of reentrant circuits and how they might activate the atria. More recently, Konings et al.17 categorized activation patterns according to the number of wavelets and the degree of conduction block observed in activation maps. Many other studies resort to a subjective description of the various patterns or the relative complexity of activation with the only quantitative data being cycle length or conduction velocity data. While these observations can be insightful and important, more quantitative measures of activation are needed in order to compare and contrast atrial fibrillation maps. One of our hypotheses is that atrial activation during atrial fibrillation has transient episodes of organization and

that the organization can be quantified. We propose that an organization map may provide new insights into atrial fibrillation mechanisms that could not otherwise be easily discerned with traditional epicardial mapping techniques. Methods

Our mapping system technology has been described previously18,19 and is briefly summarized. The front end consisted of 128 differential amplifiers with programmable gain and bandwidth. Typical settings were a gain of 100 and a bandwidth of 0.1 to 300 Hz. Each signal was sampled at 1000 Hz with a high-speed analog-todigital converter and an interchannel dwell time of 2.0 µs resulting in a maximum time skew of 0.26 ms between channels \ and 128. For late potential mapping, the electrode array was a unipolar 10x10 square grid with a 4-mm spacing between electrode centers. Each side had 6 electrodes, which "rounded out" the edges for a total of 124 epicardial sites within a 6-cm diameter. The remaining 4 channels were for bipolar surface ECG leads. The signal reference was the right leg. The data acquisition computer was an SLS-5450 (Concurrent Computer Corporation, Westford, MA) and was networked to an IBM RS6000 (IBM, Armonk, NY) for data analysis. Experimental data were obtained from the 4-dayold canine infarct model.20 The left anterior descending coronary artery was ligated using the Harris 2-stage tie21 just inferior to the first diagonal branch. All recordings were made during sinus rhythm. For our initial atrial fibrillation studies, we used a commercially available array to epicardially map canine atria during different rhythms. This array had 112 unipolar electrodes in an 8 x 14 grid spanning 2x4 cm. The elements had approximately 1-mm-diameter tips and were constructed of stainless steel. Because of the size of the array, only sections of the

METHODOLOGY OF CARDIAC MAPPING 45 atria could be mapped at any one time. These sequential maps were obtained from the right or left atrial free walls or from the right or left atrial appendages. Two atrial fibrillation models were used: vagal atrial fibrillation induced by atrial burst pacing with superimposed vagal stimulation,22 or self-sustained atrial fibrillation induced by chronic (>4 weeks), continuous rapid atrial pacing.23–25 In our initial experiments on atrial fibrillation organization, we devised a simple algorithm that quantifies the degree of nonlinearity between 2 electrograms on a relatively short time scale (72 hours).130 The region in which reentry occurs in infarcted ventricles has been localized to the surviving borders of healing or healed myocardial infarcts.116,130,144,145 The site of origin of arrhythmias at these later periods depends on the location of the surviving myocardial cells in and around the infarcted region that form the infarct border zone. The electrophysiological mechanisms causing these arrhythmias (functional or anatomical reentry) depend on the anatomical arrangement of the surviving myocardium and the alterations in their membrane function. In that reentry requires an electrophysiological substrate that includes regions of slow conduction and block, the demonstration of abnormal conduction in infarct border zone myocardium with normal, or near normal, action potential depolarization phases130,146,147 indicates that structural remodeling of the constituent myocytes, and in particular the changing balance of longitudinal and transverse connections between them that influence the anisotropic properties, may be an important determinant of arrhythmogenesis.148 Patients with sustained VT often have a large area of solid, homogeneous infarct, which may include the septum and which extends around much of the circumference of the ventricular cavity, from the anterior to the lateral wall.149 The solid infarct may be transmural in that it extends from the subendocardium into the subepicardium. On the subepicardial surface over solid infarct, there is patchy infarct and surviving subepicardial muscle, the epicardial border zone in which reentrant circuits sometimes occur. Older infarcts are composed of larger areas of patchy infarct and thinner epicardial border zones. Surviving subepicardial muscle cells can be found even in ventricular aneurysms. Similarly, in canine models of myocardial infarction caused by com-

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plete occlusion of a main coronary artery such as the left anterior descending (LAD), a narrow layer of epicardial muscle (epicardial border zone) survives over the region of solid transmural infarction.116,150,151 Muscle fibers on the epicardial surface of transmural anteroseptal canine infarcts caused by permanent occlusion of the LAD near its origin survive because they still receive blood flow from epicardial branches of the circumflex artery or from collaterals of the LAD that anastomose with the patent circumflex. A redistribution of coronary blood flow from necrotic endocardial layers to surviving epicardial ones may also maintain their viability.152 A narrow "ribbon" consisting of Purkinje fibers, and sometimes ventricular muscle, survives between the subendocardial surface of the solid infarct and the ventricular cavity in both human and experimental infarcts—the subendocardial border zone.149,153,154 Subendocardial scarring and trapping of myocardial fibers in a subendocardial scar may also extend into areas around the periphery of infarcts. This is most often the site of origin of VT in human infarcts.155 In some hearts, bundles of myocardial fibers extend from the subendocardial border zone or lateral border zone, deeper into the subendocardium, and also into midmyocardial regions of the solid infarct, forming subendocardial or intramural conducting pathways.130,145 Tracts of subendocardial and intramural muscle bundles may sometimes form reentrant circuits. The epicardial border zone is an important site of arrhythmia origin in healing experimental (canine) infarcts.116,151,156 Although there is some evidence that clinical arrhythmias sometimes arise in this region,157 it is probably not the primary site of origin of most clinical VTs. The microscopic anatomy (architecture) of the border zone of surviving epicardial muscle in canine infarcts has important influences

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on impulse conduction in this region that cause arrhythmias in the experimental model. The microscopic anatomy also changes with time as the infarct heals, causing time-dependent changes in conduction properties. The influences of architecture on conduction as determined in this model can be applied to border zones in human infarcts and provide information relevant to the origin of clinical tachycardias. The surviving muscle fibers in the epicardial border zone are arranged parallel to one another during the healing phase of myocardial infarction (first week after coronary occlusion). The long axis of the muscle fiber bundles is perpendicular to the LAD and extends from the coronary artery toward the lateral LV and apex,116,158 the same orientation as epicardial muscle fibers in the noninfarcted anterior LV.126 The muscle fibers may be either tightly packed together, as they are in the normal subepicardium, or they may be separated by edema that is commonly seen in a healing infarct (Figure 8). The parallel orientation forms an anisotropic structure that has important influences on conduction properties that may cause reentry. The intracellular ultrastructure of the surviving muscle fibers is mostly normal except for the accumulation of large amounts of lipid droplets that may be a reflection of changes in metabolism of the cells. However, a striking change in structure of this region is an abnormal distribution of gap-junctional interconnections among cells that occurs by 4 days after coronary occlusion.159 Although the surviving myocytes in the border zone adjacent to necrotic cells have normal histological features, they have varying degrees of disruption of gap junction distribution, as shown by immunolabeling of connexin43 (Figure 9), similar to that which has also been described in healed human infarcts (described in the next section). Connexin43 is distributed

around the entire cell surface, with a large amount located along the lateral membrane (Figure 9). This disturbance occurs early after infarction as a primary pathophysiological response of these cells, prior to the physical disruption of intercellular connections by extrinsic fibrotic scarring and distortion that occurs later in the healing and healed phases (see next section). The disturbed gap-junctional pattern is most prominent immediately abutting the necrotic tissue, and extends through the border zone toward the epicardial surface to a distance of up to 840 (im from the interface with the necrotic myocardium. In most regions disturbed gap-junctional distribution does not extend throughout the full thickness of the epicardial border zone, the distribution of connexin43 in myocytes closest to the epicardial surface and most distant from necrotic tissue being in the normal transversely oriented pattern describing the locations of the normal intercalated disks (partial-thickness gap-junctional disarray) (Figure 10). In thinner regions of the epicardial border zone, however, the layer of disturbed gap-junctional distribution extends throughout the entire thickness of the surviving epicardial border zone, all the way to the epicardial surface (Figure 10). The arrangement of the muscle fiber bundles and the alterations in intercellular connections as indicated by the altered connexin43 distribution are both associated with nonuniform anisotropic properties of conduction in the canine epicardial border zone and related to the mechanisms of arrhythmogenesis.116'148 The nonuniform anisotropic properties are illustrated in Figure 11 (left panel), which shows a map of impulse propagation in the epicardial border zone of a 4day-old canine infarct when the border zone was stimulated in the center of the anterior wall of the LV. Rapid activation toward the margin of the anterior LV

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Figure 8. Photomicrographs of the parallel oriented surviving muscle fibers in the epicardial border zone of a healing canine infarct (4 days old). In some regions fibers are widely separated (A), while in others (B), they are more closely packed together. Reproduced from reference 116, with permission.

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Figure 9. Confocal micrographs of connexin43-labeled canine infarct epicardial border zone myocardium, 4 days after left anterior descending artery ligation. A. The necrotic infarct (inf) is free of label, but the surviving myocytes abutting the infarct show grossly abnormal connexin43 gap junction distribution with label distributed all around the cell borders. B. A transmural section showing orderly, predominantly transversely orientated arrays of label abutting the epicardium at the top of the micrograph, contrasting with the abnormal longitudinal arrays in the myocytes abutting the label-free infarct beneath. Note the frequently observed absence of label along the border of the myocytes immediately abutting the infarct. A x700, B x300. Reproduced from reference 159, with permission.

Figure 10. Schematic representation of connexin43-immunolabeled epicardial border zone of 4day-old canine infarct showing the distinction between partial-thickness (to left of diagram) and fullthickness (to right of diagram) disturbance of connexin43 gap-junctional distribution (gj disarray). Reproduced from reference 159, with permission.

bounded by the LAD and toward the apex of the lateral left ventricle (LL) is indicated by the widely spaced isochrones. This is the direction of the long axis of the myocardial fiber bundles. Transverse to the long axis, activation is very slow and irregular as indicated by the closely bunched isochrones. Electrogram fractionation is also associated with the transverse activation.

The mechanism of the nonuniform anisotropy is uncertain. During the first 4 days after coronary occlusion, it is not a result of increased connective tissue associated with infarction,159 which is only evident at later times (see below). It is possible that the edema formation "pulls apart" muscle bundles, disrupting some of the gap-junctional connections and preferentially influencing transverse conduction.

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Figure 11. Left: Activation map of the epicardial border zone of a 4-day-old canine infarct during pacing. Each small number is the activation time at a site where an extracellular electrogram was recorded. Isochrones are drawn at 10-ms intervals and labeled with larger numbers. Margins of the recording electrode array at the left anterior descending coronary artery (LAD), base, apex, and lateral left ventricle (LL) are labeled. The border zone was stimulated in the center (pulse symbol) and activation spread toward all margins of the electrode array (arrows). Rapid activation occurred in the direction of the long axis of the myocardial fiber bundles (toward the LL and LAD margins) while very slow, nonuniform propagation occurred transverse to the long axis (toward the base and apex). Right: The activation pattern in the epicardial border zone of the same heart during sustained ventricular tachycardia induced by programmed stimulation. Two reentrant wavefronts rotate around parallel lines of functional block (thick black lines) that formed in regions of nonuniform transverse propagation (see left panel). This figure-of-8 reentrant pattern is indicated by the arrows.

The role of increased connexin43 location along lateral aspects of the cells would seem to contradict the electrophysiological findings of decreased transverse conduction; however, the functional properties of the lateral connexins have not yet been determined (discussed later). There is a relationship between regions of nonuniform anisotropic conduction and the occurrence of reentrant circuits that cause sustained VT in the canine model of infarction.116 Reentrant circuits in the epicardial border zone that cause arrhythmias are functional; they can be induced to form by programmed stimulation which initiates tachyarrhythmias. The circuits form when an appropriately timed stimulated premature impulse blocks in the epicardial border zone.116,151,156 The mechanism for block may involve anisotropic properties of this region: preferential conduction block of premature impulses in

the longitudinal direction in nonuniformly anisotropic myocardium,14 although there is also evidence for an increased refractory period at the site of block.156 There is also a relationship between regions of nonuniform anisotropic conduction and the location of the functional lines of block of stable reentrant circuits that cause sustained VT. These are not the same lines of block that occur during premature stimulation. The right panel of Figure 11 is an activation map of the reentrant circuit that formed to cause a sustained VT initiated by programmed ventricular stimulation in the same heart in which the nonuniform anisotropic activation pattern was described in the left panel of Figure 11. The map illustrates activation occurring in a figure-of-8 reentrant pattern.156 The reentrant wavefront propagates around 2 lines of functional conduction block indicated by the thick

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black lines. These lines of block formed in the regions of very slow transverse propagation resulting from the nonuniform anisotropic conduction characteristics of this area. The exact mechanism for block has not been determined but there appears to be failure of transverse propagation during the tachycardia. Sometimes very slow conduction also occurs across parts of the lines of block (pseudoblock) transverse to the long axis of the myocardial fibers.116 The formation of long lines of stable functional block and the slow activation around the ends of the lines of block that occurs transverse to the long axis of the fiber bundles are necessary for the occurrence of sustained tachycardia. When these block lines do not form, perhaps because of insufficient nonuniform anisotropy, unsustained VT or ventricular fibrillation, but not sustained tachycardia, occur. Functional reentrant circuits in which lines of block form in regions of nonuniform anisotropy and in which much of the slow activation necessary for reentry to occur is caused by slow nonuniform anisotropic conduction around the ends of the lines of block, is called anisotropic reentry.148 Although the mechanisms for the formation of the functional lines of block in anisotropic reentrant circuits has not yet been completely elucidated, the relationship between the regions in which they form and the microscopic anatomy of those regions may be relevant.159 Stable reentrant circuits associated with sustained, monomorphic VT in the canine model of infarction occur in the very thin areas of the epicardial border zone where the altered distribution of connexin43 extends throughout its full thickness. Boundaries between these regions with full-thickness abnormalities and adjacent regions that have more layers of surviving cells, and abnormal connexin43 distribution extending only part way through the epicardial border zone, are the locations

of the functional lines of block in the reentrant circuits.159 This relationship is shown in Figure 12. The top panel is an activation map of a figure-of-8 reentrant circuit in the epicardial border zone of a 4-day-old canine infarct. The bottom panel shows the location of full-thickness gap-junctional disturbances (circles) and partial-thickness gap-junctional disturbances (X's) determined by fluorescent antibody techniques. The junction of the full-thickness and partial-thickness disturbance correlates with the location of the functional lines of block of the reentrant circuit. Therefore, transverse conduction is decreased in these regions, leading to the occurrence of the lines of block. Although much has been written on the role of fibrosis and increased connective tissue septation in promoting nonuniformity of propagation,11,13,122,160 an abnormal pattern of gap junction distribution in the absence of fibrotic scarring may be an important factor in the substrate for reentry after infarction. The mechanism by which the change in gapjunctional distribution causes nonuniform anisotropy and influences the location and characteristics of the reentrant circuit in this experimental model, possibly by defining the location of the lines of functional block, has yet to be determined. The abnormal redistribution of gap junctions to the lateral interfaces between myocytes might be expected to enhance (rather than impair) side-to-side coupling, thereby improving transverse conduction and reducing anisotropy. However, the presence of connexin labeling in immunohistochemical studies, the observation of morphologically recognizable gap junctions using electron microscopic techniques, or the detection of mRNA for a particular connexin must be interpreted with some caution, as these findings do not necessarily signify the presence of intact or functional gap

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Figure 12. Top: Map of activation times of a stable reentrant circuit during sustained ventricular tachycardia in the epicardial border zone of a 4day-old canine infarct. The activation times (in ms, small numbers) are shown, as are lines of isochronal activation, at 10-ms intervals (larger numbers). The lines of functional block are shown by the thick black lines. Arrows point out the activation pattern. Bottom: Map of the distribution of fullthickness disturbance of gap junction organization (o = fullthickness disturbance, x = partial-thickness disturbance) in the same 6 x 6 cm square of the epicardial border zone. The area of full-thickness gap junction disarray coincides approximately with the common central pathway of the reentrant circuit, and the borders between full-thickness and partial-thickness gap junctional array locates the line of functional block. Reproduced from reference 159, with permission.

junctions nor do they indicate the func- dosis, increased intracellular calcium) tional status of the gap junctions. Growing that may act to uncouple the border zone knowledge of the multiplicity of connexin myocytes. Furthermore, there is a conisoforms that exist in normal mammalian centration-dependent stimulation of conmyocardium 54,113 raises the additional nexin43 mRNA and protein expression, question of alterations of the relative albeit in cultured fibroblasts,161 which expression of these connexins in disease could also have an important pathophysstates.52,129 Presently, it is unknown iological role in the early healing phase whether such changes take place in the following infarction. At present, the funcsetting of myocardial ischemia or infarc- tional status of the gap junctions in these tion; but if they do, alterations in cou- border zone cells is unknown, but one pospling characteristics would be expected sibility is that the redistribution of gap to accompany them. The redistribution junctions may be a compensatory response of connexin43 in the epicardial border to substantial metabolic uncoupling in zone should, however, be considered in this tissue. Metabolic uncoupling may the context of the likely metabolic dis- reduce conductance more in the transturbances of ischemic tissue (hypoxia, aci- verse direction than longitudinal,115, 162

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and the redistribution of gap junctions to the lateral cell borders may incompletely counteract the consequent tendency to enhanced anisotropy of conduction. A similar concept of compensatory alterations of gap junctions in pathological tissue has previously been hypothesized as a possible explanation for the alterations of connexin isoform expression in myocardial hypertrophy.52 It would therefore seem possible that, under pathological conditions, myocytes may be capable of modulating the nature of their coupling to neighboring cells by varying the organization and composition of gap junctions. If the zone of full-thickness gap-junctional disturbance was characterized by selective impairment of transverse coupling, myocardial conduction between the lines of functional block (the common central pathway) would show enhanced anisotropy, with an even greater tendency than normal for this myocardium to support longitudinal conduction more than transverse (Figure 12). However, as a propagating wavefront through the common central pathway reaches the end of the region of full-thickness disturbance, its outer edges would tend to encounter myocardium with only a partial-thickness disturbance of junction distribution and with better transverse coupling particularly in the more superficial cell layers. Propagation would therefore be improved transversely, and start turning laterally. Once transverse conduction in this direction extended beyond the line of full-thickness disturbance, propagation would then occur longitudinally (in the opposite direction) through the excitable tissue lateral to, and previously protected from depolarization by, the enhanced anisotropy defining the lines of functional block. With the curvature of the limit of full-thickness gapjunctional disturbance at the other end of the lines of functional block, the parallel wavefronts in the outer pathways will, by the same mechanism, start to propagate

transversely and turn medially to coalesce, thus defining the other end of the line of functional block (Figure 12). Remodeling of experimental and human infarct structure continues as the infarcts heal, leading to further changes with time. In particular, the deposition of connective tissue and the formation of the scar can distort the normal relationship of the surviving myocardial fiber bundles.158 This in turn influences conduction characteristics. Figure 13 illustrates these changes in the epicardial border zone of canine infarcts; however similar changes occur in the subendocardial border zone or in regions where fiber bundles penetrate into the solid core of the infarct in both experimental and human infarcts. The muscle cells become trapped in the dense scar tissue formed from the adjacent infarct. In some regions myocardial fibers can become markedly separated from each other along their length.122, 146, 158 In a quantitative study on healed canine infarcts, it was found that there is a concomitant reduction in the number of cells to which each myocyte is connected, from 11.2 in normal tissue to 6.5 in the fibrotic infarct border zone, associated with a greater reduction of predominantly side-to-side cell interconnections than end-to-end.122 Connections of cells in primarily side-to-side apposition were found to be reduced by 75% whereas primarily end-to-end connections was reduced by 22%.122 Overall, these results are consistent with the hypothesis that there is reduced cellular coupling with a disproportionate increase of resistivity in the transverse direction, thus enhancing anisotropy. In canine LVs up to 10 weeks after infarction, the surviving myocardium adjacent to the healed infarct has smaller and fewer gap junctions per unit length of intercalated disk and per unit myocyte sectional area.122 A selective reduction of the larger junctions results in a decrease in the proportion of total gap junction in the interplicate segments of the intercalated disk.122

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Figure 13. Surviving epicardial border zone muscle fibers in a 2-week-old canine infarct (A and B) and in a 2-month-old canine infarct (C and D). In A, the thin surviving rim (arrows) consists of several layers of ventricular muscle cells between the epicardium and the granulation tissue of the healing infarct. These surviving cells are separated by fibrous tissue, especially adjacent to the infarct. The parallel orientation of the myocardial fibers is maintained. At high magnification (B), these myocardial cells are shown to be intact with distinct cross striations. In C, the disorganization of the surviving myocardial cells in the thin rim at 2 months is evident. The cells are widely separated and disoriented because of ingrowth of fibrous tissue from the adjacent infarct. At high magnification (D), the myocardial cells have distinct cross striations and central nuclei. The bars represent 50 jam. Reproduced from reference 158, with permission.

Immunohistochemical examination of connexin43 gap-junctional membrane in the border zone of healed human infarcts has demonstrated the occurrence of gap-junctional reorganization in addition to the reduced transverse connections described above; altered gap junction distribution occurs in surviving myocytes up to 700 [im from the interface with the fibrotic infarcted tissue (Figure 14).111 Within this border zone region, compar-

atively few labeled gap junctions are organized into discrete, transversely orientated intercalated disks, and many are spread longitudinally over the cell surface. The dispersed connexin43 is still located at cell-to-cell appositions in regions where they are not disrupted by the encroaching scar tissue (Figure 14A). Individual junctions and groups of junctions, though often maintaining intercellular gap-junctional contact, are displaced so that discrete

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Figure 14. Confocal micrographs of longitudinally sectioned connexin43-immunolabeled human ventricular myocardium from the border of a healed infarct. A. At lower power, showing the infarct scar (s) with no labeling, the highly disrupted gap-junctional distribution within about 700 jim of the scar and the normal appearances more distant from the scar (top left corner). x210. B. At high power, showing myocytes traversing densely fibrotic scar (no labeling). There is profuse label along the length of these attenuated and degenerated but viable cells. x810. Reproduced from reference 108, with permission.

intercalated disk zones are less clearly defined (Figures 14 through 16). This latter feature is most evident in healed partial-thickness myocardial infarction, in which the demarcation between scar and myocardium is least discrete, with greater interdigitation of these tissues. The disruption of the gap junction distribution in the infarct-related tissue is possibly due to a redistribution of the preexisting population of junctions rather than the cells producing an entirely new, modified population.111 In addition, some junctional contacts are entirely disrupted, and

intracytoplasmic junctions, previously reported as a feature of degenerating myocytes in a variety of cardiac pathological conditions,163 are seen and are likely to contribute to the dispersed immunolabeling pattern observed by confocal microscopy.111 The electrophysiological effects of the anatomical structure of healed infarct border zones are striking. The reduced connections among fiber bundles described above lead to slow activation. Detailed measurements of activation patterns and transmembrane potentials in isolated,

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Figure 15. Localization of the abnormally distributed connexin43 illustrated by a confocal optical section series of images taken at 1-jim steps through a human infarct border zone myocyte, showing connexin43 label along the edge of the cell in (i) (arrow), with a progressive change in successive slices to show the upper surface of the cell in (v) and the other edge of the cell in (vi), thus describing the surface of the myocyte. Images such as these suggest that this abnormally distributed label is at or near the cell surface. x1100. Reproduced from reference 97, with permission.

superfused preparations of the epicardial border zone from healed canine infarcts

plified in the left panel, in which conduction velocity in the direction of the arrows have illustrated these conduction prop(in the direction of the long axis of the erties, which are also expected to occur in muscle fibers) is 20 to 40 cm/s. (The other regions of healed infarcts with a isochrones are much more widely spaced, similar anatomy.146 Figure 17 compares reflecting the faster conduction velocity.) activation of the epicardial border zone The very slow conduction velocity occurs in a healed infarct (2 months, right panel) in the border zone of healed infarcts (right with activation in a healing infarct (5 panel) despite the normal transmembrane days, left panel). In the 2-month infarct, potentials recorded at most sites as exemactivation moving in the directions indi- plified by the record of the action potencated by the arrows is very slow, as shown tial above the map. The slow activation is by the close bunching of the isochrones. In therefore dependent on the structural altersome regions it takes the activation wave ations that occur as the infarct heals rather 10 ms to move a distance of 0.5 mm, a con- than on abnormalities in transmembrane duction velocity of 0.05 cm/s. This is much potentials.146 In regions in which there is slower than in healing infarcts as exem- no longer parallel orientation of muscle

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Figure 16. Thin section electron micrograph showing intact gap-junctional membrane (arrows) between cell processes of 2 highly degenerated myocytes in a human infarct border zone, showing amorphous cytoplasm and an absence of contractile apparatus. x40,000. Reproduced from reference 111, with permission.

bundles, there no longer exist the welldefined anisotropic properties seen in healing infarcts, that is, conduction is slow in all directions rather than just transverse to the long axis of parallel organized muscle bundles. These same structural features found in the epicardial border zone of canine infarcts, regions of sparse, poorly connected myocardial fibers in disarray, and regions of parallel oriented bundles of fibers disconnected in the transverse direction, also occur in the epicardial and endocardial border zone of human infarcts and are expected to affect conduction properties in the same way that they do in the experimental infarcts. In studies on infarcted human papillary muscle, de Bakker et al.164 mapped impulse propaga-

tion in the thin bundles of muscle fibers that coursed through the infarct scar on the subendocardial surface. They found that the parallel oriented fiber bundles formed conduction pathways insulated from each other by the connective tissue septa except at occasional sites along the length where they were interconnected. Conduction velocity along each of the tracts, parallel to the long axis of the fiber bundles, was rapid, 0.79 m/s (probably because action potentials may be normal and longitudinal connections are not disrupted), but transverse activation was very slow because of the sparse interconnections among the bundles. These conduction pathways can form reentrant circuits.

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Figure 17. Activation maps of small regions of epicardial border zones from a 5-day-old canine infarct (left) and a 2-month-old infarct (right). Action potentials were recorded at each of the sites shown by the dots to construct the map. An electrogram was recorded at the site indicated by the larger stippled circle. Representative action potentials and electrograms are shown above each map. The arrows and isochrones show the direction of propagation. The distance scale for each panel is shown below; note that the scale is twice as large for the 5-day-old infarct than the 2-month-old infarct. Reproduced from reference 146, with permission.

Altered Expression of Connexin43— A General Occurrence in Chronic Myocardial Disease? An alteration in connexin43 gap junctions is not confined to the ischemic heart. Ischemic hearts can have associated hypertrophy,165 and the effects of hypertrophy alone have been assessed by examination of nonischemic hypertrophied myocardium obtained from patients undergoing surgical replacement of a stenosed aortic valve. Quantitative confocal microscopy revealed a 40% reduction per unit volume of connexin43 compared to control heart tissue.25 The reduction appears to occur by cells

maintaining an approximately constant gap junction complement per cell while undergoing considerable increase in size. Decreased connexin43 levels have also been reported by quantitative immunoblotting of myocytes isolated from transgenic hypertensive rats.52 A marked (54%) downregulation of connexin43 mRNA and protein expression occurs in the LVs of patients with idiopathic dilated cardiomyopathy and severely impaired LV function, which, unlike the ischemic heart, in which there is a concomitant upregulation of connexin40 mRNA, shows no change in connexin40 mRNA or protein levels.166 Infection of cultured myocytes with Trypanosoma cruzi,

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the unicellular parasite responsible for Chagas' disease (the most common cause of heart disease in South America), is reported to lead to reduced levels of immunocytochemical staining of connexin43 gap junctions.167 Altered expression of connexin43 in the heart may therefore prove to be a general feature of diverse chronic myocardial diseases. Further, that this feature is common to ischemic heart disease, hypertrophy, and Chagas' disease, all of which have an arrhythmic tendency, supports the possibility of an association between connexin43 levels and conduction disturbances. If this is the case, possible alterations in the quantity and spatial distribution of myocardial connexins and gap junctions along with changing connexin phenotypes and post-translational modification (e.g., phosphorylation states) may modulate the effects of altered connexin43 expression. The development of models for investigating the effects of overexpression and underexpression (or complete ablation) of connexin expression168 in genetically altered animals will provide a useful tool with which such fundamental questions can be investigated.

Summary and Conclusions

In the complex world of arrhythmogenesis and the electrical myocyte networks that underlie both normal and abnormal conduction, there has been progress in understanding the relevance of tissue architecture and the hardware for communication in the form of the gapjunctional channels. Myocardium has the potential for substantial remodeling of its gap-junctional network to become a fundamental component of the anatomical substrate for arrhythmogenesis. Little is yet known, however, of the language of communication via these networks and

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during early myocardial ischaemia. J Mol Cell Cardiol 1978;10:263-269. 95. Peracchia C. Structural correlates of gap junction permeation. Int Rev Cytol 1980; 66:81-146. 96. Hoyt RH, Cohen ML, Corr PB, Saffitz JE. Alterations of intercellular junctions induced by hypoxia in canine myocardium. Am J Physiol 1990;258:H1439-H1448. 97. Peters NS. Myocardial gap junction organization in ischemia and infarction. Microsc Res Tech 1995;31:375-386. 98. Burt JM. Uncoupling of cardiac cells by doxyl stearic acids: Specificity and mechanism of action. Am J Physiol 1989;256: C913-C924. 99. Massey KD, Minnich BN, Burt JM. Arachidonic acid and lipoxygenase metabolites uncouple neonatal rat cardiac myocyte pairs. Am J Physiol 1992;263:C494C501. 100. Hirschi KK, Minnich BN, Moore LK, Burt JM. Oleic acid differentially affects gap junction-mediated communication in heart and vascular smooth muscle cells. Am J Physiol 1993;265:C1517C1526. 101. Wu J, McHowat J, Saffitz JE, et al. Inhibition of gap junctional conductance by long-chain acylcarnitines and their preferential accumulation in junctional sarcolemma during hypoxia. Circ Res 1993;72:879-889. 102. Burt JM. Modulation of cardiac gap junctional channel activity by the membrane lipid environment. In: Peracchia C (ed): Biophysics of Gap Junction Channels. Boca Raton: CRC Press; 1991:75-93. 103. Laird DW, Castillo M, Kasprzak L. Gap junction turnover, intracellular trafficking, and phosphorylation of connexin43 in brefeldin A-treated rat mammary tumor cells. J Cell Biol 1995;131:11931203. 104. Takens-Kwak BR, Jongsma HJ, Rook MB, Van Ginneken ACG. Mechanism of heptanol-induced uncoupling of cardiac gap junctions: A perforated patch-clamp study. Am J Physiol 1992;262:C1531C1538. 105. Laing JG, Westphale EM, Engelmann GL, Beyer EC. Characterization of the gap junction protein, connexin45. J MembrBiol 1994;139:31-40. 106. Gourdie RG, Harfst E, Severs NJ, Green CR. Cardiac gap junctions in rat ventricle: Localization using site-directed

MYOCAEDIAL ARCHITECTURE AND ANISOTROPY AND VENTRICULAR ARRHYTHMIAS antibodies and laser scanning confocal microscopy. Cardioscience 1990; 1:75–82. 107. Green CR, Severs NJ. Distribution and role of gap junctions in normal myocardium and human ischaemic heart disease. Histochemistry 1993;99:105-120. 108. Severs NJ, Gourdie RG, Harfst E, et al. Intercellular junctions and the application of microscopical techniques: The cardiac gap junction as a case model. J Microsc 1993;169:299-328. 109. Gourdie RG, Green CR, Severs NJ. Gap junction distribution in adult mammalian myocardium revealed by an antipeptide antibody and laser scanning confocal microscopy. J Cell Sci 1991; 99:41-55. 110. Green CR, Peters NS, Gourdie RG, et al. Validation of immunohistochemical quantification in confocal scanning laser microscopy: A comparative assessment of gap junction size with confocal and ultrastructural techniques. J Histochem Cytochem 1993;41:1339-1349. 111. Smith JH, Green CR, Peters NS, et al. Altered patterns of gap junction distribution in ischemic heart disease. An immunohistochemical study of human myocardium using laser scanning confocal microscopy. Am J Pathol 1991;139:801-821. 112. Severs NJ, Peters NS, Gourdie RG, et al. Cytochemical labeling of gap junctions in ischaemic heart disease—correlative investigation by laser scanning confocal microscopy and electron microscopy. In: Rios A, Arias JM, Megias-Megias L, LopezGalindo A (eds): Electron Microscopy 92. Volume 1, Eurem 92. Granada, Spain: Secretariado de Publicaciones de la Universidad de Granada; 1992:627–628. 113. Ranter HL, Laing JG, Beyer EC, et al. Multiple connexins colocalize in canine ventricular myocyte gap junctions. Circ Res 1993;73:344-350. 114. Peters NS, Severs NJ, Rothery SM, et al. Spatiotemporal relation between gap junctions and fascia adherens junctions during postnatal development of human ventricular myocardium. Circulation 1994;90:713-725. 115. Delmar M, Michaels DC, Johnson T, Jalife J. Effects of increasing intercellular resistance on transverse and longitudinal propagation in sheep epicardial muscle. Circ Res 1987;60:780-785. 116. Dillon SM, Allessie MA, Ursell PC, Wit AL. Influences of anisotropic tissue

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application to conduction. Circ Res 1995; 76:366-380. 128. Chen PS, Cha YM, Peters BB, Chen LS. Effects of myocardial fiber orientation on the electrical induction of ventricular fibrillation. Am J Physiol 1993;264: H1760-H1773. 129. Peters NS, del Monte F, MacLeod KT, et al. Increased cardiac myocyte gapjunctional membrane early in renovascular hypertension. J Am Coll Cardiol 1993;21:59A. 130. Wit AL, Janse MJJ. The Ventricular Arrhythmias of Ischemia and Infarction. Electrophysiological Mechanisms. Mt Kisco, New York: Futura Publishing Co.; 1993. 131. Quan W, Rudy Y. Unidirectional block and reentry of cardiac excitation: A model study. Circ Res 1990;66:367-382. 132. Hiramatsu Y, Buchanan JW, Knisley SB, Gettes LS. Rate-dependent effects of hypoxia on internal longitudinal resistance in guinea pig papillary muscles. Circ Res 1988;63:923–939. 133. Ikeda K, Hiraoka M. Effects of hypoxia on passive electrical properties of canine ventricular muscle. Pflugers Arch 1982; 393:45-50. 134. Streit J. Effects of hypoxia and glycolytic inhibition on electrical properties of sheep cardiac Purkinje fibres. J Mol Cell Cardiol 1987; 19:875–885. 135. Tranum-Jensen J, Janse MJ, Fiolet JWT, et al. Tissue osmolality, cell swelling and reperfusion in acute regional myocardial ischemia in the isolated porcine heart. Circ Res 1981;49:364–381. 136. McCallister LP, Trapukdis S, Neely JR. Morphometric observations on the effects of ischemia in the isolated perfused rat heart. JMol Cell Cardiol 1979;11:619–630. 137. Unwin PNT, Zampighi G. Structure of the junction between communicating cells. Nature 1980;283:545-549. 138. Dahl G, Isenberg G. Decoupling of heart muscle cells: Correlation with increased cytoplasmic calcium activity and with changes in nexal ultrastructure. J Membr Biol 1980;53:63–75. 139. Deleze J, Herve JC. Effect of several uncouplers of cell-to-cell communication on gap junction morphology in mammalian heart. J Membr Biol 1983;74: 203-215. 140. Green CR, Severs NJ. Gap junction connexon configuration in rapidly frozen myocardium and isolated intercalated disks. J Cell Biol 1984;99:453-463.

141. Shibata Y, Page E. Gap junctional structure in intact and cut sheep cardiac Purkinje fibers: A freeze-fracture study of Ca2+-induced resealing. J Ultrastruc Res 1981;75:195-204. 142. Kleber AG, Cascio WE. Ischemia and Na+/K+ pump function. In: Rosen MR, Palti Y (eds): Lethal Arrhythmias Resulting from Myocardial Ischemia and Infarction. Boston: Kluwer Academic Publishers; 1989:77-90. 143. Cascio WE, Yan GX, Kleber AG. Passive electrical properties, mechanical activity, and extracellular potassium in arterially perfused and ischemic rabbit ventricular muscle. Effects of calcium entry blockade or hypocalcemia. Circ Res 1990;66:1461-1473. 144. Josephson ME, Horowitz LN, Farshidi A, Kastor JA. Recurrent sustained ventricular tachycardia. 1. Mechanisms. Circulation 1978;57:431-440. 145. DeBakker JMT, Coronel R, Tasseron S, et al. Ventricular tachycardia in the infarcted, Langendorff-perfused human heart: Role of the arrangement of surviving cardiac fibers. J Am Coll Cardiol 1990;15:1594-1607. 146. Gardner PI, Ursell PC, Fenoglio JJ Jr, Wit AL. Electrophysiologic and anatomic basis for fractionated electrograms recorded from healed myocardial infarcts. Circulation 1985;72:596–611. 147. Myerburg RJ, Gelband H, Nilsson K, et al. Long-term electrophysiological abnormalities resulting from experimental myocardial infarction in cats. Circ Res 1977;41:73–84. 148. Wit AL, Dillon SM, Coromilas J, et al. Anisotropic reentry in the epicardial border zone of myocardial infarcts. Ann NYAcad Sci 1990;591:86–108. 149. Bolick DR, Hackel DB, Reimer KA, Ideker RE. Quantitative analysis of myocardial infarct structure in patients with ventricular tachycardia. Circulation 1986;74:1266–1279. 150. Wit AL, Allessie MA, Bonke FIM, et al. Electrophysiologic mapping to determine the mechanism of experimental ventricular tachycardia initiated by premature impulses. Experimental approach and initial results demonstrating reentrant excitation. Am J Cardiol 1982;49:166185. 151. Mehra R, Zeiler RH, Gough WB, ElSherif N. Reentrant ventricular arrhythmias in the late myocardial infarction

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period. 9. Electrophysiologic-anatomic correlation of reentrant circuits. Circulation 1983;67:11–24. Hirzel HO, Nelson GR, Sonnenblick EH, Kirk ES. Redistribution of collateral blood flow from necrotic to surviving myocardium following coronary occlusion in the dog. Circ Res 1976;39:214–222. Friedman PL, Fenoglio JJ Jr, Wit AL. Time course for reversal of electrophysiological and ultrastructural abnormalities in subendocardial Purkinje fibers surviving extensive myocardial infarction in dogs. Circ Res 1975;36:127–144. Fenoglio JJ Jr, Pham TD, Harken AH, et al. Recurrent sustained ventricular tachycardia: Structure and ultrastructure of subendocardial regions in which tachycardia originates. Circulation 1983; 68:518–533. Josephson ME. Clinical Cardiac Electrophysiology. Techniques and Interpretations. Philadelphia: Lea and Febiger; 1993. El-Sherif N. The figure 8 model of reentrant excitation in the canine postinfarction heart. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology and Arrhythmias. New York: Grune & Stratton; 1985:363-378. Littmann L, Svenson RH, Gallagher JJ, et al. Functional role of the epicardium in postinfarction ventricular tachycardia. Observations derived from computerized epicardial activation mapping, entrainment, and epicardial laser photoablation. Circulation 1991;83:1577– 1591. Ursell PC, Gardner PI, Albala A, et al. Structural and electrophysiological changes in the epicardial border zone of canine myocardial infarcts during infarct healing. Circ Res 1985;56:436–451. Peters NS, Coromilas J, Severs NJ, Wit AL. Disturbed connexin43 gap junction

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distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. Circulation 1997;95:988–996. Saffitz JE, Hoyt RH, Luke RA, et al. Cardiac myocyte interconnections at gap junctions-role in normal and abnormal electrical conduction. Trends Cardiovasc Med 1992;2:56–60. Doble BW, Kardami E. Basic fibroblast growth factor stimulates connexin-43 expression and intercellular communication of cardiac fibroblasts. Mol Cell Biochem 1995;143:81–87. Balke CW, Lesh MD, Spear JF, et al. Effects of cellular uncoupling on conduction in anisotropic canine ventricular myocardium. Circ Res 1988;63:879-892. Buja LM, Ferrans VJ, Maron BJ. Intracytoplasmic junctions in cardiac muscle cells. Am JPathol 1974;74:613-648. de Bakker JMT, van Capelle FJL, Janse MJJ, et al. Slow conduction in the infarcted human heart. "Zigzag" course of activation. Circulation 1993;88:915–926. Anversa P, Beghi C, Kikkawa Y, Olivetti G. Myocardial response to infarction in the rat. Morphometric measurement of infarct size and myocyte cellular hypertrophy. Am J Pathol 1985;484:492. Dupont E, Kaprielian R, Yeh H-I, et al. Connexin messenger ribonucleic acid expression in the healthy and diseased human heart. Eur Heart J 1996; 17(Abstract):600. Campos De Carvalho AC, Tanowitz HB, Wittner M, et al. Gap junction distribution is altered between cardiac myocytes infected with Trypanosoma cruzi. Circ Res 1992;70:733-742. Reaume AG, De Sousa PA, Kulkarni S, et al. Cardiac malformation in neonatal mice lacking connexin43. Science 1995; 267:1831-1834.

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Chapter 11 The Figure-of-Eight Model of Reentrant Ventricular Arrhythmias Nabil El-Sherif, MD, Edward B. Caref PhD, and Mark Restivo, PhD

Reentrant excitation is an important mechanism for ventricular tachyarrhythmias. A better understanding of this mechanism can provide a basis for improved management. Reentrant excitation occurs when the propagating impulse does not die out after complete activation of the heart, as is normally the case, but persists to reexcite the atria or ventricles after the end of the refractory period. Reentrant excitation can be subdivided into circus movement excitation and reflection. In circus movement reentry, the activation wavefront encounters a site of unidirectional conduction block and propagates in a circuitous pathway before reexciting the tissue proximal to the site of block after expiration of its refractory period. In this chapter, circus movement reentry is discussed with special reference to the figure-of-8 model of reentry first described in the canine postinfarction model.1 Classification of Circus Movement Reentry Circus movement reentry can be classified into anatomical and functional

types. This classification is based primarily on the nature of the central obstacle around which the circulating wavefront propagates. A combination of functional and anatomical obstacles is sometimes necessary for the initiation of circus movement reentry. Anatomical or Ring Models of Reentry In the anatomical model of reentry, the reentrant pathway is fixed and anatomically determined. The earlier models of circus movement consisted of rings of cardiac and other tissue obtained from various animals including mammals (Figure 1).2–5 In the intact heart, excitable bundles isolated from surrounding myocardium can form anatomical rings for potential circus movement. Examples include circus movement involving normal atrioventricular (AV) conducting bundles and AV accessory pathways,6 circus movement involving the His bundle branches or Purkinje network,7 and circus movement

Supported in part by Veterans Administration Medical Research Funds to NES and MR. From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003. 237

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Figure 1. Anatomical (ring) models of reentry. A. Mines' diagram of a ring preparation composed of the auricle and ventricle of the tortoise, in which he observed reciprocating rhythm. Both connections between auricle and ventricle could transmit an excitation wave. During reciprocating rhythm, the 4 portions of the preparation marked V1, V2, A1, A2 contracted in that order. From Mines GR. J Physiol 1913;46:349–382. B. A proposed mechanism for reentry in a Purkinje-muscle loop. The diagram shows a Purkinje fiber bundle (D), which divides into 2 branches, both connected distally by ventricular muscle. Circus movement will develop if the stippled segment (A-B) is an area of unidirectional conduction. An impulse advancing from D would be blocked at A but would reach and stimulate the ventricular muscle at C by way of the other terminal branch. The excitation from the ventricular fiber would then reenter the Purkinje system at B and traverse the depressed region at a slow rate so that by the time it arrived at A, the site would have recovered from refractoriness and would again be excited. From Schmitt FO, Erlanger J. Am J Physiol 1928/1929;87:326. C. Diagram of a possible reentrant pathway, partly through bundles of surviving myocardial fibers embedded in the fibrous tissue of an old myocardial infarct. The main bundle bifurcates and gives rise to 2 possible exits toward the larger subendocardial muscle mass. Reproduced with permission from deBakker JMT, Van Capelle FJL, Janse MJ, et al. Circulation 1988;77:589–606. Copyright 1988, American Heart Association. D. Diagram of the initiation of circus movement in a ring model, emphasizing the importance of unidirectional block. A properly timed stimulus (*) will block in one direction because of nonhomogeneous refractoriness (stippled zone) but will continue to conduct in the ring in the other direction. A circus movement will be established if the returning wavefront finds that the site of unidirectional block has recovered excitability, thus permitting conduction to proceed uninterrupted.

using surviving myocardial bundles in a postinfarction scar.8 It is important to remember, however, that an anatomically determined pathway that can potentially support reentry does not automatically create circus movement. A critical functional perturbation of part of

the pathway must take place before a circus movement is initiated. Central to the initiation of a circus movement in an anatomical ring is the development of unidirectional block. Here, a stimulus blocks in one direction because of nonhomogeneous electrophysiological properties, but

FIGURE-OF-8 MODEL OF REENTRANT VENTRICULAR ARRHYTHMIAS it continues to conduct in the other direction. A circus movement is established if the returning wavefront finds that the site of unidirectional block has recovered excitability, permitting conduction to proceed uninterrupted. Thus, it is clear that in an anatomically predetermined circuit, a significant functional component exists and can be modulated, for example, by pharmacological agents. Surgical interruption of an anatomical ring-like circuit can be accomplished by cutting (or ablating) at any point along the ring. For example, in the ring circuit that uses an AV accessory pathway, the anatomical substrate consists in large part of pathways of excitable bundles that are not connected to adjacent atrial and ventricular myocardium. The circuit can be interrupted with ease by interrupting conduction of either the normal AV pathway or, as is currently the practice, the accessory AV pathways.

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model,1 the anisotropic model,16 and the spiral wave model17,18 (Figure 2). Nature and Characteristics of the Functional Obstacle of the Reentrant Circuit

The nature of the functional arc of block during the initiation of a reentrant circuit has been investigated by several groups. Allessie et al.11 were the first to show that differences in refractory periods of atrial fibers at adjacent sites can result in functional block if premature stimulation is applied to the site of shorter refractoriness. Later, Gough et al.12 showed that circus movement developed around arcs of functional conduction block in the surviving epicardial layer overlying canine ventricular infarction owing to spatial inhomogeneity of refractoriness. The latter could be due to differences in active membrane properties of adjacent fibers that affect their depolarization or repolarization characteristics, or due Functional Models of Reentry to discrete differences in intercellular Functional reentrant circuits can connections. Depression of active membrane propdevelop in the interconnected syncytium of myocardial bundles in the atria or ven- erties of myocardial fibers is a major tricles. Central to the development of a determinant of functional conduction functional circus movement is the cre- block and slowed conduction, leading to ation of a functional barrier of conduc- circus movement reentry in the acute tion block. The nature of this functional phase of myocardial ischemia.19,20 Within barrier has been investigated in some minutes of coronary artery occlusion, the detail during the initiation of circus move- cells in the center of the ischemic zone ment. Functional conduction block initi- show progressive decrease in resting ating a circus movement can be caused by membrane potential, action potential (1) abrupt changes in cardiac geometry9; amplitude, duration, and upstroke veloc(2) decremental conduction leading to ity.19 After a brief initial shortening, the propagation failure10; (3) regional differ- refractory period begins to lengthen even ences in refractory periods11–13; or (4) dif- though action potential duration continferences in conduction properties relative ues to shorten.19 El-Sherif et al.21 and to fiber orientation.14 The last 2 mecha- Lazzara et al.22 used the term postreponisms have received wider attention. The larization refractoriness to indicate that models of functional reentrant circuits at certain stages of ischemia, the memthat have been widely investigated are brane may remain inexcitable even when the leading circle model,15 the figure-of-8 it has been completely repolarized. Such

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Figure 2. Functional models of reentry. Leading Circle Model: diagrammatic representation of this model in isolated left atrium of the rabbit. The central area is activated by converging centripetal wavelets. Reproduced with permission from Allessie MA, Bonke FIM, Schopman FJG. Circ Res 1977;41:9–18. Copyright 1977, American Heart Association. Figure-of-8 Model: activation map (in 20-ms isochrones) of a figure-of-8 circuit in the surviving epicardial layer of a dog 4 days after ligation of the left anterior descending artery (LAD). The circuit consists of clockwise and counterclockwise wavefronts around 2 functional arcs of conduction block that coalesce into a central common front that usually represents the slow zone of the circuit. From El-Sherif N. In: Zipes D, Jalife J (eds): Cardiac Electrophysiology and Arrhythmias. New York: Gruneand Stratton; 1985:363-378. Anisotropic Model: activation map and schematic representation of the reentrant circuit during sustained monomorphic ventricular tachycardia in a thin epicardial layer frame obtained by an endocardial cryotechnique in a Langendorff-perfused rabbit heart. A single-loop reentry forms around a functional arc of conduction block. From Brugada J, et al. Pacing Clin Electrophysiol 1991 ;14:1943–1946. Spiral Wave Model: activation map of spiral wave activity in a thin slice of isolated ventricular muscle from a sheep heart (right panel). Isochrone lines were drawn from raw data by overlaying transparent paper on snapshots of video images during spiral wave activity (left panel not from same experiment). Each line represents consecutive positions of the activation front recorded every 16.6 ms. From Krinsky VL, et al. Proc R Soc Lond 1992;437:645–655.

increases in refractory period can exceed the basic cycle length, at which point 2:1 responses occur.19 The marked dependence of recovery of excitability on the resting potential in partially depolarized ischemic myocardial cells is probably the most

important determinant for the occurrence of slow conduction and conduction block in the acute phase of myocardial ischemia.20 The depressed upstroke of ischemic action potentials is the result of a depressed fast Na+ current.23 The postrepolarization

FIGURE-OF-8 MODEL OF REENTRANT VENTRICULAR ARRHYTHMIAS refractoriness in depolarized cells has been attributed to delayed recovery from inactivation of the fast Na+ current.24 In the subacute (healing) phase of myocardial ischemia (1 to 7 days after infarction), depressed membrane properties of surviving myocardial fibers bordering the infarction continue to be a major determinant of conduction abnormalities underlying circus movement reentry. Intracellular recordings from the surviving "ischemic" epicardial layer of 3 to 5 days postinfarction canine heart show cells with various degrees of partial depolarization, reduced action potential amplitude, and decreased upstroke velocity.25–27 Full recovery of responsiveness frequently outlasts the action potential duration reflecting the presence of postrepolarization refractoriness. In these cells, premature stimuli could elicit graded

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responses over a range of coupling intervals. Slowed conduction, Wenckebach periodicity, and 2:1 or higher degrees of conduction block could easily be induced by fast pacing or premature stimulation (Figure 3). Isochronal mapping studies have shown that both the arcs of functional conduction block and the slow activation wavefronts of the reentrant circuit develop in the surviving electrophysiological abnormal epicardial layer overlying the infarction.28–30 Studies from the same laboratory using high-resolution mapping of activation and refractory patterns have shown that functional block is necessary for both the initiation and sustenance of reentrant excitation and that the functional block necessary for initiation of reentry is due to abrupt changes in refractoriness occurring over distances of 1 mm or less (Figures 4 and 5).13 The abrupt

Figure 3. Recordings from a dog with a 3-day-old infarction, illustrating action potential characteristics in ischemic epicardium. The sketch of the preparation shows 2 intracellular recordings (X and Y) and a close bipolar recording (1) from the infarction zone (stippled area). Ischemic cells had decreased upstroke velocity, reduced action potential amplitude, and a variable degree of partial depolarization. The 2 cells were recorded 5 mm apart in the infarction zone but showed significant difference in their resting potential. The resting potential of the Y cell was only slightly reduced (-80 mV), but it still had a poor action potential. The preparation was stimulated at a cycle length of 290 ms, which resulted in a Wenckebach-like conduction pattern. Note that the pacing cycle length exceeded the action potential duration of the cells, suggesting that refractoriness extended beyond the completion of the action potential (i.e., postrepolarization refractoriness). Reproduced with permission from El-Sherif N, Lazzara R. Circulation 1979;60:605–615. Copyright 1979, American Heart Association.

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Figure 4. High-resolution determination of spatial refractory gradients and their relationship to the arc of functional conduction block from a 4-day-old canine infarction. A high-density bipolar electrode plaque with 1 -mm interelectrode spacing was positioned on the epicardial surface at the site of the arc of block induced by premature stimulation (S2) as determined from an earlier low-resolution sock electrode array. The plaque was oriented with the electrode rows perpendicular to the arc. The figure illustrates 5 bipolar electrograms recorded successively at 1-mm distance (a to e). The values of the effective refractory period in milliseconds at each site are shown. The arrows indicate the end of the effective refractory period relative to S1 activation at each site. The S1,and S2 activation maps are shown on the right. The asterisk on the S1, map denotes the site of stimulation. During S1, sites a to e were activated sequentially within a 12-ms interval (conduction velocity of 42 cm/s). During S2, conduction between sites a and c was relatively slow compared with S1,. Conduction block developed abruptly between sites c and d. Sites d and e were activated 65 ms later by the wavefront that circulated in a clockwise direction around one end of the arc of block. The site of conduction block coincided with a 35-ms abrupt increase in the effective refractory period between sites c and d. Note that the arc of block was parallel to the left anterior descending artery (LAD), represented by the broken line. Reproduced with permission from Restivo M, Gough WB, El-Sherif N. Circ Res 1990;66:1310–1327. Copyright 1990, American Heart Association.

changes in refractoriness did not seem to be related to specific geometric characteristics or anisotropic conduction properties of the ischemic myocardium. Action potential recordings from surviving myocardial bundles from hearts with chronic (healed) myocardial infarction (MI) have shown a wide spectrum of configurations. Some studies have shown normal action potential characteristics of surviving myocardial bundles from hearts in which circus movement reentry could

be initiated,8,31 whereas other studies have shown various degrees of depressed action potentials.32 In the former situation, reentrant excitation is explained primarily on the basis of the nonuniform anisotropic properties of the surviving myocardial bundles in a healed infarction scar. However, a combination of functional and anatomically determined reentrant circuits in those hearts, similar to original examples of ring model reentry, cannot be ruled out.

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Figure 5. Five successive bipolar electrograms (A-E) recorded at 1 -mm distance across an arc of functional conduction block induced by S2 stimulation (right panel). The layout of the high-density plaque was similar to that shown in Figure 4, but the recordings were obtained from a different experiment. The effective refractory period (ERP) at each site is shown, and the arrows indicate the end of the ERP relative to ST activation. Abrupt conduction block occurred during S2 stimulation between sites B and C and coincided with an abrupt increase in ERP of 25 ms. The asterisks indicate the electrotonic deflection recorded in electrograms C and D distal to block. The amplitude of the electrotonic deflection diminished with the distance from the site of block. A graphic illustration of the distribution of ERP across an 8-mm distance is shown on the left. Reproduced with permission from Restivo M, Gough WB, El-Sherif N. CircRes 1990;66:1310–1327. Copyright 1990, American Heart Association.

Primarily through the work of Spach et al.,14 anisotropic discontinuous propagation was shown to produce all of the conduction disturbances necessary for circus movement reentry without the presence of spatial differences in refractoriness. The safety factor of propagation of early premature impulses was shown to be dependent on fiber orientation, with unidirectional block occurring during propagation along the long axis of the fibers and slowed conduction persisting across the fibers, thus setting the stage

for reentrant excitation. The slower conduction in the transverse direction is due higher axial resistivity, which may be partly explained by fewer shorter gapjunctional contacts in a side-to-side direction.33 The normal uniform anisotropic conduction properties of the myocardium may be altered further after ischemia and can be markedly exaggerated in healed infarcts. Electrical uncoupling and increase of extracellular resistance resulting in reduced space constant have been shown in slowly conducting regions of chronically

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infarcted canine myocardium.34 Spach et al.35 suggested that both spatial inhomogeneity of refractoriness and anisotropic conduction properties may contribute to one model of reentrant excitation in the canine atria. The combination of spatial inhomogeneity of refractoriness and anisotropic conduction properties may be applicable to other models of reentry. A possible example is the experimental model of functional "anisotropic" reentry in which circus movement could be induced in a thin layer of normal myocardium obtained by endocardial cryotechnique in a Langendorffperfused rabbit heart.16 The nature of the central arc of functional block during sustained reentry has been more difficult to investigate. In a report by Dillon et al.,36 it was suggested that most of the central barrier around which circus movement orients in the surviving epicardial layer of the postinfarction canine heart was in fact a line of pseudoconduction block resulting from very slow conduction along the longitudinal fiber axis. However, high-resolution recordings of the central arc of block in this model13 as well as in other atrial models of functional reentry 37,38 clearly showed the presence of a discrete finite zone of functional conduction block explained by the bidirectional invasion of this zone by the opposing activation wavefronts on either side of the central barrier (Figure 6). Electrotonic conduction in this zone could create a constant functional block around which circus movement is oriented. The factors that determine the location and orientation of the central functional barrier during sustained reentry are not well defined and may be related to refractoriness or anisotropic differences. The length of the central functional barrier is also of interest. A circuit with a very small central barrier (i.e., a central core of functional refractory tissue) is typical of the leading circle model of reentry15

and resembles the vortex-like waves or spirals that have been demonstrated in a number of excitable media39 and in normal isolated ventricular muscle.17,18 However, in most of the functional circuits that have been mapped in vitro or in vivo, including the original leading circle model15 and the model of reentry in the Langendorff-perfused rabbit heart,16 the central obstacle was shown to consist of an arc of block of some finite length rather than a confluent central vortex. Topology of Functional Circus Movement The topology of functional circus movement is of both theoretical and practical importance. The typical functional circus movement in a syncytium has a figure-of-8 configuration consisting of clockwise and counterclockwise wavefronts around 2 functional arcs of block that coalesce into a central common front that commonly represents the slow zone of the circuit.1 This zone is the most vulnerable part of the circuit and the site at which pharmacological agents or ablative procedures can selectively modulate the circus movement. On the other hand, a single reentrant functional loop can also develop in a syncytium. However, it usually develops contiguous to an anatomical barrier. The most typical example of the development of a single functional reentrant loop has been shown by Schoels et al.38 in a study of circus movement atrial flutter in the canine postpericarditis model (Figure 7D). In this model, the majority of atrial flutter is due to a single-loop circus movement. During the initiation of a single reentrant loop, an arc of functional conduction block extends to the AV ring, forcing activation to proceed only as a single wavefront around the free end of the arc before breaking through the arc at a site close to the AV ring. Activation continues as

FIGURE-OF-8 MODEL OF REENTRANT VENTRICULAR ARRHYTHMIAS 243

Figure 6. Recordings of high-density bipolar electrode array at multiple locations (I to IV) along a continuous arc of functional conduction block during a figure-of-8 sustained monomorphic ventricular tachycardia (top panel). In this and subsequent maps, epicardial activation is displayed as if the heart was viewed from the apex located at the center of the circular map. The perimeter of the circle represents the atrioventricular junction. Activation isochrones are drawn at 20-ms intervals. Arcs of functional conduction block are represented by heavy solid lines. Arrows indicate wavefront direction during sustained ventricular tachycardia. Both arcs are oriented approximately parallel to the longitudinal axis of the epicardial muscle fibers. A portion of this activation map is shown in the lower right panel. The shaded rectangles represent the column for each array location. Electrograms recorded in proximity to the arc of block show split electrograms composed of 2 discrete potentials separated by a variable isoelectrical interval: one deflection represents local activation, the other deflection is an electrotonic potential reflecting activation recorded 1 mm away. The interval between the 2 deflections is greatest at the center of the arc (locations II and III), where the difference in isochronal activation, by whole ventricle mapping, is greatest. The interval between the 2 deflections is less as the reentrant impulse circulates around the end of the arc (location I). The electrographic characteristics of functional conduction block are the same at location IV, which indicates that the arc of functional conduction block was longer than that predicted by the whole ventricle mapping technique. The 2 deflections in electrogram d at location III may both represent electrotonic potentials. Reproduced with permission from Restivo M, Gough WB, El-Sherif N. Circ Res 1990;66:1310–1327. Copyright 1990, American Heart Association.

a single circulating wavefront around an arc of block in proximity to the AV ring or around a combined functional/anatomical obstacle with the arc usually contiguous with the inferior vena cava. Spontaneous38 or pharmacologically induced40 termination

of single-loop reentrant circuit occurs when conduction fails in a slow zone and the arc of block rejoins the AV ring. A critical analysis of the leading circle or anisotropic models of reentry15,16 shows that they may be a special modification of

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Figure 7. The leading circle model of reentry. A. and B. Isochronal maps of activation of a premature beat (S2) and the first reentrant beat (A1) from an in vitro preparation of atrial myocardium of the rabbit. The arcs of functional conduction block are represented by heavy solid lines. Isochrones are drawn at 5-ms intervals. Note that the properly timed premature stimulus resulted in a continuous arc of functional conduction block; the activation front circulated around both ends of the arc, coalesced, and then broke through the arc to reexcite myocardial zones on the proximal side of the arc. This resulted in splitting of the original arc into 2 separate arcs. Modified with permission from Allessie MA, Bonke Fl, Schopman FJG. Circ Res 1976;39:168–177. Copyright 1976, American Heart Association. B. A circulating wavefront continued around one of the arcs. However, the second arc of block shifted its site and joined the edge of the preparation so that the second circulating wavefront was aborted. If the preparation in B was inserted into the in situ heart, the second aborted circulating wavefront would be activated, thus resulting in a figure-of-8 reentrant pattern. C. Diagram of the leading circle model. Reproduced with permission from Allessie MA, Bonke FIM, Schopman FJG. Circ Res 1977;41:9–18. Copyright 1977, American Heart Association. D. Isochronal map of atrial epicardial activation during circus movement atrial flutter in the canine sterile pericarditis model. The atria are displayed in a planar projection as though separated from the ventricles along the atrioventricular ring and incised on the inferior bodies of both atrial appendages from the atrioventricular ring to their tips. The shaded area represents the orifices of the atrial vessels. The figure shows a single-loop reentrant circuit around a central obstacle composed of a functional arc of block (heavy solid line) and an anatomical obstacle (the orifice of the inferior vena cava). Reproduced with permission from Schoels W, Gough W, Restivo M, El-Sherif N. Circ Res 1990;67:35–50. Copyright 1990, American Heart Association.

the figure-of-8 model (Figure 7A-C). Thus, a figure-of-8 pattern may be the basic topology of a functional reentrant circuit in the interconnected syncytial structure of the atria and ventricles.1 The long arcs

of functional conduction block that sustain large reentrant circuits in the canine postinfarction ventricle and the small arcs of functional block that sustain small reentrant circuits in the leading circle or

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anisotropic models may represent 2 ends of a spectrum of the same electrophysiological phenomenon. Induced Versus Spontaneous Circus Movement Reentry Figure-of-8 reentrant excitation in the canine postinfarction heart may occur "spontaneously" during a regular cardiac rhythm41 but is commonly induced by premature stimulation. Induction of reentry by premature stimulation depends on the length of the arc of functional conduction block and the degree of slowed conduction distal to the arc induced by premature stimulation.28,29 A premature beat that successfully initiates reentry results in a longer arc of conduction block or slower conduction compared with one that fails to induce reentry (Figure 8). When a single premature stimulus (S2) fails to initiate reentry, the introduction of a second premature stimulus (S3) may be necessary. S3 usually results in a longer arc of conduction block or slower conduction around the arc. The slower activation wavefront travels around a longer, more circuitous route, thus providing more time for refractoriness to expire along the proximal side of the arc of unidirectional block. Reexcitation of this site initiates reentry. The beat that initiates the first reentrant cycle, whether it is an S2 or an S3, results in a continuous arc of conduction block. The activation front circulates around both ends of the arc of block and rejoins on the distal side of the arc of block before breaking through the arc to reactivate an area proximal to the block. This results in splitting of the initial single arc of block into 2 separate arcs. Subsequent reentrant activation continues with afigure-of-8activation pattern, in which 2 circulating wavefronts advance in clockwise and counterclockwise directions, respectively,

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around 2 arcs of conduction block. During a monomorphic reentrant tachycardia, the 2 arcs of block and the 2 circulating wavefronts remain fairly stable. On the other hand, during a pleomorphic reentrant rhythm, both arcs of block and the circulating wavefronts can change their geometric configurations while maintaining their synchrony. The development of multiple asynchronous reentrant circuits usually ushers the onset of ventricular fibrillation.29,42 Reentrant activation spontaneously terminates when the leading edge of both reentrant wavefronts encounters refractory tissue and fails to conduct. This results in coalescence of the 2 arcs of block into a single arc and termination of reentrant activation. For reentry to occur during regular cardiac rhythm, on the other hand, the heart rate should be within the relatively narrow critical range of rates during which conduction in a potentially reentrant pathway shows a Wenckebach-like pattern.41 During a Wenckebach-like conduction cycle, a beat-to-beat increment in the length of the arc of conduction block or the degree of conduction delay occurs until the activation wavefront is sufficiently delayed for certain parts of the myocardium proximal to the arc of block to recover excitability and become reexcited by the delayed activation front. A Wenckebach-like conduction sequence may be the initiating mechanism for repetitive reentrant excitation (e.g., a reentrant tachycardia) or may result in a single reentrant cycle in a repetitive pattern, giving rise to a reentrant extrasystolic rhythm (Figure 9). The majority of reentrant circuits in the canine postinfarction model develop in the surviving epicardial layer and can be viewed as having an essentially 2dimensional configuration. However, reentrant circuits can also be identified in intramyocardial41,43 or subendocardial locations.29 The latter location is of special

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Figure 8. Epicardial isochronal activation maps during a basic ventricular stimulated beat (S-,), initiation of reentry by a single premature stimulus (S2), and sustained monomorphic reentrant ventricular tachycardia (VT). A representative ECG is shown in the lower right panel. The recordings were obtained from a dog 4 days after ligation of the left anterior descending artery (LAD). Site of ligation is represented by a double bar. The outline of the epicardial ischemic zone is represented by the dotted line. During S1, the epicardial surface was activated within 80 ms, with the latest isochrone located in the center of the ischemic zone. S2 resulted in a long, continuous arc of conduction block within the border of the ischemic zone. The activation wavefront circulated around both ends of the arc of block and coalesced at the 100-ms isochrone. The common wavefront advanced within the arc of block before reactivating an area on the other side of the arc at the 180-ms isochrone to initiate the first reentrant cycle. During sustained VT, the reentrant circuit had a figure-of-8 activation pattern in the form of a clockwise and counterclockwise wavefront around 2 separate arcs of functional conduction block. The 2 wavefronts joined into a common wavefront that conducted between the 2 arcs of block. The sites of the 2 arcs of block during sustained VT were different to various degrees from the site of the arc of block during the initiation of reentry by S2 stimulation. The lower right panel illustrates the orientation of myocardial fibers in the surviving ischemic epicardial layer perpendicular to the direction of the LAD. The arrow represents the longitudinal axis of propagation of the slow common reentrant wavefront during a sustained figure-of-8 activation pattern, which is oriented parallel to fiber orientation and perpendicular to the nearby LAD segment. Modified from Assadi M, et al. Am Heart J 1990; 119:1014–1024.

interest because it may be comparable to reentrant circuits described in the surviving subendocardial muscle layer in the heart of patients with chronic ML44 This underscores the fact that, depending on

the particular anatomical features of the infarction and the geometric configuration of ischemic surviving myocardium, reentrant circuits can be located in epicardial, subendocardial, or intramyocardial zones.1

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Figure 9. Isochronal maps of a reentrant trigeminal rhythm. Epicardial activation maps as well as selected electrographic recordings from a dog 4 days after infarction in which a reentrant trigeminal rhythm developed during sinus tachycardia are shown. During sinus rhythm at a cycle length of 325 ms there was a consistent small arc of functional conduction block near the apical region of the infarct and relatively slow activation of nearby myocardial zones (map 1). The activation pattern, however, was constant in successive beats reflecting a 1:1 conduction pattern. Spontaneous shortening of the sinus cycle length to 305 ms resulted in the development of a single reentrant beat after every second sinus beat. During the reentrant trigeminal rhythm, the epicardial activation map of the first sinus beat showed the development of a longer arc of functional conduction block compared with the one during sinus rhythm at a cycle length of 325 ms (map 2). The activation front circulated around both ends of the arc of block but was not sufficiently delayed on the distal side of the arc of block. On the other hand, the activation map of the second sinus beat showed more lengthening of the arc of block at one end but more characteristically a much slower conduction of the 2 activation fronts circulating around both ends of the arc of block (map 3). The degree of conduction delay was sufficient for refractoriness to expire at 2 separate sites on the proximal side of the arc, resulting in 2 simultaneous breakthroughs close to the ends of the arc, thus initiating reentrant excitation. The leading edge of the 2 reentrant wavef ronts coalesced but failed to conduct to the central part of the epicardial surface of the infarct—that is, to areas that were showing slow conduction during the preceding cycle. This limited the reentrant process to a single cycle (map 4). It also resulted in recovery of those myocardial zones in the central part of the infarct, allowing the next sinus beat to conduct with a lesser degree of conduction delay, thus perpetuating the reentrant trigeminal rhythm. Analysis of the 2 electrograms recorded from each of the 2 reentrant pathways (B and C, and D and E, respectively) shows a characteristic 3:2 Wenckebach-like conduction pattern. The figure illustrates the complexity of conduction patterns in ischemic myocardium and the presence of a zone of dissociated conduction. This is represented by site F, which was showing a 2:1 conduction pattern during the 3:2 Wenckebach cycle and reentrant trigeminal rhythm described earlier. From El-Sherif N, et al. J Am Coll Cardiol 1985;6:124–132. Reprinted with permission from the American College of Cardiology.

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lating excitation and to identify the critical site along the reentrant circuit at which interruption of reentrant excitation could be successfully accomplished.45 Spontaneous termination of figure- These studies have demonstrated that of-8 sustained monomorphic reentrant reentrant activation could be successfully ventricular tachycardia (SMVT) always interrupted when cooling or cryoablation occurs when the 2 circulating wavefronts was applied to the part of the slow block in the central common pathway common reentrant wavefront immedi(CCP). Distinct electrophysiological chan- ately proximal to the zone of earliest reacges consistently precede spontaneous tivation (Figure 12). At this site, the termination of stable SMVT. Two basic common reentrant wavefront is usually mechanisms of spontaneous termination narrow and is surrounded on each side have been observed: (1) acceleration of by an arc of functional conduction block. conduction occurs in parts of the reen- On the other hand, localized cooling of trant circuit and is associated with slow- the site of earliest reactivation commonly ing of the conduction and finally conduction failed to interrupt reentry. The common block in the CCP. Acceleration of conduction reentrant wavefront usually broke through occurs in the last few cycles of VT both at the arc of functional conduction block to the outer border of the arcs of functional reactivate other sites close to the origiconduction block in the "normal" myocar- nal reactivation site without necessarily dial zone and at the pivot points to the changing the overall reentrant activation entrance to the CCP (Figures 10 and 11). pattern. Intraoperative detailed endocardial When acceleration of conduction was and epicardial mapping during VT in compensated on a beat-to-beat basis by an patients with previous myocardial infarct equal degree of slowing in the CCP, there and ventricular aneurysm has demowas no discernible change in the cycle nstrated the presence of a figure-of-8 length of the VT in the ECG. In some reentrant circuit in the endocardial episodes, the termination of the original region. A figure-of-8 reentrant circuit reentrant circuit was followed by the could be interrupted by electrical fulgudevelopment of a different, slower reenration of the region encompassing the trant pathway that lasted for one or a few 46 common reentrant wavefront. Recently, cycles prior to termination. (2) The activation wavefront in the CCP abruptly 3-dimensional electromagnetic mapping broke across a stable arc of functional has been used to localize the optimal site conduction block, resulting in premature for radiofrequency ablation of postinactivation of the CCP and conduction farction sustained VT. Macroreentrant circuits with 1 or 2 loops rotated around block. a protected isthmus bound by 2 approximately parallel conduction barriers of Interruption of a Figure-of-8 either a functional line of block, a scar area, or the mitral annulus. The same Reentrant Circuit critical isthmus could be shared by more Reversible cooling or cryoablation of than one VT morphology. Radiofrequency localized areas of the figure-of-8 reentrant ablation performed across the critical circuit in the canine postinfarction heart isthmus prevented the recurrence of VT was used to prove the presence of circu- in 90% of cases.47 Electrophysiological Mechanisms of Spontaneous Termination of Figure-of-8 Reentry

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Figure 10. Epicardial isochronal activation maps of the last 4 cycles of the ventricular tachycardia (VT) shown in Figure 11. Isochrones are represented by closed contours at 10-ms intervals; arcs of functional block are represented by heavy solid lines. The position of the left anterior descending coronary artery is represented by the dashed lines. The electrode sites of the electrograms shown in Figure 11 are represented by solid circles. The tachycardia was maintained by a stable clockwise wavefront at the anterolateral border of the ischemic zone, while the location and configuration of the counterclockwise wavefront at the apex varied from beat to beat. However, both wavefronts joined into a central common pathway (CCP), where conduction was significantly slowed. The maps illustrate gradual acceleration of conduction at the outer border of the arcs of block and the pivot points to the entrance to the CCP. During the last VT cycle (V_T), conduction block developed in the CCP with termination of reentry.

Entrainment, Termination, or Acceleration of Figure-of-8 Reentrant Tachycardia by Programmed Stimulation In thefigure-of-8reentrant circuit, the 2 arcs of conduction block and the slow

common reentrant wavefront are functionally determined and cycle length dependent. A tight fit exists at certain locations during the reentrant tachycardia, with the circulating wavefront closely following the refractory tail of the previous revolution. This is particularly significant in the zone of the slow common reentrant wavefront.

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ulated termination of reentrant tachycardia, the stimulated wavefront must arrive at the area with the longest refractoriness in the zone of the slow common reentrant wavefront before refractoriness expires, thus resulting in conduction block. If this area is strategically located between the 2 arcs of functional conduction block, reentrant excitation is terminated. The 3 factors that determine whether the stimulated wavefront can reach this zone in time for conduction block are (1) the cycle length of stimulation; (2) the number of stimulated beats; and (3) the site of stimulation (Figures 13 and 14).48 The optimal method for stimulated termination of reentry is to apply a critically coupled single stimulus to the proximal side of the slow common reentrant wavefront that conducts prematurely to the strategic zone for conduction block. The stimulus can only result in local capture and does not have to conduct to the rest of the ventricles (i.e., concealed conduction). When a single stimulated waveFigure 11. Surface ECG lead and selected elecfront fails to terminate reentry, one or trograms along the clockwise wavefront shown in Figure 10. Spontaneous termination of sus- more subsequent wavefronts may suctained monomorphic ventricular tachycardia (VT) ceed. However, the stimulated train must is illustrated. Numbers are in milliseconds and be terminated after the beat that interillustrate the shortening of the VT cycle length rupts reentry. Otherwise, a subsequent prior to termination at different electrode sites as shown in Figure 10. The vertical bars at the top stimulated beat could reinitiate the of the figure delineate the time intervals of the 4 same reentrant circuit or induce a difactivation maps shown in Figure 10. ferent circuit. The new circuit could have a shorter revolution time, resulting in The reentrant circuit conduction time is tachycardia acceleration and occasiondetermined by the area with the longest ally degeneration into ventricular fibrilrefractoriness in the zone of the slow lation. Overdrive termination of reentry common reentrant wavefront. It is safe requires both a critical cycle length of to assume that during reentrant tachy- stimulation and a critical number of cardia, the duration of refractoriness in beats in a stimulated train. Otherwise, the zone with the longest refractoriness the stimulated train could establish a probably cannot shorten any further. This new balance of refractoriness and conis not the case, however, with the rest of duction velocity in the reentrant paththe reentrant pathway. A stimulated way. This could perpetuate the reentrant wavefront at a cycle length shorter than process at the shorter cycle length of the the tachycardia cycle length can still con- stimulated train, resulting in entrainment, duct in these zones. In other words, these and spontaneous reentry would resume zones have a gap of excitability. For stim- on termination of the train. Studies of

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Figure 12. Interruption of a figure-of-8 reentrant tachycardia in the epicardial layer overlying 4-dayold canine infarction by cryothermal techniques. The control activation map is shown on the left (VT), and the map of the last reentrant beat before termination on the right (VT-CRYO). Selected epicardial electrograms are at the bottom. The position of the cryoprobe is represented by the shaded circle. The reentrant circuit was interrupted by reversible cooling of the distal part of the common reentrant wavefront (site H). During control, the conduction time between the proximal electrode site G and the more distal site H was 33 ms. Before termination of the tachycardia, an incremental beat-to-beat increase of the conduction time between sites G and H occurred, associated with equal increases in the tachycardia cycle length. When conduction block developed between the 2 sites, the reentrant circuit was terminated and electrogram H recorded an electrotonic potential but no local activation potential. This was represented on the isochronal map by an arc of conduction block (heavy solid line) that joined the 2 separate arcs of conduction block into one. Modified from Assadi M. Am Heart J 1990; 119:1014–1024.

the effects of programmed stimulation on figure-of-8 reentrant tachycardia illustrate the significance of the site of stimulation and emphasize the need for more precise localization of the slow zone of reentry and the direction of the activation front in this zone in the clinical setting.

Effects of Modulation of Spatially Nonhomogeneous Refractory Patterns on the Initiation of Reentry Evidence of the role of spatially nonhomogeneous distribution of refractoriness

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Figure 13. Electrocardiographic recording showing that a train of 4 stimulated beats (marked by vertical bars) resulted in entrainment, termination, or acceleration of a monomorphic reentrant tachycardia, depending on the cycle length of stimulation. Recordings were obtained from 4-dayold canine infarction. The numbers are in milliseconds. The time lines represent 100 ms. From El-Sherif N, et al. Pacing Clin Electrophysiol 1987; 10:341–371.

in the formation of the arc of functional conduction block in the figure-of-8 model of reentry in the canine subacute infarction heart can be obtained from at least 4 types of experiments: (1) experiments in which a short-long-short stimulated cardiac sequence is required for successful initiation of reentry49; (2) experiments in which the initiation of reentry can be prevented by changing the activation pattern of the basic stimulated beat50; (3) experiments showing the effects of adrenergic stimuli on the initiation of reentrant excitation51; and (4) data on the modulation of refractoriness by antiarrhythmic agents. Short-Long-Short Cardiac Sequence Facilitating Induction of Reentry A short-long-short cardiac sequence frequently precedes episodes of ventricular

tachyarrhythmias. Programmed electrical stimulation techniques that use such a sequence have been shown to facilitate the induction of VT52 and macroreentry within the His-Purkinje system.53 For the His-Purkinje system, a short-long-short cardiac sequence has been shown to result in differential changes in refractoriness of Purkinje and muscle fibers that could facilitate the initiation of reentry.54 For the canine postinfarction model, it was also shown that a critically coupled premature stimulus applied after a conditioning train consisting of a series of short cardiac cycles with abrupt lengthening of the last cycle of the train was more successful in inducing a reentrant ventricular tachyarrhythmia than were fixed conditioning trains of short or long cycles (Figure 15).49 The abrupt lengthening of the cardiac cycle before the introduction of a premature stimulation resulted in differential

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Figure 14. Diagram of the mechanisms of entrainment, termination, and acceleration of reentrant ventricular tachycardia by overdrive stimulation as shown in Figure 13. In each of the 3 panels, the control reentrant circuit is labeled 1 and the 4 beats of the stimulated train are labeled 2 to 5. The control circuit has a figure-of-8 configuration, and conduction in the slow zone of reentry proceeds from left to right. The heavy solid lines represent arcs of functional conduction block. Stimulation was applied at the distal side of the slow zone, as shown by the asterisks. During entrainment (left panel), the stimulated wavefront collides with the emerging slow reentrant wavefront. It then circulates and arrives earlier to the proximal part of the slow zone of reentry. This is consistently associated with a change in the conduction pattern in the slow zone, with the development of new functional arcs of block and much slower conduction in parts of this zone. However, a new equilibrium quickly develops in which successive stimulated beats, represented by cycles 3, 4, and 5, maintain the same new conduction pattern at the shorter cycle length of stimulation, thus entraining the tachycardia. On cessation of stimulation, reentry will resume as shown in cycle 6. For termination of reentry, on the other hand (middle panel), successive stimulated beats, now applied at a relatively shorter cycle compared with the entraining train, will result in gradually more conduction delay. Conduction block eventually develops at the proximal part of the slow zone of reentry, as shown in cycle 5. Right panel: The same 4-beat stimulated train is applied at a still shorter cycle length. In this case and because of the short cycle length of stimulation, the second stimulated beat represented by cycle 3 has already blocked in the proximal part of the slow zone of reentry. If stimulation is stopped at this point, the reentrant tachycardia terminates. However, if stimulation is continued, the third and fourth stimulated beats represented by cycles 4 and 5 initiate new arcs of block and different reentrant pathways so that on termination of the stimulated train, a new and possibly faster reentrant circuit will occur. From El-Sherif N, et al. Pacing Clin Electrophysiol 1987;10:341–371.

lengthening of effective refractory periods (ERPs) at adjacent sites within the border of the epicardial ischemic zone. On the other hand, those same sites showed comparable shortening of refractory periods after a train of regular short cycles and comparable lengthening of ERPs after a train of regular long cycles (Figure 16).

Epicardial sites closer to the center of the ischemic zone that showed more electrophysiological abnormality, as suggested by their longer refractory periods, showed greater dependence on the immediately preceding cycle compared with more normal sites located close to the border of the ischemic zone. This suggested that

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Figure 15. Epicardial activation maps of the premature stimulus following 3 different conditioning stimulated trains from a dog with 4-day-old myocardial infarction. Protocol A consisted of a train of 8 beats at a cycle length of 300 ms. Protocol B consisted of a train of 8 beats at a cycle length of 300 ms, with the exception of the last cycle before the premature stimulus, which was abruptly increased to 600 ms. Protocol C consisted of a train of 8 beats at a cycle length of 600 ms. The coupling interval of the premature stimulus was the same during the 3 stimulation protocols at 170 ms. During protocol A, the premature stimulus resulted in an arc of functional conduction block (heavy solid line) within the border of the ischemic zone. The activation wavefront circulated around both ends of the arc, coalesced, and reached the distal side of the arc at the 100-ms isochrone. The relatively short circulation time around the arc did not allow for refractoriness to expire proximal to the arc and for reexcitation to take place. The epicardial activation pattern of the premature stimulus during protocol C was largely similar to that during protocol A. On the other hand, during protocol B, the premature stimulus resulted in a significantly longer arc of functional conduction block by extending the arc during protocols A and C on both the septal and lateral borders of the ischemic zone. The activation wavefront circulated around both ends of the arc, coalesced, and advanced slowly to reach the distal side of the arc at the 160-ms isochrone. The longer circulation time allowed for refractoriness to expire on the proximal side of the arc and for reexcitation to take place. Reproduced with permission from El-Sherif N, Gough WB, Restivo M. Circulation 1991;83:268–278. Copyright 1991, American Heart Association.

ischemic myocardium may have less memory of the cumulative effect of preceding cycle lengths than does normal myocardium. The differential lengthening of refractory periods at adjacent sites after abrupt lengthening of the cardiac cycle resulted

in sufficiently increased dispersion of refractoriness during which a premature stimulus resulted in the development of functional conduction block between those sites. The development of longer arcs of functional conduction block with the short-long-short cardiac sequence resulted

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Figure 16. Recordings obtained from the same experiment shown in Figure 15, illustrating effective refractory measurements at selected adjacent sites proximal and distal to the arc of block during stimulation protocols A to C. During the 3 stimulation protocols, the difference in refractory periods between adjacent paired sites that spanned the arc of block was 20 ms or longer, whereas adjacent sites on the same side of the arc of block differed by less than 20 ms. The refractory periods at all sites were shortest during protocol A, showing an increment during protocol B, and generally increased further during protocol C. However, the percentage of increment in the refractory periods between protocols A, B, and C differed at sites proximal and distal to the arc. At sites proximal to the arc, the step increment in refractory period was approximately equal between protocols A and B and between protocols B and C. On the other hand, at sites distal to the arc, most of the increment in refractory period occurred between protocols A and B. This differential behavior of refractory period in response to protocol B resulted in an increased dispersion of refractoriness between adjacent sites within the border of the ischemic zone and in the development of functional conduction block between these sites. Reproduced with permission from El-Sherif N, Gough WB, Restivo M. Circulation 1991 ;83:268-278. Copyright 1991, American Heart Association.

in a longer reentrant pathway and, hence, an increased reentrant circuit conduction time. Another factor that contributed to increased reentrant circuit conduction time was further slowing of conduction

around the arc of block. The combination of these factors allowed more time for refractoriness to expire proximal to the arc of block and for the circulating wavefront to reexcite those sites to initiate reentry.

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Prevention of Reentrant Excitation by Dual Stimulation During Basic Rhythm Initiation of reentrant excitation can be prevented by changing the activation pattern of the basic stimulated beat. The spatial patterning of recovery time depends on the activation pattern of the basic beat, in addition to the spatially nonhomogeneous refractory distribution induced by ischemia. The dispersion of recovery time can be modified by stimulation at 2 ventricular sites during the basic beat. The arc of conduction block can be modified or abolished entirely by appropriate selection of the secondary stimulation site in the ischemic zone and the temporal sequencing of the paired

stimuli (Figure 17). Asynchronous dual stimulation, with preexcitation of an appropriate site in the ischemic zone, was frequently successful in preventing the initiation of reentry by a fixed coupled premature stimulus. In all instances that resulted in the prevention of reentry, the secondary site was distal to the arc of block that formed after the control S2 stimulation. The secondary site should be in an area of long refractoriness that activated late during the basic beat. Properly applied dual stimulation differentially peels back recovery time in the ischemic zone. Successful dual stimulation depended on the reduction of 2 factors: the spatial gradient of recovery time and the dispersion of recovery time across the arc. The former determines

Figure 17. Abolition of the arc of functional conduction block by dual S1 stimulation. Top (control): S1 activation occurred within 60 ms. A gradient of recovery time between the 190and 230-ms isochrones supported the formation of an arc of block during S2. Bottom (dual asynchronous stimulation): The 2 sites of stimulation, one from the right ventricle (as in control) and one from the ischemic zone distal to the arc of block, are represented by asterisks. When the dual ischemic site was preexcited by 40 ms, no 2 adjacent sites differed in recovery time by more than 20 ms. A zone of graded recovery time that could support functional conduction block was not present. An arc of conduction block did not form. In this experiment, the recovery time was computed by the sum of the activation time (stimulus artifact to response during S1,) plus the effective refractory period at each site. Reproduced with permission from Restivo M, Gough WB, El-Sherif N. Circulation 1988;77:429-444. Copyright 1988, American Heart Association.

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the extent and location of the continuous arc of conduction block and the latter determines whether areas distal to block have recovered during the premature stimulation. Reducing the difference in activation time across the arc of block to a value less than the ERP of the premature stimulus proximal to the arc is the mechanism by which dual S1 stimulation can prevent the initiation of reentry.50 Recently, the technique of biventricular pacing that involves simultaneous pacing of the right and left ventricles has gained wide acceptance. The technique is indicated in patients with depressed left ventricular function and a wide QRS complex and is primarily intended to improve the ventricular function. However, it is also expected to be antiarrhythmic by decreasing the spatial dispersion of repolarization. Effects of Adrenergic Stimuli on the Initiation of Reentrant Excitation It is well known that adrenergic autonomic activity has a role in the generation and perpetuation of cardiac arrhythmias.55,56 However, ischemia can directly affect the sympathetic innervation of the ventricles and thereby alter the effects of sympathetic tone on the ventricle.57 Transmural myocardial ischemia has been shown to disrupt sympathetic innervation of the ventricles and to cause denervation hypersensitivity.58,59 In this case, sympathetic stimulation would increase the dispersion or gradient of refractoriness between innervated and denervated regions.57 The adrenergic effects on reentrant excitation in the canine postinfarction model were investigated by Butrous et al.51 Bilateral stimulation of the ansae subclaviae preferentially improved conduction of premature beats in the normal zones. This corresponded to an improvement in excitability, as measured by a

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decrease in stimulus strength at the same premature coupling interval as control. Consequently, the ERP was preferentially shortened at normal sites but not at ischemic sites. Both of these changes contributed to a shift of the arc of functional conduction block toward more normal tissue. As a result, sites proximal to the arc of functional conduction block had more time to recover excitability and thereby were available to be reexcited by the distal activation wavefront (Figure 18). These observations are consistent with the tenet that sympathetic denervation occurred in the ischemic area, where a thin epicardial layer of myocardium survived the infarction. Another effect of preferential shortening of the refractory period in the normal zone was the extension of the arc of functional conduction block. The lengthening of the arc of functional conduction block or the de novo creation of an arc of functional conduction block in the ischemic zone can potentially facilitate the occurrence of reentrant excitation. In contrast to sympathetic stimulation, intravenous infusion of norepinephrine preferentially shortened the ERP of sites in the ischemic zone, thereby indicating that denervation hypersensitivity had occurred at those sites. The spatial dispersion of refractoriness and the arc of functional conduction block were significantly reduced in size. As a consequence, previously inducible reentrant rhythms were no longer inducible (Figure 19). Thus, sympathetic stimulation can be considered an arrhythmogenic intervention, whereas norepinephrine infusion may be considered antiarrhythmic in this model. Effects of Antiarrhythmic Agents on Figure-of-8 Reentry The pharmacological basis of antiarrhythmic drug therapy in the treatment of reentrant tachyarrhythmias has been

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Figure 18. Epicardial activation patterns and representative electrograms from a dog with 4-dayold myocardial infarction showing the effects of sympathetic stimulation (SS) on the initiation of reentrant excitation. The heart was stimulated at a basic cycle length of 400 ms (S^, and a premature beat (S2) was introduced at a cycle length of 160 ms. During control, S2 resulted in an arc of functional conduction block. Activation arrived on the distal side of the arc of block but did not reexcite areas proximal to the arc (i.e., no reentrant beat occurred). During subsequent bilateral ansae subclaviae stimulation, an S2 at 160 ms produced an arc of functional block and a reentrant beat. The upward arrows on the electrograms represent the effective refractory periods (values indicated) relative to the time of activation at 3 sites across the arc of block. During the control S2, the arc of block was located between sites b and c. During bilateral ansae subclaviae stimulation, the arc of block shifted toward the more normal myocardium (to between sites a and b). Conduction was improved proximal to the arc, as evidenced by the reduction in response interval (R^)- The R1R2 interval at site a shortened during sympathetic stimulation, but the effective refractory periods at sites a, b, and c were not changed. Therefore, S2 arrived earlier at site a, and R2 was unable to propagate directly to site b because it was still refractory (see electrograms). Consequently, the wavefront conducted around the arc of block and then excited site b. The conduction time from site a to site b provided sufficient time for site a to recover its excitability, and the wavefront was then able to reexcite site a. Thus, a reentrant beat was initiated. Reproduced with permission from Butrous GS, Gough WB, Restivo M, et al. Circulation 1992;86:247-254. Copyright 1992, American Heart Association.

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Figure 19. Epicardial activation maps of a premature stimulus (S2) during control (left) and during norepinephrine infusion (right) from a dog with 4-day-old myocardial infarction. During control S2, a long continuous arc of functional conduction block developed. The activation wavefront circulated around the arc then reexcited a site proximal to the arc to initiate a reentrant beat. The dotted line in the control map represents the area of earliest reentrant excitation. The enlarged section (bottom) is from the area of the arc of functional conduction block, with the refractory period of each respective site noted. During norepinephrine infusion, the arc divided into 2 smaller arcs. The dotted line in the norepinephrine maps represents the previous position of the arc of functional conduction block during control. The total activation time shortened during norepinephrine infusion, and there was preferential shortening of the effective refractory period at sites previously distal to the arc of functional conduction block. In this example, the average refractory period for all sites proximal to the arc of functional conduction block during control was 179 ± 12 ms. It was shortened to 161 ± 10 ms (an average shortening by 18 ms) during norepinephrine infusion. The average refractory period for all sites distal to the arc of functional conduction block during control was 249 ±15 ms. It was shortened to 195 ± 18 ms (an average shortening by 54 ms) during norepinephrine infusion. Therefore, norepinephrine decreased the gradient of refractoriness between the normal and ischemic sites. Consequently, the length of the arc of functional conduction block was reduced and shifted toward more ischemic tissue, resulting in prevention of the initiation of reentrant excitation. Reproduced with permission from Butrous GS, Gough WB, Restive M, et al. Circulation 1992;86:247-254. Copyright 1992, American Heart Association.

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guided mostly by the original observations of Mines.5 For any model of reentrant activity, the key ingredients are unidirectional block and conduction around an alternate pathway that is impaired to a degree to permit reexcitation. Drug action is usually defined by its effect on action potential characteristics (upstroke velocity and action potential duration). In the not too distant past, if one were to pick up Goodman & Gilmaris The Pharmaceutical Basis of Therapeutics,60 one would find that antiarrhythmic efficacy was based on drug action on reentry within an anatomically predetermined pathway. In the simplest sense, Class I agents were believed to cause conduction failure in the slow conduction portion of the circuit and Class III agents were believed to cause block within the circuit due to prolonged refractoriness. Besides the simplicity of the reentrant circuit topology, the primary flaw in this reasoning was that drug action was evaluated in normal tissue. Even the sophistication of the more recent Sicilian Gambit61 classification system is limited because of insufficient allowance for evaluation of drug action in diseased myocardium. The results of the Cardiac Arrhythmia Suppression Trial (CAST)62 brought attention to drug-induced proarrhythmia and, in particular, to the problems associated with the means by which the efficacy of potential antiarrhythmic drugs are determined. While there is a heightened awareness of the problems associated with antiarrhythmic drugs (especially in the treatment of ventricular tachyarrhythmias), drug development is hampered by the fact that the mechanisms of drug-induced antiarrhythmic or proarrhythmic effects still remain unclear. The induction or suppression of reentrant activation in the figure-of-8 model

involves a complex interplay of functional activation properties and changes in these properties that are associated with the pathological state of the heart. The antiarrhythmic or proarrhythmic effect of a drug can be best studied by measuring the rate-dependent effects of the agent on conduction and refractory properties of normal and ischemic zones in the heart.63-65 The proceeding section reviews the electrophysiological actions of 3 antiarrhythmic agents, flecainide, lidocaine and azimilide, in the figure-of-8 model of circus movement reentry in the subacute MI period in the dog. The working model is based on the facts that functional conduction block occurs because of differentially prolonged refractoriness between normal and ischemic zones and that tachycardiadependent slow conduction occurs in the hypoperfused ischemic layer. The hypothesis tested is that agents that promote slower conduction in the ischemic zone or extend the line of block by differential prolongation of refractoriness in the ischemic zone favor reentry. Figure 20 is a bubble diagram illustrating the antiarrhythmic (or proarrhythmic) effects of all 3 drugs. Results are from 3 different studies and no statistical comparisons were made to compare antiarrhythmic efficacy between the 3 drugs. Flecainide is a Class Ic agent whose effects are believed to be highly selective for use-dependent blockade of sodium channels. Some of the proarrhythmic effects of flecainide were known prior to CAST. Ranger et al.66 made the interesting observation that VT could be aggravated in patients by exercise, i.e., fast heart rates. We studied the rate-dependent effect of flecainide in the canine subacute infarction model. The ECGs in Figure 21 illustrate the rate-dependent aggravation of arrhythmia due to flecainide. Insight into

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Figure 20. Bubble diagrams illustrating the effects of flecainide, azimilide, and lidocaine for induction of reentry with only a single premature beat (S2). Responses were classified as follows: VT = sustained monomorphic ventricular tachycardia; NS-RA = nonsustained reentrant activity; NR = no response (less than 3 unstimulated responses). Proarrhythmic effects (upward sloping lines) are defined as the drug-induced transformation of: (1) NR to either NS-RA or VT, or (2) NS-RA to VT. Antiarrhythmic affects are the converse of above and are indicated by downward sloping lines. Horizontal movement indicates no effect of the drug on arrhythmia induction. A. Flecainide was administered as a bolus dose of 1 mg/kg given over 8 minutes, followed by a maintenance infusion of 1 mg/kg/h. For flecainide, there were 4 proarrhythmic events in 16 dogs (25%) at a basic cycle length (BCL) of 500 ms, and 10 proarrhythmic events at a BCL of 300 ms (62.5%). The proarrhythmic effect of flecainide was more prominent at a BCL of 300 ms (P < 0.005, Pearson chi-square). B. Azimilide was tested at 3 doses. It had essentially no effect at 3 mg/kg. The drug was effective in suppressing reentrant ventricular arrhythmias in 6 dogs at a dose of 10 mg/kg and 2 additional dogs at 30 mg/kg. In 2 dogs, there was a drug-induced aggravation of inducible reentrant VT at a dose of 10 mg/kg and at 30 mg/kg there was one case of drug-induced conversion of NR to NS-RA. C. Lidocaine was administered as a bolus dose of 6 mg/kg, i.v., delivered over 10 minutes, followed by a maintenance infusion of 75 jig/kg/min. For lidocaine, there were 3 proarrhythmic events in 18 dogs (16.7%) at a BCL of 500 ms, and 8 proarrhythmic events at a BCL of 300 ms (44.4%). The overall proarrhythmic effect of lidocaine showed increased tendency at a BCL of 300 ms, but the difference was not statistically significant. On the other hand, the proarrhythmic effect of lidocaine through transformation to VT was more prominent at a BCL of 300 ms compared to 500 ms and was statistically significant (P < 0.05). There were no cases of drug-induced transformation of VT to NS-RA or NR.

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Figure 21. A. Lead II ECG from an experiment during which, in the control pre-drug state, S1,S2 of 170 ms did not induce any response at basic cycle lengths (BCLs) of 300 ms or 500 ms. After flecainide infusion, no response was elicited at a cycle length of 500 ms. However, at a cycle length of 300 ms, a single extrastimuli induced a sustained monomorphic ventricular tachycardia. B. and C. Isochronal activation maps during regular pacing and premature stimulation. The maps show the epicardial ventricular surface with the perimeter representing the atrioventricular ring and the center the apex; the left anterior descending coronary artery is shown by the dotted line. In these maps each isochronal contour represents a portion of the heart that was activated within a 20-ms time frame. Panel B shows S1, activation patterns during BCLs of 500 ms and 300 ms. In control, the ventricles were activated within 80 ms. There was no evidence of conduction block in any of the maps. After flecainide, the heart activated within 80 ms at a BCL of 500 ms and increased slightly to 100 ms at a BCL of 300 ms. The S2 activation maps for an S^ coupling of 170 ms are shown in C. The upper left map shows the control pre-drug activation pattern at BCL of 500 ms. An arc of functional conduction block formed during the 40-ms isochrone. Activation reached the distal border of the arc during the 160-ms isochrone. Because the maximum activation time difference across the arc of block was only 120 ms, the impulse was unable to reenter. Following flecainide, reentry could not be induced by premature stimulation at that cycle length. The activation map was essentially the same as control. At a BCL of 300 ms, reentry was not induced during control, but following flecainide, more dramatic changes in S2 activation are apparent. Again, the premature wavefront blocked within 40 ms. Flecainide depressed conduction in the slow zone and delayed activation at the distal border of the arc of block to the 200-ms isochrone, increasing the activation time difference across the line of block to 160 ms, and the impulse was able reenter near the site of initial conduction block.

the mechanism is revealed by analysis of the isochronal activation maps in panels B and C, which show that conduction in the ischemic zone is differentially depressed (without conduction failure) relative to

the normal zone. In the S2 maps, there is little difference in the size of the line of block before or after flecainide. Because we have shown that block results from differences in ERPs between normal and

FiGURE-OF-8 MODEL OF REENTRANT VENTRICULAR ARRHYTHMIAS ischemic zones, we measured ERPs before and after flecainide. Consistent with its Class Ic action and lack of change in the lines of block, we found no statistically significant difference in ERP.63 We then

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measured the rate dependence of conduction velocity in normal and ischemic tissue using a specially designed highresolution cross electrode. The results, shown in Figure 22, show a rate-dependent

Figure 22. Rate dependence of conduction velocity in control and in the presence of flecainide. Results shown are from 6 dogs. In these graphs, conduction velocities were normalized to the longest basic cycle length (BCL) (600 ms). The effect of the drug was more pronounced for propagation in the ischemic zone relative to the normal zone and was statistically significant at the shorter BCLs in all 4 groups. Flecainide caused a rate-dependent reduction of conduction velocity of 14% (longitudinal) and 8% (transverse) for a change in basic drive from 600 ms to 250 ms in normal tissue, and a reduction of 27% (longitudinal) and 25% (transverse) for a change in basic drive from 600 ms to 250 ms in ischemic tissue.

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preferential depression of conduction in the ischemic zone. Azimilide is a Class III agent that acts by prolonging refractoriness and has little effect on conduction velocity. Figure 23 shows maps from a representative experiment in which a sustained monomorphic VT was induced by a single premature beat. A dose of 10-mg/kg azimilide slowed the VT with termination coinciding with block of the reentrant impulse within the slow common reentrant pathway. To understand the mechanism of azimilide action, we measured ERPs in this vicinity at cycle lengths of 350 ms and 600 ms, before and after drug infusion. Data shown in panel A of Figure 24 indicate that block occurred because of a prolongation of ERP at the

critical sites. The preferential prolongation of ERP in the ischemic zone by azimilide is illustrated in panel B. Recently we have shown that in the canine right atrial enlargement model of circus movement atrial flutter, both azimilide and dofetilide were 100% effective in terminating flutter and preventing reinduction. Efficacy relied on a similar mechanism of differentially prolonged refractoriness in the slow conduction component of the reentrant circuit where drug-induced termination occurred.67 Lidocaine is a familiar and widely used antiarrhythmic agent, with occasional proarrhythmic effects having been noted for years.68,69 Lidocaine is more of a mixed bag compared to the previous drugs described above. Lidocaine has

Figure 23. Isochronal activation maps of control ventricular tachycardia (VT) induction and termination of VT by azimilide. The left panel shows the map of the control VT induced by a single premature beat. The cycle length of the VT in this example was 285 ms. In this experiment, the reentrant circuit had a figure-of-8 morphology in which 2 wavefronts circulated around 2 lines of functional conduction block. Each isochronal contour line represents the boundary of a region activated by the reentrant wavefronts in successive 10-ms intervals. In this particular experiment, there was a region of necrosis extending through to the epicardial surface and is indicated in the maps by shaded region. The 2 wavefronts joined once every cycle and conducted slowly through the ischemic epicardial layer in the area bounded between the 2 lines of block (isochrones 120 through 250). The maps in the middle panel show that following a 10 mg/kg infusion of azimilide, the cycle length of the VT progressively slowed to 320 ms before druginduced termination of the rhythm. Azimilide caused a marked increase in overall conduction time within the slow conducting pathway. In the last beat (right panel; VTerm), the reentrant impulse failed to penetrate through the ischemic zone and blocked during the 470-ms isochrone between sites L and M.

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Figure 24. A. Effective refractory period (ERP) values near the site of block during termination for the example shown in Figure 23. The lines of block from the activation maps are shown with ERP values, and clearly show that conduction block occurred near sites with the greatest refractory period values in control (sites M and N). These sites also had the longest refractory period values after 10 mg/kg azimilide. B. A grouped analysis on the effect of azimilide on increasing ERP in normal and ischemic zones using 2 basic cycle lengths (BCLs). Data presented in this figure are for those sites in which ERP data was obtained in control, 10 mg/kg azimilide, and 30 mg/kg azimilide. One way analysis of variance was performed to test for significant differences between the groups. Student's paired Mest for paired data was then performed to test for differences between control ERP and ERP at both drug doses. There was a statistically significant increase in ERP by azimilide in normal and ischemic tissues at both BCLs. The drug-induced increase in ERP was statistically greater in ischemic tissue compared to normal tissue for both drug doses and at both BCLs.

been shown to completely abolish membrane responsiveness in severely ischemic cells in the epicardial border zone during the subacute phase of MI.69 Not only does lidocaine depress conduction, but it also has a prolonging effect on ERP. Similar to flecainide, lidocaine has been shown to cause a selective ratedependent decrease in conduction velocity in the ischemic zone. This is keeping with its possible proarrhythmic action.

We examined the effect of lidocaine on normal and ischemic tissue.63 The proarrhythmic effects of lidocaine, shown in Figure 25, are due not only to depressed conduction in the ischemic zone but an increased path length resulting from differential prolongation of ERP. Figure 26 shows that lidocaine could be antiarrhythmic only if ERPs in the ischemic zone were prolonged to such a degree that the reentrant impulse blocked in

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Figure 25. Proarrhythmic effect of lidocaine. Activation maps from a representative experiment illustrating the effects of lidocaine at different basic cycle lengths (BCLs). The upper left panel shows a control isochronal map of a premature beat following a drive of 29 basic beats at a BCL of 300 ms. After an S1,S2 of 180 ms, the premature activation wavefront encountered a continuous line of block within 40 ms. Conduction then proceeded retrogradely through the slow zone and blocked at 140 ms distal to the block. After lidocaine, premature stimulation at the sameS1S2coupling interval had a proarrhythmic effect. The line of block was longer compared to the control pre-drug map, and conduction within the slow zone proceeded much slower. Because of the additional delays incurred, the impulse reached the distal border of the block later than in control and reactivation occurred within 240 ms. In this experiment, a sustained monomorphic ventricular tachycardia (VT) (upper right panel) was induced. The VT cycle length was 184 ms. In the same experiment, lidocaine also had a proarrhythmic effect (nonsustained VT) at a BCL of 500 ms but no sustained VT was induced.

the common reentrant pathway. The effects of lidocaine on ERP in normal and ischemia tissue are summarized in Figure 27. In summary, in the subacute MI model, pure Class I drug action appears to be proarrhythmic with regard to reentrant substrates. This is due to a preferential depression of conduction in the

ischemic zone, a factor that favors reentry. The role of Class III or Class Ib agents is more complex. In this functional model of reentry, the obstacle around which the reentrant impulse circulates is most probably due to differential prolongation of refractoriness between normal and ischemic zones. Therefore, any agent that preferentially prolongs refractoriness

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Figure 26. Antiarrhythmic effect of lidocaine. Lidocaine exhibited antiarrhythmic behavior if there was a marked increase in effective refractory period (ERP) after drug, as illustrated in the following maps. In this example at a basic cycle length of 500 ms, a single premature beat at 200 ms (left panel) caused block and reentry within 200 ms. After lidocaine (right panel), reentry did not occur with the same premature coupling interval. The impulse coalesced at the entrance of common reentrant pathway within 120 ms, and blocked within the common reentrant pathway within 180 ms. ERPs were measured at critical sites within the common pathway. Though conduction in the vicinity of sites C and D was slowed after lidocaine, there was a marked prolongation of refractoriness at sites within the ischemic zone (C and D) relative to border sites (B) and normal sites (A). Site D could not activate because it was still refractory; block occurred between sites C and D.

may increase the length of the functional obstacle, again a factor that favors reentry. In the examples presented here, antiarrhythmic action occurs only when refractoriness is prolonged to such a degree that conduction block within the slow pathway of the circuit is possible. Because it

is impossible to predict the wide range of electrophysiological consequences of MI in all cases, antiarrhythmic drug therapy must be carefully tailored to individual situations. What may be good in one situation may result in opposite results in another.

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CAEDIAC MAPPING Figure 27. Effect of lidocaine on effective refractory period (ERP) in normal and ischemic tissue. Lidocaine increased refractoriness to a greater extent in the ischemic zone compared with the normal zone, but tne effect was rate independent. The drug-induced ERP increase (ERPlidocaine-ERPcontrol) was more pro-

nounced in the ischemic zone compared to normal. The difference was statistically significant at 300 ms (16.3 ±19.1 versus 9.8 ± 10.7; P < 0.05). Pacing threshold increased significantly after lidocaine in both normal (0.9 ± 0.7 mA versus 1 .4 ± 1.3mA; P< 0.01) and ischemic (0.8 ± 0.5 versus 1.2 ± 0.9; P < 0.01) zones, but there was no statistically significant difference in excitability between normal and ischemic zones before or after drug. Our previously published reports established that arcs of functional conduction block result from regional disparities in refractoriness along a continuous region of the ischemic border zone. Arcs of block were measured before and after lidocaine by planimetry on a 3-dimensional heart model. The lengths of the arcs of functional conduction block for all experiments were 11 .8 ± 3.9% longer after lidocaine; the effect was statistically significant (P < 0.01). The lengths of arcs of block were computed in the proarrhythmic and antiarrhythmic groups for those beats in which the activation wavefront reached the distal side of the arc. The lengthening by lidocaine was greater (14.3 ± 5.2%; P< 0.05) in the proarrhythmic group compared to the antiarrhythmic group (10.2 ± 1.7%).

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30. Mehra R, Zeiler RH, Gough WB, El-Sherif N. Reentrant ventricular arrhythmias in the late myocardial infarction period. 9. Electrophysiologic-anatomic correlation of reentrant circuits. Circulation 1983;67: 11-24. 31. Gardner PI, Ursell PC, Fenoglio JJ, Wit AL. Electrophysiologic and anatomic basis for fractionated electrograms recorded from healed myocardial infarcts. Circulation 1985;72:596-611. 32. Spear JF, Horowitz LN, Hodess AB, et al. Cellular electrophysiology of human myocardial infarction. 1. Abnormalities of cellular activation. Circulation 1979;59:247-256. 33. Spach M, Miller WT, Geselowitz DB, et al. The discontinuous nature of propagation in normal canine cardiac muscle: Evidence for recurrent discontinuities of intracellular resistance that affect the membrane currents. Circ Res 1981;48: 39-54. 34. Spear IF, Michelson EL, Moore EN. Reduced space constant in slowly conducting regions of chronically infarcted canine myocardium. Circ Res 1983;52: 176-185. 35. Spach MS, Dolber PC, Heidlage IF. Interaction of inhomogeneities of repolarization with anisotropic propagation in dog atria. A mechanism for both preventing and initiating reentry. Circ Res 1989;65: 1612-1631. 36. Dillon SM, Allessie A, Ursell PC, Wit AL. Influences of anisotropic tissue structure in reentrant circuits in the epicardial border zone of subacute canine infarcts. Circ Res 1988;63:182-206. 37. Allessie M, Lammers W, Bonke F, Hollen I. Intra-atrial reentry as a mechanism for atrial flutter induced by acetylcholine and rapid pacing in the dog. Circulation 1984;70:123-135. 38. Schoels W, Gough W, Restivo M, El-Sherif N. Circus movement atrial flutter in the canine sterile pericarditis model. Activation patterns during initiation, termination and sustained reentry in vivo. Circ Res 1990;67:35-50. 39. Winfree AT. When Time Breaks Down: The Three-Dimensional Dynamics of Electromechanical Waves and Cardiac Arrhythmias. Princeton: Princeton University Press; 1987:154-186. 40. Schoels W, Yang H, Gough WB, El-Sherif N. Circus movement atrial flutter in the sterile pericarditis model: Differential

effects of procainamide on the components of the reentrant pathway. Circ Res 1991;68:1117-1126. 41. El-Sherif N, Gough WB, Zeiler RH, Hariman R. Reentrant ventricular arrhythmias in the late myocardial infarction period. Spontaneous versus induced reentry and intramural versus epicardial circuit. J Am Coll Cardiol 1985;6:124-132. 42. Janse MJ, Van Cappelle FJL, Morsink H, et al. Flow of "injury" current and patterns of excitation during early ventricular arrhythmias in acute regional myocardial ischemia in isolated porcine and canine hearts. Evidence for two different arrhythmogenic mechanisms. Circ Res 1980;47: 151-165. 43. Kramer JB, Saffitz JE, Witkowski FX, Corr PB. Intramural reentry as a mechanism of ventricular tachycardia during evolving canine myocardial infarction. Circ Res 1985;56:736-754. 44. Fenoglio JJ Jr., Pham TD, Harken AH, et al. Recurrent sustained ventricular tachycardia: Structure and ultrastructure of sub-endocardial regions where tachycardia originates. Circulation 1983;68: 518-533. 45. El-Sherif N, Mehra R, Gough WB, Zeiler RH. Reentrant ventricular arrhythmias in the late myocardial infarction period. Interruption of reentrant circuits by cryothermal techniques. Circulation 1983;68: 644-656. 46. Downar S, Mickleborough L, Harris L. Intraoperative electrical ablation of ventricular arrhythmias: A "closed heart" procedure. J Am Coll Cardiol 1987; 10:10481056. 47. de Chillou C, Lacroix D, Klug D, et al. Isthmus characteristics of reentrant ventricular tachycardia after myocardial infarction. Circulation 2002;105:726-731. 48. El-Sherif N, Gough WB, Restivo M. Reentrant ventricular arrhythmias in the late myocardial infarction period: 14. Mechanisms of resetting, entrainment, acceleration, or termination of reentrant tachycardia by programmed electrical stimulation. Pacing Clin Electrophysiol 1987;710:341371. 49. El-Sherif N, Gough WB, Restivo M. Reentrant ventricular arrhythmias in the late myocardial infarction period: Mechanism by which a short-long-short cardiac sequence facilitates the induction of reentry. Circulation 1991;83:268-278.

FiGURE-op-8 MODEL OF REENTRANT VENTRICULAR ARRHYTHMIAS 50. Restivo M, Gough WB, El-Sherif N. Reentrant ventricular rhythms in the late myocardial infarction period: Prevention of reentry by dual stimulation during basic rhythm. Circulation 1988;77:429-444. 51. Butrous GS, Gough WB, Restivo M, et al. Adrenergic effects on reentrant ventricular rhythms in subacute myocardial infarction. Circulation 1992;86:247-254. 52. Denker S, Lehman MH, Mahmud R, et al. Facilitation of ventricular tachycardia induction with abrupt changes in ventricular cycle length. Am J Cardiol 1984; 53:508-515. 53. Denker S, Lehman MH, Mahmud R, et al. Facilitation of macroreentry within the His-Purkinje system with abrupt changes in cycle length. Circulation 1984;69:26— 32. 54. Denker S, Lehman MH, Mahmud R, et al. Divergence between refractoriness of HisPurkinje system and ventricular muscle with abrupt changes in cycle length. Circulation 1983;68:1212-1221. 55. Zaza A, Schwartz PJ. Role of the autonomic nervous system in the genesis of early ischemic arrhythmias. J Cardiovasc Pharmacol 1985;7:8-12. 56. Szekeres L, Boros E, Pataricza J, Udvary E. Sympathetic neural mechanisms in cardiac arrhythmias. J Mol Cell Cardiol 1986; 18:369-373. 57. Inoue H, Skale BT, Zipes DP. Effects of myocardial ischemia and infarction on cardiac afferent sympathetic and vagal reflexes in the dog. Am J Physiol 1988; 255:H26-H35. 58. Kammerling JJ, Green FJ, Watanabe AM, et al. Denervation supersensitivity of refractoriness in noninfarcted areas apical to transmural myocardial infarction. Circulation 1983;67:787-796. 59. Inoue H, Zipes DP. Results of sympathetic denervation in the canine heart: Supersensitivity that may be arrhythmogenic. Circulation 1987;75:877-887. 60. Goodman AG, Goodman LS, Gilman A (eds): Goodman & Oilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan; 1980.

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61. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology: The Sicilian Gambit. A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Circulation 1991;84:1831-1851. 62. Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: Effect of encainide and flecainide on mortality in randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989;321:406-412. 63. Restivo M, Yin H, Caref EB, et al. Reentrant arrhythmias in the subacute infarction period. The proarrhythmic effect of flecainide acetate on functional reentrant circuits. Circulation 1995;91:1236-1246. 64. Yin H, El-Sherif N, Caref EB, et al. Actions of lidocaine on reentrant ventricular rhythms in the subacute myocardial infarction period in dogs. Am J Physiol 1997;272:H299-H309. 65. Restivo M, Yin H, Caref EB, et al. Selective effect of class III antiarrhythmic agents on refractoriness determines efficacy in post infarction reentrant ventricular tachyarrhythmias (VT). Circulation 1996;94(Suppl):I-161. 66. Ranger S, Talajic M, Lemery R, et al. Amplification of flecainide-induced ventricular conduction slowing by exercise. A potentially significant clinical consequence of use-dependent sodium channel blockade. Circulation 1989;79:1000-1006. 67. Restivo M, Hegazy M, El-Hamami M, et al. Efficacy of azimilide and dofetilide in the dog right atrial enlargement model of atrial flutter. J Cardiovasc Electrophysiol 2001;12:1018-1024. 68. Krejcy K, Krumpl G, Todt H, Raberger G. Lidocaine has a narrow antiarrhythmic dose range against ventricular arrhythmias induced by programmed electrical stimulation in conscious dogs. Pflugers Arch 1992;346:213-218. 69. Lazzara R, Hope RR, El Sherif N, Scherlag BJ. Effects of lidocaine on hypoxic and ischemic cardiac cells. Am J Cardiol 1978; 41:872-879.

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Chapter 12 Demonstration of Microreentry Hasan Garan, MD

The accepted criteria for demonstrating that the mechanism of an arrhythmia is reentry include the presence of a region of unidirectional conduction block with return of an impulse to its site of origin via retrograde conduction in the previously blocked, but now recovered, pathway before the onset of the next cardiac cycle, and perpetuation of this geometry during the subsequent cardiac cycles.1 Reentry as the underlying mechanism becomes more convincing if the impulses expected to arise from reentry are eliminated by reversible or irreversible interruption of this pathway. When a wavefront satisfying these criteria travels along pathways several centimeters long, reentrant excitation in the form of a closed loop can, at least in theory, be detected directly by examining the local electrograms recorded by electrodes positioned along the pathways provided that the mapping system allows recordings dense enough to define the entire circuit.2 This finding has been termed macroreentry. Demonstration of the classic criteria for entrainment,3 such as progressive fusion during pacing at decreasing cycle

lengths from a site outside the circuit, is used to further support macroreentry as mechanism. However, if reentry is present but confined to a smaller area, e.g., 1 cm in diameter, direct demonstration of reentrant excitation underlying a clinical arrhythmia may not be possible within the resolution of the recording system. Reentry confined to such a small volume of myocardium has been termed microreentry to distinguish it from macroreentry. Definition of Microreentry It is difficult to formulate a canonical definition of microreentry based on circuit size alone since it may not be possible to determine pathway size with precision in clinical tachycardias using intracardiac recording techniques. This task, difficult enough sometimes for even obviously reentrant rhythms such as atrioventricular nodal reentrant tachycardia, may be more difficult for intra-atrial reentry and even more so for the majority of clinical reentrant ventricular tachycardias (VTs). Circuit size and geometry

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003. 275

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are likely to be complex and determined by the underlying individual pathology. Furthermore, only certain special components of the circuit may be fixed while other components may be dynamically coupled or uncoupled to the former resulting in changes in cycle length or surface QRS morphology.4 Therefore, rather than being categorical, the distinction between "microreentry" and "macroreentry" becomes a question of degree, and the circuit size may display a continuum from small to large. A more practical and clinically relevant definition of microreentry may be based on operational criteria. The tachycardia in question should manifest the accepted general characteristics of reentry rather than triggered activity or automaticity.5 Other supporting observations for reentry such as classic criteria for entrainment should be sought, although inability to demonstrate entrainment does not rule out microreentry since the excitable gap may be narrow and attempts to entrain may result in entry block. Furthermore, in microreentry, activation sequence mapping during tachycardia usually identifies an early site of origin, but in contrast to macroreentry where a circular loop of electrical activity can be demonstrated during each cardiac cycle, e.g., atrial flutter,6 the global activation pattern during a tachycardia with underlying microreentry manifests a radial, centrifugal spread away from this site of earliest activation or the "source." The practical question then becomes whether any component of microreentry, located close to the site of breakthrough, can be identified during endocardial catheter mapping. A Protected Zone with Altered Conduction Most models of reentry incorporate a zone of slow, often decremental, conduction taking place in a region that is "protected," or surrounded by nonconducting

tissue that prevents the wavefront, which is progressing unidirectionally in the area of slow conduction, from breaking through into the surrounding tissue at random sites. The absence of conduction in the surrounding tissue may be due to an anatomical barrier or, more commonly, to functionally refractory tissue.7 It is no longer generally accepted that these areas have well-defined and fixed entry and exit sites and also well-defined orthodromic and antidromic directions of conduction during arrhythmia. Such regions of slow conduction have been clearly demonstrated in animal models of experimental infarction.7-9 They may be epicardial,7 endocardial,8 or intramural (midmyocardial)8'9 in location, depending on the specific model and the technique used to create the experimental myocardial infarction. Extracellular recordings from such regions often display fractionated, low-amplitude electrograms with long duration.8,10 The electrophysiological and anatomical bases for the fractionated electrograms have been carefully investigated in a canine model.11 The fractionated electrograms correspond to regions where fibrosis during infarct healing has caused wide separation of individual myocardial fibers and has distorted their orientation.11 This distortion results in a matrix of inhomogeneous anisotropy, and even if transmembrane action potentials recorded from individual myocytes may be normal, the overall conduction in the area is abnormally slow due to its fiber geometry, and the extracellular electrograms recorded from within such a region look fractionated and prolonged.11 For the clinical cardiac electrophysiologist, the demonstration of microreentry during mapping requires (1) identification of a zone of slow conduction manifesting either fractionated and prolonged local electrograms spanning diastole and recorded from closely spaced sites or, rarely, continuouelPANDIASTOLIC ectrical

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this would be reentry in a small confined area. It has been demonstrated in an experimental canine model that in cases of midmyocardial reentry, the zone of slow conduction may remain "hidden" from the electrodes confined to the endocardial and the epicardial surfaces.8 Thus, specific location as well as the orientation of the slowly conducting pathways will determine whether they can be detected by endocardial catheters, and not all such regions can be adequately investigated by endocardial catheters. Intimately tied in with these issues is the question of Location of Microreentry whether there is a critical myocardial The electrode catheters are confined thickness necessary for observation comto the endocardial surface of the heart. patible with microreentry as defined above. Since the site of origin for clinical ischemic For example, in contrast to macroreentry, sustained VT frequently resides in a suben- microreentry is rarely, if ever, observed as docardial region,12 it is usually possible to a mechanism of clinical arrhythmia in record electrograms from such a subendo- the human atrial myocardium, and focal cardial region of abnormal conduction with atrial tachycardias almost always result the use of endocardial catheters. However, from automaticity or triggered activity.16 not all regions of slow conduction are Furthermore, it is not entirely clear subendocardial, and in a small number of whether microreentry is an arrhythmia cases of clinical VT, intraoperative record- mechanism that can occur solely in disings have convincingly demonstrated the eased myocardium, which provides the presence of epicardial reentry incorporat- substrate for nonuniform anisotropy. ing a zone of slow conduction with com- Spach at al.17 have demonstrated in superplete diastolic bridging in electrodes limited fused human atrial pectinate muscle fibers age-related obliteration of side-to-side to the epicardial surface.13,14 The orientation of the zone of slow electrical coupling between fibers resultconduction is also critical. Slow conduc- ing in reentry, even if not sustained reention taking place in a midmyocardial trant activation, arising within very small region may be difficult if not impossible areas. This mechanism results from the to detect by endocardial electrodes. Con- age-related exaggeration of the homogesider for example the mechanism of non- nous or uniform anisotropy and may be homogeneous anisotropic reentry.15 A scar categorized as microreentry due to the or a functional arc of conduction block small dimensions of the interdigitating may be located in the midmyocardium fibers involved (Figure 1).17 It is not clear if with slow transverse conduction moving such a mechanism in aging but undiseased around a fulcrum point resulting from human atrium can result in "idiopathic" the geometry of the edges,15 alternating clinical atrial tachycardia. Atrioventricuwith faster longitudinal conduction which lar nodal reentry may be the best undermay result in a discrete focus of endocar- stood clinical microreentry in the atrium. dial breakthrough and a "monoregional It had been believed that the circuit underspread" of activation from this source on lying this arrhythmia was confined to the the endocardial surface, whereas, in fact, compact atrioventricular node, but recent activity recorded from a single site, and (2) proof that these electrograms represent electrical activity in an essential component of the circuit, rather than representing activity in pathways outside the circuit, bearing no relationship to the reentry process. In other words, demonstration of microreentry requires finding a zone manifesting early, mid, and late diastolic potentials all recorded within a "reasonably small" site, and demonstrating their specificity as part of the arrhythmia mechanism.

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Figure 1. Microreentry in response to premature stimulation in superfused nonuniform anisotropic atrial bundle. Results were obtained at basic stimulus rate of 171/min; a premature stimulus was introduced every 10th beat at interval shown in box above each group of waveforms. Drawing at upper left shows locations where each waveform was recorded. Drawing at lower right shows perimeter of reentrant circuit, indicated by solid lines with arrows. Shaded region denotes surrounding areas in which 0 waveforms were measured at 16 sites; at each of these peripheral sites, local excitation occurred after that of sites confined to perimeter of reentrant circuit for the corresponding areas. From Spach et at. Circ Res 1988;62:828.

data from several electrophysiology laboratories suggest a substantially larger circuit incorporating atrial tissue with slow conduction due to anisotropy.18 Intrafascicular microreentry, as opposed to interfascicular macroreentry, has been proposed as a plausible mechanism for idiopathic left ventricular VT in the absence of myocardial pathology.19 Detection of the Region of Slow Conduction No matter where it is, microreentry has to "solve" the problem of slow conduction taking place in a small region.

In order to have "hidden" diastolic activation for a long time, sometimes few hundreds of milliseconds, taking place in such a small region, the average local velocity must be exceedingly low. There are several possible mechanisms, including nonhomogeneous anisotropy, of such a slow average conduction. It is not known whether directional differences in velocity in nonuniformly anisotropic tissue of the diseased myocardium alone may account for a very low average velocity necessary for clinical microreentry. Alternatively, a very special redundant pathway geometry may be needed. As a third mechanism, one may think of isolated but closely spaced myocardial fibers, able

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to communicate with each other by elec- from this site displays potentials throughtrotonus not altogether interrupting but out the entire cardiac cycle without any slowing continuous conduction by pro- appreciable isoelectric diastolic interval, ceeding in "jumps." Clinically used endo- thereby bridging the discrete local eleccardial electrode catheters are incapable trograms that do have such isoelectric of making a distinction among these interectopic intervals recorded from neighboring sites.22-24 Initiation of VT preceded mechanisms. Fractionated, prolonged local elec- by critical delay and fractionation in local trograms may be recorded from several electrograms bridging the interectopic disparate sites in the myocardium if the interval between the last extrastimulus underlying pathological process is wide- and the first VT complex was first demonspread. The zone of slow conduction of the strated in a canine model25 and subsegreatest interest is the one linked to the quently recorded during endocavitary earliest "presystolic" local electrogram left ventricular mapping with the use that precedes the onset of the QRS deflec- of electrode catheters during clinical tion in any surface ECG lead. Electrical VT.22 In a larger series, some form of activity in the small pathways with abnor- CEA bridging 2 consecutive QRS commal conduction participating in microreen- plexes during monomorphic VT was try is thought to contribute little, if any, demonstrated in 36% of the 56 patients to the surface ECG signal whose onset studied.23 According to the microreentry model, comes after the electrical activity exits the slow pathway and begins to rapidly electrical activity is present in some comdepolarize the bulk of the surrounding ponent of a small circuit at any moment myocardium. Thus, the distal segment or throughout the entire cardiac cycle. CEA, the site of exit of such a pathway is likely recorded by closely spaced bipolar electo be at or near the site that displays the trodes,24 rather than composite electrodes earliest discrete local electrogram in the covering a large area of the ventricular tachycardia cycle, preceding the onset of wall,25 is more likely to represent microreenthe QRS complex. The surface ECG algo- try. Furthermore, CEA should demonrithms applied to the surface QRS com- strate an organized pattern that displays plexes recorded during sustained VT and repeating and reproducibly identifiable pace mapping techniques20,21 may be used components bearing the same temporal to facilitate the detection of the approximate relation to each other during every carlocation of the earliest local electrogram, diac cycle (Figure 2).24 However, CEA, and therefore, by proximity, the approxi- even if it manifests an organized pattern mate location of the zone of microreentry. with regularly recurring, reproducible comBeyond this approximate localization, ponents, and recorded by closely spaced defining the exact site and various com- bipolar electrodes, should not be equated ponents of microreentry requires detailed with microreentry unless other confirmapping in a relatively small area of the matory electrophysiological phenomena ventricle. are shown to be present. Marked fractionation of a bipolar electrogram into multiple asynchronous high-frequency signals during pacing has been observed Continuous Electrical Activity before and interpreted as exaggerated Continuous electrical activity (CEA) is desynchronization of activation within a said to be present at a recording site when region comprising distorted heterogeneous the local bipolar electrogram recorded fibers.26

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Figure 2. The reproducible components of continuous electrical activity (CEA) during sustained monomorphic ventricular tachycardia (VT) in a canine model of experimental myocardial infarction recorded by endocardial left ventricular electrodes. The components display the same temporal relationship during each cardiac cycle.

In order to prove its close relationship to reentry in a small region, one must show that CEA is coextensive and coterminal with the tachycardia. This means, among other things, that at the recording site manifesting CEA during the tachycardia, CEA should not be present during pacing (with sinus rhythm background) at the same cycle length as the tachycardia. This however, is a necessary but not a sufficient criterion. During the arrhythmia, CEA should not only be present at the critical site of reentry, but during a train of stimuli that entrain the tachycardia

without interrupting it, its reproducible components should manifest simultaneous entrainment. Conversely, stimuli that terminate the tachycardia should interrupt the CEA first and transform it into more discrete electrograms after which no tachycardia complexes should be observed (Figure 3).24 Pacing during the tachycardia at cycle lengths shorter than the tachycardia cycle length, which captures the ventricle but encounters entry block at the site of origin of the tachycardia and therefore fails to either entrain or terminate the tachycardia,

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Figure 3. Ventricular pacing during sustained monomorphic ventricular tachycardia (VT) in the same canine model as in Figure 2. The arrowheads depict the reproducibly recurrent components of continuous electrical activity (CEA). Despite capture, the first train of stimuli neither terminates nor entrains VT (entry block) and at the same time leaves the components of CEA unaffected. The second train of stimuli transforms CEA into fractionated but discrete local electrograms (penetration of the circuit), and at the same time interrupts VT.

should not reset or alter in any way the pattern of organized CEA since there is no penetration into the area where CEA is taking place (Figure 3). After cessation of pacing, the tachycardia and the components of CEA should both continue unaffected, bearing the same temporal relationships and phase delays (Figure 3).

By contrast, extrastimuli that reset the tachycardia should also reset the components of CEA and should leave them unaffected. One of the most convincing ways to demonstrate the basic relationship between organized reproducible CEA and the tachycardia circuit is to terminate the

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Figure 4. Interruption of continuous electrical activity (CEA) with termination of ventricular tachycardia (VT) by a single subthreshold stimulus delivered at a site immediately adjacent to the site of CEA, during the refractory period of the ventricular myocardium, 85 ms after the onset of the surface ECG QRS complex.

tachycardia using a subthreshold stimulus scanning the diastolic CEA and delivered to the site of CEA. If such a stimulus is delivered during the refractory period of the tissue surrounding the protected zone, e.g., within or immediately after the QRS complex, it may still penetrate the circuit locally and terminate microreentry. If such a subthreshold stimulus terminates CEA and at the same time interrupts the tachycardia (Figure 4), the cause-effect relationship will be established. Isolated Mid-diastolic Potentials Pandiastolic CEA with reproducible components manifesting all the criteria mentioned above is a rare finding in the clinical cardiac electrophysiology labora-

tory. It is much more common during mapping to record isolated, low-amplitude, middiastolic electrograms corresponding to electrical activity in a protected zone of abnormally slow conduction, especially when mapping VT or ischemic disease (Figure 5).27-30 It is not possible to define local geometry with precision using a single mapping catheter in the left ventricle. However, fractionated, prolonged, mid-diastolic potentials may result from activity in different nonlinear components of the microreentry circuit.29,30 These potentials may thus represent specific segments of CEA associated with microreentry, all of which may not be recorded with a single bipolar electrode. As with CEA, demonstrating the specificity of these mid-diastolic signals is of greatest importance, and electrophysiological phenomena confirming

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Figure 5. Fractionated low-amplitude local electrograms identified with arrows recorded in middiastole (160 ms prior to surface EGG fiducial point) recorded during clinical sustained monomorphic ventricular tachycardia, with the use of a quadripolar exploring (Expl.) electrode. RVA = right ventricular apex.

that these potentials are recorded from pathways within the VT circuit must be sought. First, it should be demonstrated that the low-amplitude, mid-diastolic electrogram results from conduction in a pathway which gives rise to the subsequent VT wavefront, rather than resulting from secondary, late activation of a site outside the circuit from the previous VT beat. Careful examination of resetting and entrainment patterns may help to make this distinction. An extrastimulus applied during VT to a site spatially remote from the catheter recording the mid-diastolic potential, and synchronized to this middiastolic signal, that resets the VT should also reset the mid-diastolic potential with little or no change in the temporal relationship and phase delay between the mid-diastolic potential, the surface QRS complex, and the rest of the local electro-

grams (Figure 6).29 Similarly, trains of extrastimuli applied at a site far from the electrode recording the mid-diastolic potential that entrain the VT must entrain the mid-diastolic potential as well,27,30 again with no variation in the temporal relationship of this mid-diastolic component and the QRS complex of the VT which follows (Figure 7). With the geometry shown in Figure 8A, microreentry appears as a modified version of figure-of-8 mechanism.31 Prototypical figure-of-8 reentry incorporates one central pathway of slow conduction with larger, faster conducting pathways coupled to it.31 Similarly, microreentry may be considered a mechanism incorporating multiple small pathways coupled to each other, making up a small circuit with narrow exit points simulating focal mechanism with monoregional spread.

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Figure 6. Resetting of ventricular tachycardia (VT) and the mid-diastolic potential recorded from an exploring electrode (Expl.) during diastole from the right ventricular apex, remote from the site of earliest recorded electrogram. The resetting stimulus is delivered at a ventricular site outside the VT circuit.

An extrastimulus during VT delivered at a site within the microreentry circuit produces results different from the findings described above. First of all, one would expect a narrow excitable gap in a small area manifesting nearly CEA. If the paced wavefront propagates only in antidromic direction, VT is likely to terminate, possibly after a fusion beat. If the stimulus propagates in the orthodromic direction, the VT will be reset, but with no change in QRS morphology. Such a finding should be spatially (site of stimulation) and temporally (coupling interval) reproducible. Similarly, as with macroreentry, entrainment from a site within the protected zone of slow conduction should cause no fusion activation, and therefore no change in the surface QRS morphology of the entrained complexes27 (Figure 9).

This brings up another mapping-related question, namely whether entrainment with concealed fusion can be used to assess the approximate size of the reentrant circuit. The size of the area over which entrainment with concealed fusion is demonstrable, possibly with different degrees of latency, may be assessed with reasonable accuracy. This observation alone is not able to determine the actual geometry or the orientation of the pathways but may provide a rough estimate of the relative size of the tissue in which microreentry is confined. Figures 8C and 8D show schematically how pacing attempts from closely spaced sites may be used to probe the geometry of the underlying circuit. Newly available techniques of electroanatomical mapping may be superior to conventional fluoroscopy for this purpose.32

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Figure 7. "Entrainment" of the diastolic potentials recorded during the same ventricular tachycardia (VT), as shown in Figure 6. The low-amplitude, fractionated potentials recorded by the exploring electrode (Expl.) are accelerated to the pacing cycle length (300 ms) with long stimulus-to-potential interval, but without disturbing the potential-to-VT temporal relationship in the first VT return beat.

Another rare finding that may increase the specificity of mid-diastolic potentials as electrical activity recorded from within a protected zone of microreentry is the demonstration that isolated diastolic potentials march through the entire diastole in a continuous fashion, during small displacements of the recording electrode. This finding is almost as specific as pandiastolic CEA with all components recorded from a single recording site. It also identifies the proximal and the distal segments of the circuit for purposes of ablation. As the diastolic potential marches temporally from early to mid to late portions of diastole, it is assumed that the recording electrode catheter is marching spatially from proximal to middle to distal segments of the circuit, relative to the site of exit. It should be

realized, however, that this temporal-spatial correlation may be the consequence of our perception of a 3-dimensional mechanism as 2-dimensional, confined to the endocardial surface. Resetting and entrainment maneuvers may be tried at successive catheter sites for acquiring corroborating data. It is important to emphasize that local geometry cannot be defined with precision with the use of endocardial electrode catheters, even with ones incorporating multiple recording bipoles. Furthermore, the novel techniques of noncontact mapping are not likely to elucidate the components of microreentry, as it is likely to be identified with this technique as any other focal mechanism with centrifugal spread.

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Figure 8. A. Schematic diagram representing a microreentry circuit with the slowly conducting pathway depicted by a wavy line (p) and surrounded by functionally (broken line) and anatomically (hatched rectangle) refractory zones. The site of exit is marked by the letter E. B. Resetting of ventricular tachycardia (VT) and the microreentry circuit by a stimulus delivered at a site remote from the site of exit (E) from the circuit. The VT cycle number is indicated by n. C. Resetting of VT and microreentrant activation by a stimulus delivered at a site within the slow component of reentry, resulting in antidromic conduction block and orthodromic propagation. D. Termination of VT with a stimulus delivered slightly more distally in the pathway blocking both in antidromic and in orthodromic directions.

Termination of the Tachycardia -with Interruption of Conduction Within Microreentry Another method of confirming the specificity of the mid-diastolic potentials as basic to VT mechanism involves interruption of VT by interventions that

reversibly inhibit conduction in the circuit located within the protected region where these mid-diastolic fractionated potentials are recorded.33 Unlike the operating room, the electrophysiology laboratory is not a setting where reversible cooling of a recording site can readily be carried out, at least with currently available electrode catheters. Subselective cold saline

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Figure 9. Entrainment with concealed fusion during ventricular tachycardia with a cycle length of 500 ms. Pacing at a cycle length of 460 ms accelerates the tachycardia rate with no change in surface QRS morphology in surface ECG leads I, aVF, and V^ . Latency during pacing is similar to the diastolic potential-to-QRS interval during the ventricular tachycardia.

injections into coronary artery branches can be used to terminate VT, but this technique is not specific enough to serve as a probe for a microreentry circuit. Subthreshold stimuli delivered within the refractory period to the zone of slow conduction and timed appropriately to prolong the refractoriness in the slow pathway, but without resulting in a propagated beat, may be used to attempt termination of the VT. When such a subthreshold stimulus captures the local tissue that does not generate a surface vector, and fails to propagate in both the orthodromic and the antidromic directions and eliminates the mid-diastolic potential, one would expect VT to terminate if the site of stimulation is instrumental for giving rise to the following VT wavefront (Figures 8D and 10). Although a rare finding, if present and reproducible, this observation lends powerful support to the idea that a small protected zone, the site of the mid-diastolic potential recording, is within the VT circuit. It is less likely for a macroreentry or a large figure-of-8 mechanism to be affected by a subthreshold stimulus since there would be a greater chance for the participation

of alternate pathways or alternate exit sites necessary for the continuation of the tachycardia. Conclusion

Microreentry is an arrhythmia mechanism that may be difficult to define with precision in the cardiac electrophysiology laboratory. For the practical purposes of endocardial mapping, it may be reduced to the simplified concept of slow conduction in pathways confined to a small volume of myocardium protected by surrounding refractory tissue. Demonstration of microreentry then requires a search for bridging diastolic CEA or isolated, mid-diastolic, fractionated electrograms scanning diastole, whose specificity must be properly tested before their putative link to the reentry process can be established. Several questions remain. First, whether microreentry, based on unusual geometry or physiological aging, can exist in cardiac tissue without injury or disease, is an interesting question that warrants further investigation. Second, it is not clear whether microreentry can be the basis of

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Figure 10. Termination of clinical ventricular tachycardia (VT) by a subthreshold stimulus delivered to a recording site manifesting prolonged fractionated electrograms. A bipolar stimulus is delivered by the distal pair of electrodes and the local electrogram is recorded by the proximal pair on a quadripolar electrode catheter.

clinical atrial arrhythmias or can be confined to the endocardial or the epicardial layers of the ventricular myocardium rather as a 2-dimensional mechanism. If, alternatively, microreentry can occur only as a 3-dimensional mechanism in the ventricular myocardium, it may represent, as described above, the special case of a small figure-of-8 circuit, which, because of its orientation and special geometry, mimics a focal mechanism. Clarification of these issues influences the success of ablative therapies for clinical tachycardias.

References I. Mines GR. On circulating excitations in heart muscles and their possible relation to tachycardia and fibrillation. Trans S Soc Can 1914;8:43-52.

2. Frame LH, Page RL, Hoffman BF. Atrial reentry around an anatomic barrier with a partially refractory excitable gap. Circ Res 1986;58:495-511. 3. Okumura K, Henthorn RW, Epstein AE, et al. Further observations on transient entrainment: Importance of pacing site and properties of the components of the reentry circuit. Circulation 1985;72:1293— 1302. 4. Osswald S, Wilber DJ, Lin J, et al. Mechanisms underlying different surface EGG morphologies of recurrent nionomorphic ventricular tachycardia and their modification by procainamide. J Cardiovasc Electrophysiol 1997;8:11-23. 5. Rosen MR, Reder RF. Does triggered activity have a role in the genesis of cardiac arrhythmias? Ann Intern Med 1981;94: 794-801. 6. Casio FG, Lopez-Gil M, Giocolea A. Radiofrequency ablation of the inferior vena cava-tricuspid valve isthmus in common atrial flutter. Am J Cardiol 1993;71:705-709.

DEMONSTRATION OF MICROREENTRY 7. Mehra R, Zeiler R, Gough WB, El-Sherif N. Reentrant ventricular arrhythmias in the late myocardial infarction period. 9. Electrophysiologic-anatomic correlation of reentrant circuits. Circulation 1983;67: 11-24. 8. Garan H, Fallon JT, Rosenthal S, Ruskin JN. Endocardial, intramural, epicardial activation patterns during sustained monomorphic ventricular tachycardia in late canine myocardial infarction. Circ Res 1985;56:736-754. 9. Kramer JB, Saffitz JE, Witkowski FX, Corr PB. Intramural reentry as a mechanism of ventricular tachycardia during evolving canine myocardial infarction. Circ Res 1985;56:736-754. 10. Okumura K, Olshansky B, Henthom RW, et al. Demonstration of the presence of slow conduction during sustained ventricular tachycardia in man. Circulation 1987;75:369-378. 11. Gardner PI, Ursell PC, Fenoglio JJ Jr., et al. Electrophysiologic and anatomic basis for fragmented electrograms recorded from healed myocardial infarcts. Circulation 1985;72:596-611. 12. Josephson ME, Harken AH, Horowitz LN. Endocardial excision. A new technique for the treatment of recurrent ventricular tachycardia. Circulation 1979;60:14301439. 13. Littman L, Svenson RM, Gallagher JJ, et al. Functional role of the epicardium in postinfarction ventricular tachycardia. Circulation 1991;13:1577-1591. 14. Harris L, Downar E, Mickleborough L, et al. Activation sequence of ventricular tachycardia: Endocardial and epicardial mapping studies in the human ventricle. JAm Coll Cardiol 1987;10:1040-1047. 15. Wit AL, Dillon SM. Anisotropic reentry. In: Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping. Mount Kisco, NY: Futura Publishing Co.; 1993:127-154. 16. Wellens HJJ, Brugada P. Mechanisms of supraventricular tachycardia. Am J Cardiol 1988;62:10D-15D. 17. Spach MS, Dolber PC, Heidlage JF. Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle. Circ Res 1988;62:811-832. 18. Janse MJ, Anderson RH, McGuire MA. AV nodal reentry: Part I: AV nodal reen-

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try revisited. J Cardiovasc Electrophysiol 1993;4:573-586. 19. Tai Y, Lee KL. Interfascicular macroreentry versus intrafascicular microreentry. J Cardiovasc Electrophysiol 1996;7:275. Letter. 20. Josephson ME, Waxman HL, Cain ME, et al. Ventricular activation during ventricular endocardial pacing. II. Role of pacemapping to localize origin of ventricular tachycardia. Am J Cardiol 1982;50:11-22. 21. Kuchar DL, Ruskin JN, Garan H. Electrocardiographic localization of the site of origin of ventricular tachycardia in patients with prior myocardial infarction. JAm Coll Cardiol 1989;13:843. 22. Josephson ME, Horowitz LN, Farshidi A. Continuous local electrical activity. A mechanism of recurrent ventricular tachycardia. Circulation 1978;57:659-665. 23. Brugada P, Abdollah H, Wellens HJJ. Continuous electrical activity during sustained monomorphic ventricular tachycardia. Am J Cardiol 1985;55:402-411. 24. Garan H, Ruskin JN. Localized reentry: Mechanisms of induced sustained ventricular tachycardia in canine model of myocardial infarction. J Clin Invest 1984; 74:377. 25. El-Sherif N, Hope RR, Scherlag BJ, Lazzara R. Reentrant arrhythmias in the late myocardial infarction period. 2. Patterns of initiation and termination. Circulation 1977;55:702-719. 26. Elharrar V, Foster PR, Jirak TL, et al. Alterations in canine myocardial excitability during ischemia. Circ Res 1977;40: 98-105. 27. Morady F, Fran R, Kou WH, et al. Identification and catheter ablation of a zone of slow conduction in the reentrant circuit of ventricular tachycardia in humans. J Am Coll Cardiol 1988;ll:775-782. 28. Fitzgerald DM, Friday KJ, Yeung JA, et al. Electrogram patterns predicting successful catheter ablation of ventricular tachycardia. Circulation 1988;4:806-814. 29. Garan H, Ruskin JN. Reproducible termination of ventricular tachycardia by a single extrastimulus within the reentry circuit during the ventricular effect refractory period. Am Heart J 1988; 11:546-550. 30. Kay GN, Epstein AE, Plumb VJ. Region of slow conduction in sustained ventricular tachycardia: Direct endocardial recordings and functional characterization in

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humans. J Am Coll Cardiol 1988; 11:109116. 31. El-Sherif N, Smith A, Evans K. Canine ventricular arrhythmias in the late myocardial infarction period: Epicardial mapping of reentrant circuits. Circ Res 1981;49:255-265. 32. Shpun S, Gepstein L, Hayam G, BenHaim SA. Guidance of radiofrequency

endocardial ablation with real-time threedimensional magnetic navigation system. Circulation 1997;96:2016-2021. 33. El-Sherif N, Mehra G, Gough WB, Zeiler RH. Reentrant ventricular arrhythmias in the late myocardial infarction period: Interruption of reentrant circuits by cryothermal techniques. Circulation 1983; 68:644-656.

Chapter 13 Optical Mapping of the Effects of Defibrillation Shocks in Cell Monolayers Vladimir G. Fast, PhD and Andre G. Kleber, MD

Introduction Strong electrical shocks are applied to terminate life-threatening cardiac arrhythmias such as ventricular fibrillation. Although this procedure is used in patients on a routine basis, the mechanism by which the extracellular electrical field affects the transmembrane potential (Vm) of cardiac cells and terminates fibrillation is not fully understood. From theoretical studies it has been proposed that the microscopic structure of cardiac tissue might cause Vm changes (AVm) necessary for defibrillation. Until recently, the experimental verification of this hypothesis was not possible because of the complex 3-dimensional structure of cardiac tissue and the lack of methods to measure distribution of Vm at the microscopic level. These problems were overcome with the development of a new experimental approach that combines high-resolution optical mapping of Vm and techniques for growing cardiac tissue

with defined architecture in cell culture. This chapter discusses the application of this approach to studying effects of extracellular shocks on Vm and presents a short overview of recent experimental results. Mechanisms for Vm Changes During Defibrillation Analysis of the classic cable model indicates that in a structurally continuous tissue, the Vm changes induced by a uniform extracellular field should be limited to a very small tissue area near the shock electrodes.1,2 With increasing distance from the electrodes, changes in Vm will decay exponentially and approach zero beyond 1 to 2 mm from the shock electrodes. To induce Vm changes in tissue far from the shock electrodes, a redistribution of axial current between intracellular and extracellular spaces must take place. In general, this can occur either because of the nonuniform distribution of the extracellular shock field or because of the

This work was supported by the Swiss National Science Foundation and the Swiss Heart Foundation. From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003.

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spatial variation in the tissue structure. The first mechanism relates AVm, or "virtual electrodes," to the spatial derivative of the extracellular field called activating function. 3-6 Several mechanisms of the second kind have been proposed. One of them, known as the mechanism of secondary sources, suggests that changes in Vm are produced by the microscopic resistive barriers associated with cell boundaries7-10 or by larger resistive barriers associated with the vasculature, intercellular clefts, or connective tissue sheets separating cell bundles and cell layers.11-12 Another structure-dependent mechanism relates Vm changes to rotation of anisotropy axes in space.13 Combination of both structural factors (tissue anisotropy) and the nonuniform shock field can produce Vm changes via the "dog-bone" effect.14-15 Cell Culture as a Model for Studying Defibrillation Mechanisms Until recently, the effects of tissue structure on defibrillation were investigated almost exclusively in computer models.7-10,16,17 Experimental studies of the structural effects in the heart are hampered by the 3-dimensional anatomy of cardiac muscle that prevents precise correlation of Vm changes with the tissue structure, especially at the microscopic level. Also, because cardiac muscle contains structural discontinuities of multiple types, separating the effects of one individual structure from another as well as from effects of other, structureindependent, factors is extremely difficult. These obstacles can be overcome using cultures of cardiac cells. The advantage of cell cultures is that they grow as 2-dimensional monolayers and their microscopic structure can be precisely determined and correlated with electrophysiological measurements. In addition, the monolayer structure can be modified in

a desirable way using techniques for directed cell growth, which greatly facilitates structure-function studies. A number of such techniques were developed at the Department of Physiology of the University of Bern (Switzerland) that allow the growth of cell cultures in predetermined geometric patterns such as cell strands and geometric expansions,18,19 or in anisotropic patterns.20,21 Electrophysiological parameters of cell cultures such as the maximal upstroke rate of rise and the conduction velocity are quite similar to those measured in adult ventricular tissue.18,22 The differences include smaller cell size and more uniform distribution of gap junctions along the cell perimeter in cell cultures as compared to the adult tissue.20,21 Microscopic Optical Mapping of Vm in Cell Cultures The optical mapping technique was used to measure Vm changes with microscopic resolution. This technique, which involves staining of excitable tissue with a voltage-sensitive dye and measurement of the dye fluorescence with an array of photodetectors, has been widely used for multisite recordings of Vm from brain and cardiac tissue.23 We have adapted this method for microscopic measurements of Vm in myocyte cultures.20-"22,24 The key elements of this technique, a voltagesensitive dye, a light source, optical filters, objectives, and amplifiers, were selected to achieve high signal-to-noise ratio when measuring weak optical signals from a small cell membrane area. The experimental set-up for optical recordings, shown schematically in Figure 1, was built around an inverted epifluorescent microscope (Axiovert 35M, Zeiss, Germany). To optically record Vm, the voltage-sensitive dye RH-237 (Molecular Probes, Eugene, OR) was used. The excitation light was provided by a 100-W arc

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Figure 1. Schematic diagram of the optical mapping set-up. See text for detailed description.

mercury lamp, which delivers a strong light in the green range, where the RH237 dye has its absorption maximum. The light was passed through a heat filter and a band-pass exciting filter with a transmittance range of 530 to 585 nm. The light was deflected by a dichroic mirror with transmittance at greater than 600 nm, and focused on the preparation by the objective lens. The emitted fluorescent light was collected by the same objective, passed through the dichroic mirror, filtered with a low-pass filter at greater than 615 nm, and measured using a 10 x 10 photodiode array (Centronic Ltd., Surrey, England) attached to the photographic port of the microscope. Individual diodes in this array have dimensions of 1.4 x 1.4 mm2 with an interdiode distance of 0.1 mm. Microscopic objectives with magnification lOx, 20x, 40x, 63x, and lOOx (Zeiss) and numerical apertures of 0.5, 0.75, 1.3, 1.25, and 1.3, respectively, were used. Objectives with lower magnifications are also available but, because of

their small numerical apertures and poor light collecting efficiency, they did not provide enough light for the voltagesensitive measurements in cell cultures. Taking into account the additional magnification of the photographic port of 2.5x, the total optical magnification was in the range between 25x and 250x that resulted in an imaged area of 56 x 56 (im2 (lOx magnification) to 5.6 x 5.6 Jim2 (lOOx magnification) per diode. The photocurrents from the 96 diodes were converted to voltages by custom-built current-to-voltage converters. The 2 most important parameters of the converters are the gain and the bandwidth. The gain depends on the value of the feedback resistors, Rf. The bandwidth depends on the speed of operational amplifiers and, because of the presence of a stray capacitance parallel to the feedback resistors, on the Rf value as well. To faithfully reproduce a normal cardiac action potential upstroke, the system bandwidth should be greater than 1 kHz. We achieved a

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Figure 2. A. Schematic diagram of the experimental chamber showing an area of cell growth (black) on a glass cover slip (white) and shock electrodes (+ = anode; - = cathode). B. Optical recording of background fluorescence and an action potential upstroke. The fractional change of fluorescence associated with the action potential was 12% of the background level. C. Determination of shock-induced change in transmembrane potential (AVm). A stimulus was applied to induce an action potential. Action potential amplitude (APA) was measured as the difference between the fluorescence levels immediately before and after the upstroke. The Vm was measured twice: without a shock (gray line) and with a 10-ms shock applied during action potential plateau (black line). The shock-induced AVm was measured as the difference in fluorescence intensity between a linear fit of the plateau phase depicted by a thin line and the signal magnitude 5 ms after the shock onset and expressed as a percentage of APA. This linear fit corresponded to the time course of Vm without a shock.

bandwidth of ~1.6 kHz and a low noise level by using feedback resistors with a value of 100 MO and operational amplifiers OPA121 from Burr-Brown (Tucson, AZ). A typical signal at the output of a current-to-voltage converter is shown in Figure 2B. It consists of a large negative deflection associated with the beginning of light exposure and corresponding to background fluorescence. The smaller positive deflection corresponds to the upstroke of an action potential initiated by a stimulation pulse. The fractional change of fluorescence given by the ratio of the action potential amplitude (APA) and the value of the background fluorescence can vary throughout the preparation and it also changes during the course of the experiment. Immediately

after the dye staining, the fractional change can be as high as 15%. As a result of dye internalization, the fractional fluorescence change decreases down to 5% within the first hour after staining. The useful portions of optical signals typically do not exceed a few dozen millivolts, which is too small to be measured without amplification by standard 12-bit analog-to-digital (A/D) converters. However, amplifying the useful signals also amplifies the portions corresponding to the background fluorescence, which may saturate the A/D converters. To avoid this limitation, the background fluorescence was subtracted before amplification. Both background subtraction and subsequent amplification were performed using second-stage

OPTICAL MAPPING OF EFFECTS OF DEFIBRILLATION SHOCKS amplifiers with a sample-and-hold circuitry (Figure 1). Subsequently, signals were multiplexed and digitized at 12-bit resolution and sampling rate of 10 to 25 kHz for each of the 96 channels. One of the major limitations of optical mapping is the phototoxic effect of voltage-sensitive dyes. This effect is especially important in cell cultures in which a relatively small amount of light is emitted by a cell monolayer and achievement of a high signal-to-noise ratio demands loading cells with a dye at a high concentration and a strong light excitation. To limit the phototoxic effect, cells were illuminated by excitation light for only a short period, typically 80 ms. Depending on optical magnification and intensity of illumination, up to 6 measurements can be performed in these conditions without significant cell deterioration. Measurements of the Shock-Induced Vm Changes An important advantage of optical mapping over conventional recordings using electrodes is that optical signals are devoid of stimulation artifacts. This is especially important for defibrillation studies where strong artifacts created by the defibrillation shocks interfere with conventional measurements of Vm during shocks and during at least the first 20 to 50 ms after the shocks. The disadvantage of optical recordings is that the optical signals reflect only relative changes of Vm. The absolute value of optical signals depends, in addition to Vm, on density of dye staining, degree of dye internalization, and uniformity of light intensity. Combination of these factors results in a significant variability of fluorescence intensity throughout the preparation, independently of the underlying variation of Vm. The V m -independent variability of

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optical signals can be reduced somewhat by measuring the fractional changes in fluorescence. This does not, however, eliminate the signal variability completely, because the fractional change of fluorescence itself varies throughout the preparation (mainly because of nonuniform dye internalization). To eliminate the V m -independent variability, optical signals were normalized relative to the portion of optical signals, which represents the APA. To accomplish that, an action potential was initiated before each shock, the optical APA was measured, and the shockinduced changes in Vm were normalized by the APA (Figure 2C). In doing so, an assumption was made that APA does not vary throughout the imaged area. This assumption is likely to be true in the microscopic measurements when the size of an imaged area is comparable to the length of the electrotonic constant, which in cell monolayers is about 360 urn.25 This assumption might not hold true on a larger spatial scale in pathological conditions, such as ischemia, favqring nonuniform distribution of APA. To create a uniform extracellular field, electrical shocks were applied via 2 large platinum plate electrodes positioned at opposite ends of the perfusion bath (Figure 2A). The bath measured 2.2 x 2.2 cm2 and the electrode dimensions were 2 x 0.2 cm2. Monophasic truncated exponential shocks with a duration of 10 to 12 ms were delivered using custom-built shock generators. The generators were triggered by the stimulus pulse and could produce shocks at specified times during the cardiac cycle. In most of the measurements, the extracellular voltage gradient produced by the shock in the bath was measured simultaneously with the optical recordings of Vm by 2 silver electrodes with a diameter of 0.2 mm and an interelectrode distance of 3.5 mm.

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The electrodes were positioned near the mapping area and aligned with the direction of the electrical field. Effects of Cell Boundaries on AVm One of the intriguing possibilities is that changes in Vm can be created by boundaries of the individual cell. This idea was proposed in 1986 by Plonsey and Barr,7 based on theoretical studies of a 1-dimensional cable model with periodic resistive barriers. In this model, changes in Vm appear as periodic ("sawtooth") oscillations with hyperpolarization on one side of a resistive barrier and depolarization on the other side. The idea that cell boundaries account for defibrillation was attractive because this type of structural discontinuity is the most universal feature of cardiac tissue. However, the hypothesis that cell boundaries induce major changes in Vm was not confirmed experimentally.

The effect of cell boundaries on shock-induced Vm changes was investigated in narrow cultured cell strands with a width of 30 to 60 (im.26 In such strands, because of the aligning influence of the strand edges, cells were oriented along the strand axis. A uniform extracellular shock field was applied along the strand axis and changes in Vm were measured with subcellular resolution. Figure 3 shows an example of AVm/ APA measured with resolution of 6 um during application of a shock with strength of 11 V/cm. Panel A shows the phase-contrast image of cells with superimposed grid of photodiodes, and panel B illustrates selected action potentials. At all measuring sites, the cell membrane was hyperpolarized during the shock. There was no abrupt transition from hyperpolarization to depolarization as expected from secondary sources, and no significant changes in AV m / APA were found between measuring sites localized in neighboring cells.

Figure 3. Effect of cell boundaries on transmembrane potential (VJ. A. Image of cells at xlOO magnification with overlaid photodiode array grid. B. Drawing of the cell strand with outlined boundaries of individual cells and selected optical recordings of change in Vm during application of shock. Reproduced from reference 26, with permission.

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Similar results were obtained in 12 cell in Vm, the search for secondary sources preparations. shifted to larger anatomical discontinuA likely explanation for the discrepancy ities. One type of such a discontinuity in between the theory and the experiments cardiac muscle is related to the incluregarding secondary source formation is the sions of connective tissue into the effect of "lateral averaging" described for myocardial structure that interrupt the microscopic conduction.22 The mechanism continuity of the intracellular space on a of secondary source formation was origi- scale of several cell lengths or more, i.e., nally proposed from 1-dimensional models several hundred micrometers. To invesof cardiac tissue where axial current is tigate the effect of such discontinuities on forced to flow through each resistive bar- Vm, we have produced cell monolayers rier represented by an intercellular junc- with intercellular clefts of variable tion, which resulted in a large voltage dimensions.29 Uniform-field shocks were drop across this junction. In a 2-dimen- applied across clefts and the Vm changes sional tissue, however, a portion of local were measured as a function of the cleft axial current can bypass an individual length. resistive barrier and flow through cell juncFigure 4 demonstrates the effect of an tions offered by lateral cell connections. In electrical shock on Vm near an intercellucell cultures, this averaging effect might lar cleft. Panel A shows an image of the cell be especially prominent because of the monolayer and the grid indicating the posirelatively uniform distribution of gap tion of the photodiodes. The intercellular junctions along the cell perimeter.21 cleft is delineated with a dashed line. The Whether cell junctions can change Vm sub- length and the width of the cleft were stantially in adult cardiac tissue in vivo is approximately 240 |nm and 60 |im, respecnot known. On one hand, adult myocytes tively. The stimulation electrode was are longer than the neonatal cells in cul- located above the mapping area and the ture and gap junctions in the ventricular shock electrodes were located on the left myocardium tend to be more concentrated and the right sides. Panel B shows the at cell ends27 thus favoring the formation isochronal map of activation spread initiof secondary sources. On the other hand, ated by the stimulus. Panels C and D cells in the intact tissue are arranged in depict isopotential maps of the relative a 3-dimensional structure, which increases changes in Vm, AVm/APA, caused by electhe degree of intercellular connectivity trical shocks of opposite polarities. The and is predicted to reduce effects of indi- pattern of AVm/ APA distribution was convidual resistive discontinuities on Vm. sistent with the mechanism of secondary How these opposing influences interplay sources. In panel C, cells were depolarized is not presently known. Measurements of on the right side and hyperpolarized on the effects of shocks carried out recently in the left side of the cleft. The isopotential rabbit papillary muscle using a roving map contained 2 localized regions of microelectrode did not reveal secondary maximal depolarization and maximal sources at the cell boundaries,28 adding hyperpolarization adjacent to the obstasupport to the conclusions drawn from the cle, corresponding to current sources and current sinks, respectively. With the cell culture studies. reversed shock polarity (panel D), the Effects of Intercellular Clefts on AVm regions of depolarization and hyperpolarization were interchanged. After it was found that cell boundIndividual recordings illustrating aries do not produce significant changes changes in Vm across the obstacle from the

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Figure 4. Effect of an intercellular cleft on transmembrane potential (Vm). A. Image of a cell monolayer (x20 magnification) with the grid illustrating the position of the photodiodes and the dashed line outlining the position of the intercellular cleft (length = 240 (im). B. Isochronal map of activation spread initiated by stimulation from above the mapping area. Activation times are determined from the time of earliest activation within the mapping region. Isochrones are drawn at intervals of 100 us. C and D. Isopotential maps of change of Vm/action potential amplitude (AVm/APA; in %) induced by shocks of opposite polarities. Shock strength was 7.5 V/cm (A) and 8.5 V/cm (B). Gray areas depict the intercellular cleft. The outline corresponds to the boundary of the photodiode array. See color appendix. Reproduced from reference 29, with permission.

OPTICAL MAPPING OF EFFECTS OF DEFIBRILLATION SHOCKS same experiment are shown in Figure 5 (panels A and B) for opposite shock polarities. The shape of AVm traces in most cases corresponded to the truncated exponential field pulse in both depolarized and hyperpolarized areas. Panels C and D illustrate profiles of AVm/APA along the horizontal axis for the 2 shock polarities. In the first case (panel C), the profile was symmetrical with depolarization and hyperpolarization decaying within a short distance from the

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obstacle. A slightly asymmetrical voltage profile was observed when shock polarity was reversed (panels B and D). The strength of secondary sources depended on both field strength and cleft length. We defined the magnitude of secondary sources as the difference of AVm/APA measured across the middle of an obstacle, (AVm/APA)diff. For a given obstacle, the average of 2 (AVm/APA)diff values was taken that were measured in

Figure 5. Action potentials near intercellular cleft during shock application. A and B. Selected optical traces recorded across the cleft at 2 shock polarities. The numbers correspond to the photodiode locations in Figure 4C and D. C and D. Dependence of change of transmembrane potential/action potential amplitude (AVm/APA; in %) on distance. Distance 0 corresponds to the center of the photodiode 1 in Figure 4C. Reproduced from reference 29, with permission.

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response to shocks of opposite polarities. Figure 6 demonstrates the dependence of the (AVm/APA)diff on the obstacle length for 2 shock strengths. In the first group, the average shock strength was 8.5 ± 0.6 V/cm (range of 7.5-9.4 V/cm, n=14). In the second group, the average shock strength was 18.0 ± 1.0 V/cm (range of 16.1-19.3 V/cm, n=16). The (AVm/APA)diff values measured across 20 clefts are plotted in Figure 6B. The cleft lengths were in the range of 45 to 270 jam. Within this range of cleft lengths, the relation between the obstacle length and the magnitude of the secondary sources could be closely approximated by a linear fit. From these data, an estimate of the critical obstacle length necessary for direct activation of cells can be predicted. Assuming that a shock produces symmetrical changes in Vm and that cells are excited in the area of maximal depolarization (if Vm is depolarized by 25% APA above the resting level, corresponding to a depolarization of 25 mV30), cells will be directly activated when the (AVm/APA)diff value is larger than 50%. From the linear functions in Figure 6B, this estimated critical obstacle length is approximately 85 ± 8 urn for a shock strength of 18.0 V/cm and 171 ± 7 |um for a shock strength of 8.5 V/cm. Direct Stimulation by Secondary Sources To test the prediction that resistive discontinuities cause direct excitation of cardiac tissue during application of extracellular shocks, shocks were delivered during diastole and the isochronal maps of activation spread initiated by shocks were analyzed. Figure 7 illustrates direct activation of myocytes by a secondary source created by an inexcitable obstacle. Panels A and C show isochronal maps of activation spread initiated by shocks of opposite polarities, and panels B and D

show the corresponding recordings of Vm from the sites surrounding the obstacle. With one shock polarity (panel A), a small cell region adjacent to the obstacle on the left side was directly activated by the shock. This was evident from the fact that the cells in this region had the earliest activation times, and action potential upstrokes (panel B, traces 1 and 2) exhibited biphasic shapes: the shock caused initial rapid membrane depolarization (shown by arrows), which was followed by excitation. This area of earliest activation was superimposed on the region of maximal depolarization produced by the shock during the plateau phase of the action potential (Figure 4D). Away from this area the amplitude of initial depolarization decreased (traces 3 through 6). The cells on the right side of the obstacle were transiently hyperpolarized by the shock, with hyperpolarization gradually increasing toward the center (traces 7 through 10). The initial membrane hyperpolarization was followed by depolarization, which resulted from the propagating wave initiated on the left side of the obstacle. An almost symmetrically reversed activation pattern was observed when the shock polarity was reversed (panels C and D). The site of the earliest activation in this case was located on the right side, superimposed on the area of maximal depolarization during application of shock in the plateau phase (Figure 4C). The stimulating efficacy of secondary sources depended on both shock strength and obstacle length. With an average strength of 8.2 V/cm (number of obstacles, n=28), shocks of both polarities directly excited cells when the obstacle length was 196 ± 53 [im (n = 14). Shocks of only one polarity resulted in direct activation when the obstacle length was 134 ± 49 fim (n=5, Pe) during LP and during the change from LP to TP at varying angles to the long axis of the fibers. The original Oe waveforms during LP (waveform #1) and TP (waveform #11) appear smooth in contour (Figure IB), which also is expected in a continuous anisotropic medium.13 Although the original Oe waveforms appeared smooth in contour, the first and second derivatives of the original Oe waveforms revealed small notches (dOe/dt and d2Oe/dt2, respectively, in Figure IB).12 Also, the notches increased in number as the amplitude of Oe decreased when propagation changed from along the longitudinal axis of the fibers to a direction across the fibers. Notches in the derivative waveforms indicate asynchronous excitation of small groups of cells at a microscopic level.3,9 Thus, the irregular shapes of the first and second derivatives of the original extracellular waveforms indicate that propagation was discontinuous in nature at a small size scale in this normal uniform anisotropic ventricular preparation. Electrical Loading in Normal Mature Myocardium at a Microscopic Level When one attempts to study the mechanisms of discontinuous conduction at a microscopic level in naturally occurring normal or diseased cardiac muscle, significant difficulties become evident.

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A major problem is that electrical loading, which greatly affects the safety factor of conduction,1,14 is strongly dependent on the nonuniform and irregular distribution of the electrical connections between cells. Consequently, electrical loading in a multicellular network is like the effective coupling coefficient between cells15 in that it cannot be measured directly. Further, this problem cannot be resolved by measurements in isolated cell pairs because their isolation removes the nonuniform loading produced by the stochastic distribution of their interconnections to other contiguous cells present in the intact cellular network. These difficulties likely account for the paucity of experimental information about the most fundamental features of cardiac excitation waves—the events associated with excitation spread within individual cells and the transfer of the excitatory impulse to neighboring cells in normal and abnormal cardiac muscle. The high-resolution optical mapping techniques used by Fast and Kleber16,17 and by Rohr18 provide an important recent experimental advance for the measurement of excitation spread at a microscopic level in synthetic neonatal cellular monolayers. However, at present it is not clear how to achieve the increased spatial resolution needed to evaluate electrical loading within individual myocytes, as well as the transfer of the excitation impulse from cell to cell, in naturally occurring cardiac muscle. Possibly combined optical and microelectrode measurements, along with high-resolution extracellular potential measurements like those in Figure 1, or the greater spatial resolution of Oe measurements achieved by Hofer et al.19 with thin-film sensors, will be a next experimental step. Increases in electrical load produce a decrease inV max , and decreases in electrical load are associated with increases in Vmax.4,20 Therefore, one experimental approach to evaluate spatial differences

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in electrical loading, as well as differences in load at a given site for different directions of conduction, is to measure Vmax at multiple sites and at each site change the direction of conduction from along the longitudinal axis of the fibers to a direction across the fibers. This method changes the complex geometric relationships between the impalement site, the

boundaries of the impaled and juxtaposed cells, and the associated contiguous gap junctions.12 Figure 2A shows the arrangement of 2 pairs of electrodes used to produce bidirectional longitudinal propagation (LP1 and LP2) and bidirectional transverse propagation (TP1 and TP2) at each of 17 centrally located microelectrode impalement sites in an uniform

Figure 2. A. Arrangement of 4 pairs of unipolar stimulus electrodes to produce 4-way plane wave conduction along the longitudinal and transverse axis of the fibers. The solid circles represent 17 microelectrode impalement sites at which 4-way conduction was produced. B. Histograms illustrate values of the maximum rate of rise of the transmembrane potential (Vmax) for one direction of longitudinal propagation (LP) and one direction of transverse propagation (TP) at each impalement site. C. Bar graph shows values of Vmax during one direction of LP and TP at each of the 17 microelectrode impalement sites. Reproduced from reference 12, with permission of the American Physiological Society.

MICROSCOPIC DISCONTINUITIES AS A BASIS FOR REENTRANT ARRHYTHMIAS anisotropic adult canine ventricular preparation. Figure 2B shows the histograms of the Vmax values obtained at each site for one direction of LP and for one direction of TP. The mean value of TP Vmax was greater than the mean value of LP Vmax (P < 0.001), as expected1; however, there was considerable variation in the values of Vmax in both directions. The histograms for each group (Figure 2B) show that a few of the lowest values of TP Vmax were in the same range of some of the LP Vmax values. The paired values of LP and TP Vmax for each of the 17 impalement sites are shown in the bar graph of Figure 2C. Note that at 2 sites LP Vmax exceeded TP Vmax (arrows), and some of the lowest values of LP Vmax occurred at the same sites that had the highest TP Vmax values. The major point illustrated by Figure 2 is that in mature uniform anisotropic bundles the distribution of electrical load on the sarcolemmal membrane is quite nonhomogeneous. Also, changes in electrical load are quite sensitive to the direction of propagation relative to the impalement site, as reflected in the differences of Vmax at the same site for different directions of conduction and at different sites for the same direction of conduction. It is interesting that these variations in electrical load produce undulating values of Vmax in any given direction of propagation, and it is the average Vmax value that is larger during TP than LP.12 Electrical Description of Myocardial Architecture and Its Application to Conduction Only recently have analyses of cardiac conduction begun to include the details of the arrangement of cardiac myocytes, their irregular shapes, and the associated nonuniform distribution of

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their gap junctions. Also, to this point, experimental mapping has not provided sufficient detailed data to produce a clear picture of the cellular events that occur with anisotropic conduction in naturally occurring preparations. Thus, electrical representation (models) of the microarchitecture of normal and abnormal cardiac muscle should become an integral part of the task to gain insight to propagation events at a cellular level. As an example, the effects of normal cellular structure on conduction have been shown in a recent 2-dimensional cellular model based on the nonuniform shapes of disaggregated adult ventricular canine myocytes. Details of the model are presented in prior papers.4'21 Variations in cell shape and in the topology of the gap junctions of any one model, however, represent only one of an infinite number of possible configurations. Thus, rather than emphasize a specific cardiac structure, the following results illustrate how the variable sizes and shapes of cardiac myocytes, along with the nonuniform arrangement of the gap junctions, have a major effect on propagation events at a microscopic level. Figure 3 shows diagrams of the formation of a 33-cell basic unit of the 2-dimensional cellular model.4 Intracellular space is represented by the cytoplasm of each myocyte surrounded by discrete cellular boundaries, and the myocytes are coupled together by gap junctions located in the intercalated disks and in areas juxtaposed to the disks as described by Hoyt et al.,22 i.e., plicate and interplicate gap junctions, respectively. This model, like several well-known 1-dimensional23,24 and 2-dimensional16,25 models, is a "monodomain" model in which the active membrane (sarcolemma) separates intracellular space from a large volume conductor of low resistance. Thus, the cellular model of Figure 3 does not include an electrical representation of the

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Figure 3. Diagrams showing the formation of a 33-myocyte basic unit to produce a 2-dimensional cellular model. A. Outlines of 5 myocytes and the manner they were fitted together to form a multicellular network. The stippled areas next to the intercalated disks represent interplicate gap junctions.22 The grids show 10-^im x 10-fim segments that represent the sarcolemmal membrane patches and the interior of each cell. B. Arrangement of 3 types of gap junctions (symbols) that electrically interconnect the 5 myocytes (a through e). C. Arrangement of 33 myocytes and the distribution of their intercellular connections (symbols). The 33-cell unit could be replicated longitudinally and vertically by fitting the ends and sides together to form cellular arrays of different sizes and shapes. The group of 5 myocytes (a through e) is highlighted within the 33-cell unit by marking each segment within these myocytes. Reproduced from Spach MS, Heidlage JF. The stochastic nature of cardiac propagation at a microscopic level. An electrical description of myocardial architecture and its application to conduction. Circ Res 1995;76:366-380, with permission.

interstitium that separates myocytes cellular boundaries was best depicted by beneath the surface of a cardiac bundle.11 perspective plots, which provided a view of the multidimensional spatial distribution of the activation times. A represenThe Nature of Excitation Spread tative result is presented in Figure 4 for Between Myocytes in the the 5 myocytes highlighted within the Multicellular Network 33-cell unit shown in Figure 3C. To examine cell-to-cell excitation spread during LP and TP, the times of Vmax were identified in each of the segments of 16 interconnected myocytes at the center of an array of 700 cells.4 The sensitivity of excitation spread to the

Longitudinal Propagation During LP, step increases in activation time (discontinuities) occurred at the end-to-end connections between myocytes

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Figure 4. Perspective plots of activation spread through a network of 5 myocytes within the 2-dimensional cellular model. The activation sequence was determined from the time of Vmax at each of the segments (8 rows of longitudinal marks) with the 5 myocytes that formed a group 80 urn wide and 300 |im long as shown at the top of the figure. A. Longitudinal propagation in a left-to-right direction. B. Transverse propagation in a bottom-to-top direction. In each perspective plot, the activation times along each of the 8 rows of segments are plotted as a function of distance along the long axis of the cells. The hatched steps denoted delays across the plicate gap junctions at the intercalated disks. In both panels the letters a through e are included to identify each myocyte with the activation times along the corresponding rows. Reproduced from Spach MS, Heidlage JF. The stochastic nature of cardiac propagation at a microscopic level. An electrical description of myocardial architecture and its application to conduction. Circ Res 1995;76:366-380, with permission.

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(Figure 4A). The major increases in activation time, however, occurred along the sarcolemmal membrane of each cell. The overall process resulted in a predominantly smooth pattern of activation spread. A major feature of LP was that the locations of the discontinuities of propagation along the longitudinal axis corresponded to the irregular distribution of the plicate gap junctions at the intercalated disks. These irregular delays at the end-to-end connections of the cells produced asynchrony of excitation in different portions of myocytes located side by side. Consequently, superimposed on the overall smooth process of LP, the nonuniformly distributed discontinuities of activation spread reflected the irregular shapes of the cells (Figure 4A).

Excitation Spread Within Individual Myocytes Longitudinal Propagation

Representative intracellular excitation sequences during LP are shown in Figure 5A for the 5 interconnected myocytes shown in Figure 4. The isochrones maintained a vertical orientation throughout each myocyte, except there was slight bending near the intercalated disks at the ends of the irregularly shaped cells. Within each cell, however, the isochrones shifted further apart as excitation moved from the subcellular area where the action potential entered the myocyte to the area where the action potential exited the myocyte. As a result, the major subcellular feature of LP was that conduction was slower in the proximal part and Transverse Propagation faster in the distal part of each cell.4 These events produced an alternating During TP, there were large lateral sequence of slower and faster conduction '^jumps'' of activation time between myocytes, along the pathway of longitudinal conwhile within each myocyte the entire sar- duction. Reversing the direction of longicolemma activated very rapidly (Figure 4B). tudinal conduction showed that the Further, there were a few prominent step subcellular differences in the speed of increases in activation time in the region conduction were not created by variations of the end-to-end plicate gap junctions in the cross-sectional area within each (Figure 4B, steps connecting cells c and e). myocyte. As shown in Figure 5A, when Therefore, the cell-to-cell pattern of trans- the direction of longitudinal conduction verse activation spread was quite differ- was reversed, the proximal part of each ent from that which occurred during LP. myocyte with respect to the direction of LP TP occurred as large jumps in activation remained the region of slowest conduction time between the lateral borders of jux- and the distal part of each cell remained taposed cells, while within each myocyte the region of fastest conduction. there was almost simultaneous activation of the entire sarcolemmal membrane. A general conclusion to be drawn Transverse Propagation from the results of Figure 4 is that for The major subcellular feature of actiany given direction of conduction, plane waves of excitation do not occur at a vation spread during TP was the rapidity microscopic level because of the disrup- with which excitation of each myocyte tion of the excitation wave by the irregu- occurred (Figure 5B). Unlike LP, during larly distributed cell boundaries and the TP the pattern of excitation spread was associated irregular locations of the gap different in each myocyte. Within the same cell, the isochrones were oriented junctions.4

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Figure 5. Intracellular activation sequences during 4-way propagation along the longitudinal and transverse axes of the myocytes. A. Isochrones within each of the myocytes (a through e) during propagation in both directions (arrows) along the longitudinal axis of the myocytes. The isochrones are separated by 4 (is. B. Intracellular isochrones during propagation in both directions (arrows) along the transverse axis of the cells. The isochrones are separated by 3 jus. Cells a through e are the same 5 myocytes shown in Figure 4. Reproduced from Spach MS, Heidlage JF. The stochastic nature of cardiac propagation at a microscopic level. An electrical description of myocardial architecture and its application to conduction. Circ Res 1995;76:366-380, with permission.

in different directions, and there were collisions (asterisks) inside a few cells when TP occurred in a top-to-bottom direction (cells a and c in Figure 5B, top). The pattern of excitation spread within

each cell changed markedly when the direction of conduction was reversed along the transverse axis of the myocytes (Figure 5B), and the collisions shifted to other cells; e.g., a collision occurred only

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in cell b when TP occurred in a bottom-to- (Figure 6, LP). When comparing the 2top direction. dimensional cellular model results to the experimentally observed variation in Vmax at differnt locations along the axis of conVmax Variations Within Adult duction (Figure 2C), it is reasonable to Ventricular Myocytes presume that in the experimental measurements the tip of the microelectrode Longitudinal Propagation varied randomly in its intracellular location relative to the ends of the impaled cell. During LP, Vmax was lowest in the prox- The cellular model results show that at difimal area of each cell (Figure 6, LP), where ferent locations within each cell the values intracellular conduction was slowest. Vmax of Vmax would be different due to the flucincreased to a maximum value between the tuation of Vmax within the individual cells. middle and distal fourth of each myocyte. Consequently, the cellular model results In the distal part of each myocyte, Vmax indicate that variations in electrical load decreased although subcellular conduction within individual cells can account for the was fastest in this area. During longitu- experimental variety of Vmax values observed dinal conduction, the Vmax minimum in at different impalements sites during LP. the output area of each cell had a higher That is, the variable values of Vmax within value than did the minimum at input area each myocyte resulted in an undulating

Figure 6. Subcellular distribution of Vmax within 3 myocytes during longitudinal and transverse propagation. In each panel the values of Vmax are plotted as a function of distance (|o.m) along a line of consecutive segments extending between the ends of the each cell. The outline of each myocyte with the accompanying intracellular activation sequences for transverse conduction (isochrones separated by 3 |is) is presented above each panel. A similar outline of the myocyte with the accompanying intracellular activation sequence for longitudinal conduction (isochrones separated by 4 |is) is presented below each panel. Myocytes a, c, and e are those of the previous 2 figures. Reproduced from Spach MS, Heidlage JF. The stochastic nature of cardiac propagation at a microscopic level. An electrical description of myocardial architecture and its application to conduction. Circ Res 1995;76:366-380, with permission.

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region of the highest value of Vmax. Consequently, in normal adult myocardium the greatest electrical load within each cell is concentrated at the intercalated disks near the ends of the cells where curTransverse Propagation rents are received and transferred to The same general subcellular pat- adjoining cells via the associated gap tern of Vmax variability occurred during junctions. TP as during LP; i.e., in each cell the maximum Vmax value occurred near the center Microfibrosis with Loss of of the myocyte and lower Vmax values Side-to-Side Cellular occurred at the ends of each cell. The Interconnections Alters the mean Vmax value within almost every cell was greater during TP than during LP. Curvature of Wavefronts However, the TP Vmax minima near the ends of each cell were often lower in value In the foregoing sections, adult carthan the LP Vmax maximum located near diac myocytes have been considered to form the center of each cell (cells c and e of networks in which each myocyte is conFigure 6). This feature resulted in con- nected to multiple surrounding cells.22'26'27 siderable overlap of TP and LP Vmax val- This normal arrangement produces tight ues when comparing Vmax values from electrical coupling in all directions relative different subcellular areas of the same or to the orientation of the fibers. However, different cells. The different TP Vmax values aging is associated with the deposition within each myocyte thereby were consis- of fine, longitudinally oriented collagetent with the experimental results, which nous septa (microfibrosis) that surround demonstrated considerable variation in the small groups of cells in atrial bundles TP Vmax values, and some of the TP Vmax (Figure 7), and coarse collagenous septa values overlapped those that occurred develop in healed myocardial infarcts.8 during longitudinal conduction. When the Because sarcolemmal membrane appopaired values of Vmax were compared for sition does not occur between cells sepeach membrane segment (Figure 6), TP arated by collagen, the deposition of Vmax was greater than LP Vmax through- collagenous septa in interstitial space out most myocytes. However, near the marks areas where there has been loss of ends of a few cells there was a reversal of side-to-side electrical connections over the usual TP > LP Vmax relationship, e.g., variable distances. The "normal" deposicell e in Figure 6. These areas near the ends tion of collagenous septa occurs in atrial of myocytes likely provide a subcellular bundles at 2 widely separated time peribasis for the experimental result that at ods—during the first months of life 28 and a few microelectrode impalement sites, during the aging process.9 This structural TP Vmax was found to be less than LP Vmax. arrangement produces nonuniform A major conclusion to be drawn from anisotropic electrical properties of carFigure 6 is that for all directions of prop- diac bundles. agation the greatest load within each cell The deposition of collagen also reoccurs in the sarcolemmal membrane sults in the loss of tight packing of the located adjacent to the intercalated disks myocytes; i.e., there is a relative widenat the ends of cells in the regions of the ing of interstitial space, which should Vmax minima, and the least load occurs reduce the interstitial resistance to curtoward the center of each cell in the rent flow.11 A reduction in interstitial sequence of lower and higher Vmax values along the longitudinal axis of the network of cells.

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Figure 7. Collagenous septa in an atrial bundle with nonuniform anisotropic electrical properties from a 64-year-old patient. The collagenous septa (gray to black) are thick and long and result in isolation of adjacent cells and groups of cells (white). Bar = 50 |im. Reproduced from Spach MS, Dolber PC, Heidlage JF. Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle. A model of reentry based on anisotropic discontinuous propagation. Circ Res 1988;62:811-832, with permission.

resistance secondary to an increase in interstitial volume at sites of collagen deposition is consistent with the demonstration by Fallert et al.29 that the impedance of the dense scar of healed infarcts is 50% lower than the impedance of normal myocardium. Further, recent evidence indicates that there are unexpected (and unexplored) mechanisms of extracellular loading of the sarcolemmal membrane due to resistive discontinuities produced by the spatial variations in the volume of interstitial space associated with collagenous septa.11 When analyzing the curvature of wavefronts, puzzling questions arise as to whether the conduction events are due to 1 of the 2 following phenomena: (1) At the larger macroscopic size scale (>1 to 2 mm), variations in conduction velocity are considered to occur in relation to the degree of

curvature of wavefronts that form spiral waves in a continuous medium,5-7 i.e., a greater curvature is associated with a greater electrical load, which generates a decrease in conduction velocity. (2) Conduction events are related to variations in loading produced by differences in cellular connectivity that occur in anisotropic cardiac bundles.2,3 To illustrate that differences in the curvature of cardiac wavefronts are highly determined by the anisotropic distribution of the cellular interconnections, Figure 8 shows activation sequences in 2 types of anisotropic cardiac muscle. In the well-coupled uniform anisotropic preparation (Figure 8, left), the effective longitudinal conduction velocity was 0.51 m/s and the effective transverse velocity was 0.17 m/s, which resulted in an LP/TP velocity ratio of 3.0. In the nonuniform anisotropic preparation with

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Figure 8. Effect of uniform versus nonuniform anisotropy on the spread of activation. The sequence for a uniform anisotropic preparation of canine ventricular epimyocardium is shown on the left, along with unipolar extracellular waveforms (bottom) recorded at the sites noted on the isochrone map. The sequence for a nonuniform anisotropic canine atrial preparation (crista terminalis) is shown on the right. Each activation sequence was associated with normal action potentials. The isochrones represent 1-ms intervals. Reproduced from Spach MS. The stochastic nature of cardiac propagation due to the discrete cellular structure of the myocardium. Int J Bifurcation Chaos 1996;6:16371656, with permission.

decreased side-to-side coupling between fibers (Figure 8, right), the effective LP conduction velocity was 1.0 m/s and the effective TP conduction velocity was 0.1 m/s, which produced an LP/TP velocity ratio of 10. Myocardial bundles with uniform anisotropic properties usually have an LP/TP ratio between 2 and 4, and bundles with nonuniform anisotropic properties produce a much higher LP/TP velocity ratio ranging from 7 to 15.2 As can be seen in Figure 8, in the shift from LP to TP the curvature of the wavefronts was much greater in the preparation with -I side-toside coupling between the fibers than in the well-coupled anisotropic preparation.30 Figure 8 also shows that a major effect of the loss of side-to-side electrical

coupling between fibers is a prominent decrease in the effective conduction velocity in the transverse direction. The decrease in the effective transverse conduction velocity largely accounts for the high LP/TP velocity ratio exhibited by nonuniform anisotropic bundles with microfibrosis. Further, in nonuniform anisotropic atrial bundles from humans older than 60 years of age, the effective transverse conduction velocities are as low as 0.04 m/s in the presence of rapid upstroke action potentials.10 This type of very slow anisotropic conduction should be of increasing importance in the analysis of the low conduction velocities that enhance the initiation of atrial fibrillation in the geriatric age group, as well as in the initiation of

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have different effective refractory periods in the absence of repolarization inhomogeneities.10 A representative wellcoupled uniform anisotropic atrial bundle Proarrhythmic Effects of from a child is illustrated in Figure 9A. Microfibrosis with Loss of This shows the pattern of activation spread and associated extracellular waveSide-to-Side Gap Junctions forms of TP (waveform 1) and LP (waveA widely used electrophysiological forms 2 and 3) of a normal beat at an parameter is the effective refractory period, interstimulus interval of 800 ms (left which is measured as the shortest pre- side) and the earliest propagated premamature interval at which a propagated ture beat that occurred at an interval of action potential occurs. Moe et al.31 initially 345 ms (right side). As the premature demonstrated that an abrupt increase (dis- interval was reduced to the earliest stimcontinuity) in a conduction time curve, ulus that would produce a propagated which is produced by initiating progres- response, all of the extracellular wavesively earlier premature stimuli, indi- forms remained smooth in contour and cates that there are 2 or more functionally maintained the same general shape as different pathways in the total conduc- they decreased in amplitude. Earlier pretion circuit. Such discontinuities in a con- mature stimuli failed to produce conducduction time curve occur when the tion in any direction. Figure 9B shows the corollary results effective refractory period of one pathway is longer than that of another. In this sit- in a nonuniform anisotropic atrial bundle uation, when a premature beat occurs at from a 64-year-old patient. Normal beats an interval that is shorter than that of the produced TP extracellular waveforms that longer refractory period of one pathway, the had irregular deflections superimposed on propagation of premature impulses can the overall waveforms (waveforms 1 and 2); continue in another pathway that has a these multiphasic or fractionated waveforms shorter effective refractory period. This were associated with the underlying microphenomenon produces unidirectional fibrosis shown in this patient's atrial bundle block, which is a requirement for the in Figure 7. When the premature interval initiation of a reentrant arrhythmia. was decreased to 327 ms (Figure 9B, right), Mechanistically, the importance of uni- stable but very slow TP continued in assodirectional block is that it must occur in ciation with a considerable increase in the order for the remaining activation wave time intervals between the multiple small to circulate back and reexcite the initial deflections in the multiphasic TP wavestimulus area. Spatial differences in forms. In the longitudinal direction of the action potential duration (inhomogeneities fibers, however, decremental conduction to of repolarization) are usually consid- block occurred. The same events occurred ered the underlying cause of spatial dif- when the stimulus site was moved to differences in the effective refractory period ferent locations throughout the bundle, and unidirectional block. Figure 9, how- which again demonstrated that the direcever, demonstrates that changes in cel- tion of unidirectional block of the premature lular connectivity associated with the impulses was related to the orientation of microstructural remodeling of uniform the fibers. Although not shown, further anisotropic properties to nonuniform aniso- slight shortening of the premature interval tropic properties create the general property resulted in anisotropic reentry within the of functionally different pathways that muscle bundle.10 ventricular tachycardia in patients with healed infarcts.8

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Figure 9. Propagation responses to premature action potentials in atrial bundles with (A) uniform and (B) nonuniform anisotropic properties. Each panel shows the normal activation sequence and a few of the extracellular waveforms on the left, and those of an early premature beat are shown on the right. The interstimulus intervals (ms) are listed in the boxes above each set of extracellular waveforms. A. Isochrones are separated by 1 ms. The atrial bundle is from a 12-year-old patient. B. Activation sequences in the transverse direction were so complex that it was not possible to construct isochrone maps. In the drawing of the normal activation sequence (B, left), the elongated open arrow represents the narrow region of fast longitudinal conduction. On the right side, the elongated triangle represents decremental conduction to block along the longitudinal axis of the fibers. Reproduced from Spach MS, Dolber PC, Heidlage JF. Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle. A model of reentry based on anisotropic discontinuous propagation. Circ Res 1988;62:811-832, with permission.

activation waves at a macroscopic level, the events of propagating excitation at the The results presented in this chapter microscopic level are constantly changing show that the microstructure of the and disorderly due to intracellular loading myocardium creates inhomogeneities of effects and conduction delays between electrical load that cause cardiac propaga- cells.4 An important feature of the stotion to be discontinuous and stochastic in chastic nature of discontinuous propaganature at a microscopic level. Thus, under- tion at a microscopic level is that small lying the movement of smooth appearing input changes produce major changes in Significance

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the events of propagation. For example, a simple change in the direction of conduction of the excitation wave produces considerable change in the excitatory events during the upstroke of the action potential and in the delays between cells. Although the events of discontinuous conduction are stochastic in nature at a microscopic level, these stochastic events become averaged and appear consistent with a continuous medium at the larger macroscopic size scale, as depicted experimentally.32 It may seem bewildering that excitation spread in normal anisotropic muscle can be viewed as continuous and discontinuous. Although these phenomena may appear contrasting at first sight, they present a biological analogy to the theory of Bohr and Heisenberg in quantum physics in the context that there are 2 truths rather than 1. At a large size scale in normal ventricular muscle, curved wavefronts appear continuous, but when analyzed at a microscopic size scale they are discontinuous and stochastic in nature.4 This is only one example of a general principle that when biological phenomena (e.g., bursting of pancreatic (3-cells,33 ion channel events, etc.) are examined at a small enough size scale, they are found to occur in steps with abrupt changes (discontinuous), and normally their stochastic properties become averaged to produce order at a larger spatial or time scale. This relationship is a feature of the central limit theorem,34 which provides a course from discontinuous events at a microscopic level to smoothed (averaged) events at a macroscopic level. A fundamental property of the stochastic nature of normal propagation is that it provides a major protective effect against arrhythmias by reestablishing the general direction of wavefront movement when small variations in excitation events occur. However, a loss of side-toside electrical connections between small groups of fibers results in a decrease in

the diversity of conduction events at a very small size scale. This produces relatively isolated groups of cells throughout cardiac bundles in which larger fluctuations of electrical load can develop and be distributed over more cells than occurs normally. Now, due to the relative isolation of small groups of cells, the discontinuous events at a microscopic size scale no longer can be averaged to produce the smooth curved wavefronts that occur at a macroscopic level in normal cardiac muscle. As illustrated in Figure 9B, at this point premature impulses can induce abnormal conduction events that produce breaks in the overall wavefront,35 resulting in the initiation of a reentrant circuit. This view implies an important synthesis for future combined structuralelectrical mapping studies to establish a new relationship between discontinuous propagation at a microscopic level and spiral waves at a macroscopic size scale.3 Such a synthesis will be necessary to understand how the occurrence of wavefront breaks35 and spiral waves5-7 (reentry) are enhanced by the loss of side-to-side cellular interconnections in association with collagen accumulation in interstitial space. Thus, a variety of improved mapping techniques will be needed to obtain needed information about microscopic conduction events in normal and diseased cardiac structures. Such highresolution mapping studies should be analogous to the fact that quantum physics takes advantage of the "microscopic" variations of particles to predict new phenomena not possible from the measurements of classic physics at a larger size scale. There are some events related to discontinuous anisotropic propagation at a microscopic level that are not accounted for by the theory of the curvature of wavefronts at a macroscopic level. One example is the relationship between conduction velocity and Vmax. According to the theory of spiral

MICROSCOPIC DISCONTINUITIES AS A BASIS FOR REENTRANT ARRHYTHMIAS waves in a continuous medium, when the local curvature of a wavefront becomes sufficiently great, there is a reduction in the local conduction velocity.36 These decreases in velocity related to wavefront curvature should be associated with a reduction in the rate of rise of the action potential37; i.e., changes in wavefront curvature produce a monotonic relationship between the local conduction velocity and Vmax. However, in anisotropic cardiac bundles, there is a general reciprocal relationship between the local conduction velocity and Vmax. Fast longitudinal conduction is associated with a relatively low Vmax compared to the increase in Vmax that occurs when the local conduction velocity decreases as the wavefront propagates at progressively greater angles with respect to the longitudinal axis of the fibers. Here, the highest values of Vmax are associated with the lowest conduction velocities of the macroscopic activation wavefront (see Figures 4 and 5 in reference 1). Of considerable long-term interest is the elucidation of the specific proarrhythmic mechanisms associated with the accumulation of collagen in interstitial space. The results presented here indicate there is a close relationship between the deposition of collagen and the loss of lateral interconnections between small groups of fibers. This relationship provides a major challenge to develop interventions that alter collagen deposition as an antiarrhythmic therapeutic measure. References 1. Spach MS, Miller WT III, Geselowitz DB, et al. The discontinuous nature of propagation in normal canine cardiac muscle: Evidence for recurrent discontinuities of intracellular resistance that affect the membrane currents. CircRes 1981;48:39-45. 2. Spach MS. Discontinuous cardiac conduction: Its origin in cellular connectivity with long-term adaptive changes that

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cause arrhythmias. In Spooner P, Joyner RW, Jalife J (eds): Discontinuous Conduction in the Heart. Armonk, NY: Futura Publishing Co.; 1997:5-51. 3. Spach MS, Heidlage JF, Dolber PC. The dual nature of anisotropic discontinuous conduction in the heart. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology: From Cell to Bedside. 3rd ed. Philadelphia: W.B. Saunders; 2000:213-222. 4. Spach MS, Heidlage JF. The stochastic nature of cardiac propagation at a microscopic level. An electrical description of myocardial architecture and its application to conduction. CircRes 1995;76:366380. 5. Cabo C, Pertsov AM, Baxter WT, et al. Wave-front curvature as a cause of slow conduction and block in isolated cardiac muscle. CircRes 1994;75:1014-1028. 6. Davidenko JM, Kent PF, Chialvo DR, et al. Sustained vortex-like waves in normal isolated ventricular muscle. Proc NatlAcad Sci USA 1990;87:8785-8789. 7. Pertsov AM, Jalife J. Three-dimensional vortex-like reentry. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia: W.B. Saunders; 1995:403-410. 8. Dillon SM, Allessie MA, Ursell PC, et al. Influences of anisotropic tissue structure on reentrant circuits in the EBZ of subacute canine infarcts. CircRes 1988;63:182-206. 9. Spach MS, Dolber PC. Relating extracellular potentials and their derivatives to anisotropic propagation at a microscopic level in human cardiac muscle: Evidence for electrical uncoupling of side-to-side fiber connections with increasing age. Circ Res 1986;58:356-371. 10. Spach MS, Dolber PC, Heidlage JF. Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle. A model of reentry based on anisotropic discontinuous propagation. CircRes 1988;62:811-832. 11. Spach MS, Heidlage JF, Dolber PC, et al. Extracellular discontinuities in cardiac muscle: Evidence for capillary effects on the action potential foot. Circ Res 1998;83: 1144-1164. 12. Spach MS,.Heidlage JF, Darken ER, et al. Cellular Vmax reflects both membrane properties and the load presented by adjoining cells. Am J Physiol 1992;263: H1855-H1863.

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13. Spach MS, Miller WT III, Miller-Jones E, et al. Extracellular potentials related to intracellular action potentials during impulse conduction in anisotropic canine cardiac muscle. Circ Res 1979;45:188— 204. 14. Rushton WA. Initiation of the propagated disturbance. Proc R Soc Lond (Biol) 1937; 124:124-210. 15. Socolar SJ. The coupling coefficient as an index of junctional conductance. J Membr Biol 1977;34:29-37. 16. Fast VG, Kleber AG. Microscopic conduction in cultured strands of neonatal rat heart cells measured with voltage-sensitive dyes. Circ Res 1993;73:591-595. 17. Fast VG, Kleber AG. Anisotropic conduction in monolayers of neonatal rat heart cells cultured on collagen substrate. Circ Res 1994;75:591-595. 18. Rohr S. Determination of impulse conduction characteristics at a microscopic scale in patterned growth heart cell cultures using multiple site optical recording of transmembrane voltage. J Cardiovasc Electrophysiol 1995;6:551-568. 19. Hofer E, Urban G, Spach MS, et al. Measuring activation patterns of the heart at a microscopic size scale with thin-film sensors. Am JPhysiol 1994;35:H2136-H2145. 20. Joyner RW, Westerfield M, Moore JW. Effect of cellular geometry on current flow during a propagated action potential. Biophys J I980;3l:183-194. 21. Spach MS, Heidlage JF. A multidimensional model of cellular effects on the spread of electrotonic currents and on propagating action potentials. Crit Rev Biomed Eng 1992;20:141-169. 22. Hoyt RH, Cohen MI, Saffitz JE. Distribution and three-dimensional structure of intercellular junctions in canine myocardium. Circ Res 1989;64:563-574. 23. Joyner RW. Effects of the discrete pattern of electrical coupling on propagation through an electrical syncytium. Circ Res 1982;50:192-200. 24. Rudy Y, Quan W. A model study of the effects of the discrete cellular structure on electrical propagation in cardiac tissue. Circ Res 1987;61:815-823.

25. Leon LJ, Roberge FA. Directional characteristics of action potential propagation in cardiac muscle. A model study. Circ Res 1991;69:378-395. 26. Gourdie RG, Green CR, Severs NJ. Gap junction distribution in adult mammalian myocardium revealed by anti-peptide antibody and laser scanning confocal microscopy. J Cell Sci 1991;99:41-55. 27. Dolber PC, Beyer EC, Junker JL, et al. Distribution of gap junctions in dog and rat ventricle studied with a double-label technique. JMol Cell Cardiol 1992;24:1443-1457. 28. Spach MS, Miller WT III, Dolber PC, et al. The functional role of structural complexities in the propagation of depolarization in the atrium of the dog. Cardiac conduction disturbances due to discontinuities of effective axial resistivity. Circ Res 1982;50:175-192. 29. Fallert MA, Mirotznik MS, Downing EB, et al. Myocardial electrical impedance mapping of ischemic sheep hearts and healing aneurysms. Circulation 1993;87:199-207. 30. Spach MS. The stochastic nature of cardiac propagation due to the discrete cellular structure of the myocardium. Int J Bifurcation Chaos 1996;6:1637-1656. 31. Moe GK, Preston JM, Burlington H. Physiologic evidence for a dual A-V transmission system. Circ Res 1956;4:357-375. 32. Clerc L. Directional differences of impulse spread in trabecular muscle from mammalian heart. J Physiol (Lond) 1976;255: 335-346. 33. Sherman A, Rinzel J. Model for synchronization of pancreatic (3-cells by gap junction coupling. Biophys J 1991;59:547-559. 34. Kleinbaum DG, Kupper LL, Muller KE. Applied Regression Analysis and Other Multiuariable Methods. Boston: PWSKent Publishing Co.; 1988:17. 35. Agladze K, Keener JP, Muller SC, et al. Rotating spiral waves created by geometry. Science 1994;264:1746-1748. 36. Tyson JJ, Keener JP. Singular perturbation theory of traveling waves in excitable media. Physica D 1988;32:327-361. 37. Zykov VS. Spiral waves in two-dimensional excitable media. Ann NY Acad Sci 1990;591:75-88.

Chapter 16

Mapping in Explanted Hearts Jacques M. T. de Bakker, PhD and MichielJ. Janse, MD

Introduction

Electrophysiological changes in cardiac muscle and mechanisms of arrhythmias caused by heart diseases cannot easily be studied in patients, and therefore experimental models are frequently used. Animal models are usually the first choice for investigations on electrophysiological mechanisms of arrhythmias. In the development of animal models, attempts must be made to fulfill the criteria that would make the model a realistic representation of the clinical events. A large number of laboratory models that use experimental animals have been developed in an attempt to achieve this goal. In these models, different approaches are applied. Different procedures of occlusion have been used to create infarction, resulting in different anatomical characteristics of the infarcts, which makes comparison between the models and the clinical setting difficult. x~5 In addition, various species are being used, which introduces differences in electrophysiological properties of the heart and differences in cardiac and coronary anatomy. In an effort to introduce some sort

of standardization, a set of guidelines for the study of arrhythmias caused by ischemia, infarction, and reperfusion, known as the Lambeth Convention, was published by Walker et al.6 in 1988. This convention addresses statistical problems, uniformity of animals, classification and detection of arrhythmias, and definition and detection of ischemia and infarction. To delineate the electrophysiological abnormalities in dilated cardiomyopathy, various experimental models have been developed as well.7"10 While arrhythmias frequently occur in patients with dilated cardiomyopathy, monomorphic, sustained ventricular tachycardias (VTs) are rare,11'12 hampering their mechanistic delineation. The animal models have also mainly been used to study cellular electrophysiological abnormalities. Although animal models have all fallen short in one respect or another, each has provided important information that has improved our understanding of the pathophysiology of arrhythmias in the diseased human heart. The use of Langendorff-perfused human hearts from patients who underwent

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003.

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heart transplantation because of extensive infarction or cardiomyopathy presents an alternative method to study electrophysiology and arrhythmias caused by these diseases. Although the pathology is a realistic representation of the clinical events, this model also lacks some clinical characteristics. Explantation results in denervation of the heart, which may affect arrhythmogenicity. It has been shown in animal models that transmural infarcts that extend to the epicardial surface may damage efferent sympathetic fibers in the subepicardium and produce heterogeneous sympathetic denervation of normal myocardium apical to the infarct.13'14 In addition, only studies in the healed phase of myocardial infarction are possible, because infarctions in these patients already exist long before transplantation. Although sustained VTs are usually not present spontaneously in the explanted infarcted hearts, they often can be induced by programmed stimulation. This is compatible with clinical observations that sustained VTs can be induced in approximately 50% of patients with healed myocardial infarction but without documented arrhythmias.15^17 This suggests that in at least half of the patients who survive myocardial infarction, the substrate for sustained VT is present but, in most cases, the trigger for starting the tachycardia never occurs because only a small percent of patients who survive myocardial infarction develop sustained VT late after the onset of infarction. In contrast to infarcted hearts, we were unable to induce sustained monomorphic VTs in explanted hearts from patients with dilated cardiomyopathy. Although innervation in explanted hearts is corrupted by the resection procedure, study of these hearts is particularly helpful to correlate electrophysiology with anatomy of the arrhythmogenic area.

LangendorfF Perfusion of the Isolated Human Heart Langendorff perfusion of explanted human hearts does not differ essentially from that procedure applied in animal hearts except for the cannulation procedure. In animal hearts, a cannula is inserted into the aorta and fixed with a suture around the aortic root. In the explanted human heart, the aorta is often too short for the cannula and the left main artery and right coronary artery must be cannulated separately. To avoid blood clotting in the arteries and to protect the heart directly after explantation, hearts were perfused with cardioplegia just before explantation. After removal, hearts were submerged in Tyrode's solution containing (in mmol/L): sodium (Na+) 156.5; potassium (K+) 4.7; calcium (Ca2+) 1.5; phosphate (HaPO^) 0.5; chlorine (Clr) 137; bicarbonate (HCOg) 28; and glucose 20. The left and right coronary arteries were cannulated via the ostia with the heart submerged in the cold Tyrode's solution. Thereafter, the heart was attached to the Langendorff perfusion system. Details of this system are given elsewhere.18 The perfusion fluid consisted of a mixture of 50% human blood and 50% of the Tyrode's solution (total volume 2 L). After the heart was connected, coronary flow was stabilized to approximately 200 mL/min. The ventricles were drained by rubber tubes in the apex, one into the left and the other into the right cavity. Hearts started to beat spontaneously or to fibrillate within minutes of perfusion. If fibrillation occurred, the heart was defibrillated after approximately 5 minutes. Perfusion was maintained at a temperature of 37±0.5°C until either the measurements were completed or contraction noticeably decreased (after 4 to 5 hours).

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Recording Electrical Activity

Histology of the Hearts

Electrograms recorded with bipolar hook electrodes attached to the base of the left and right ventricles served as a time reference and were used to distinguish the configuration of induced tachycardias. Epicardial as well as endocardial mapping of the electrical activity was performed during tachycardia. Tachycardia was induced by premature stimulation via a bipolar hook electrode attached to the left ventricular wall. Endocardial electrical activity of the left ventricle (and of the right ventricle in a number of cases) was recorded with a balloon electrode covered with 64 electrode terminals. The interelectrode distance was approximately 1.2 cm. The balloon was introduced into the left ventricular cavity through the mitral (or tricuspid) valve orifice. For recording of epicardial signals, flexible grid electrodes with 64 electrode terminals were used. High-resolution mapping of electrical activity using plaque electrodes (105 to 208 electrode terminals; interelectrode distance 0.8 and 0.5 mm, respectively) was carried out to determine the role of the architecture of interstitial fibrosis for activation delay.

Figure 1 shows typical examples of the histology of the explanted hearts. Panel A, a section of the posteroseptal wall of one of the hearts, illustrates that the endocardium (endo) is thickened by fibroelastosis (dark rim). This is a frequent finding in these hearts, where the endocardium can be as thick as 1 mm.19 A major part of the posterior wall is fibrotic (F), but a thin rim of surviving myocardial tissue is found subendocardially along the entire posterior wall (arrow) and contacts remaining healthy myocardium (M) of the septal wall. A surviving subendocardial rim is a common finding in infarcted myocardium and is supposed to be caused by the presence of a subendocardial plexus.20'21 White areas along the epicardium (epi) point to fatty tissue. Panel B, a section from the septal wall of another heart, shows that myocardial bundles (dark areas) may also survive deep in the infarcted zone. Note that these surviving myocardial bundles are often divided into smaller bundles by strands of fibrous tissue, yielding a complex structure of isolating and conducting tissue. Such areas of intermingled muscle bundles and fibrous septae may cause profound conduction delay (discussed later in this chapter). A similar architecture has been found in the infarcted canine heart.22 Panel C is a section from the apical part of the septum in the same heart. The left wall (top) of the septum is entirely fibrotic (light area marked F) in contrast to the right wall (bottom). A myocardial bundle, entirely encaged by fibrosis, seems to have survived in the left septal wall (arrow). It is conceivable that such bundles, when they traverse the infarcted zone, may constitute the return path of a reentry circuit.

Characteristics of the Infarcted Human Heart Studies were carried out at 9 hearts from patients who underwent heart transplantation because of congestive heart failure caused by myocardial infarction. The location of the infarct was in the anterior wall including the septum in 6 patients, inferoposterior in 2, and diffuse in 1. Ejection fraction before transplantation ranged from 13% to 27%. A history of sustained VT was documented in one patient only.

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Figure 1. A. Histologic section of the infarcted area in the posteroseptal region of an explanted human heart. The posterior wall consists mainly of fibrous tissue (F); in contrast, the septal region is not affected and consists of healthy myocardial tissue (M). The endocardium is thickened by fibroelastosis, which is present along the entire posterior wall (dark rim). A small rim of surviving myocardium is present between the endocardium and the infarcted area (arrow). The white zone along the epicardium indicates the presence of fatty tissue. B. Histologic section from the infarcted mid septal region of another explanted heart. In contrast to A, this region consists of numerous surviving myocardial bundles (dark areas) that survive within the fibrotic regions (F). Note that the myocardial bundles are often divided into smaller bundles by fibrotic strands. Areas in which numerous myocardial bundles are embedded in fibrous tissue are a common finding in infarcted myocardium.C. Histologic section from the same heart as in B. This section is taken from the septal wall as well, but at a more apical position. The infarction is almost transmural at this level, but a large strand of myocardium was able to survive in the middle of the septum (arrow). F = fibrous tissue.

MAPPING IN EXPLANTED HEARTS Spread of Activation During Tachycardia In the 9 isolated hearts, 15 monomorphic sustained VTs were induced. The cycle length (CL) ranged from 260 to 560 ms. In 7 of 10 tachycardias, earliest epicardial activation appeared more than 20 ms after earliest endocardial activation, whereas in 3 tachycardias, earliest epicardial and endocardial activation was almost simultaneous. In all cases, the endocardial activation pattern showed a focal area of earliest activity from which activation spread more or less centrifugally with activation block toward the infarcted zone. The site of earliest activation was always located within 2 cm of the border of the infarct. These characteristics were similar to those of the tachycardias recorded in patients during arrhythmic surgery.23"27 Although the tachycardias induced in healed myocardial infarction usually reveal a focal activation pattern, there was convincing evidence from clinical and experimental studies28"33 that reentry is the underlying mechanism of these arrhythmias. It was supposed that activation returned from the latest activated site of one cycle to the earliest activated site of the next cycle via surviving myocardial fibers in the infarcted zone. Remaining healthy myocardium constituted the other part of the circuit. The exact path within the infarcted area was, however, unknown. Because electrophysiology and histology can be well correlated in explanted hearts, detection of the reentry circuit within the compromised area was expected to be possible. In 2 tachycardias recorded in 2 different hearts, activation delay between earliest and latest endocardial activation was approximately 30 ms. The distance between earliest and latest activated sites was approximately 1.2 cm. Assuming that activation returns from the latest activated

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site to the earliest activated site via surviving myocardial bundles yields a mean conduction velocity of 0.4 m/s in the return path. Thus, in these cases, which are rather exceptional, the conduction velocity in the return tract was close to normal. In contrast, the majority of activation maps showed delays of more than 120 ms between latest and earliest activation over a similar distance, resulting in conduction velocities of less than 0.1 m/s. Endocardial activation patterns of 2 tachycardias induced in the same heart are shown in Figure 2. VT1 shows a tachycardia where conduction in the return path was close to normal; in contrast, the activation map of VT2 shows that the conduction velocity in the presumed return path is low. Hatching indicates that an area of damaged tissue extended from base to apex in the posterior wall. Activation of VT1 started at the right border of the infarct, and main activation (arrows) spread out toward the base and the lateral wall. Activation toward the septum was blocked after 120 ms; 240 ms after the onset of endocardial activation, activity reached the septal side of the infarct (site e). Delay between activation at this site and the onset of the next cycle (at site a) was only 30 ms, suggesting reexcitation at the "origin" by means of activation through surviving myocardial tissue between sites e and a. The electrogram recorded at site f, located between a and e, had 3 deflections; the first and third deflection were remote and caused by activation removing from the right side of infarcted zone and the wavefront approaching the left side of the infarcted zone, respectively. The second deflection did not coincide with documented activity anywhere else in the tissue, which indicated that it was generated by viable tissue underneath the recording site. The time delay of 30 ms between activation at the sites e and a (distance approximately 1.2 cm) suggested that activation was carried back toward

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Figure 2. Endocardial activation patterns of 2 monomorphic sustained ventricular tachycardias that were induced in a Langendorff-perfused human heart with extensive posterior infarction. Isochrones are in ms and timed with respect to the onset of endocardial activation. Arrows indicate main spread of activation. The activation map of VT1 shows that there is a time gap of 30 ms between latest activation of one cycle (recorded at site e) and earliest activation of the next cycle (recorded at site a). Reentry probably occurred through surviving pathways in the infarct zone between sites e and a (distance, 1.2 cm). The conduction velocity in the return tract, is approximately 0.4 m/s, which is close to normal. In contrast, delay in the return tract of VT2 is 140 ms, while the distance between the earliest and latest activated sites is 1.2 cm as well. This implies that the conduction velocity in the return tract of VT2 is low, approximately 0.07 m/s.

MAPPING IN EXPLANTED HEARTS the "origin" with close to normal conduction velocity (0.4 m/s). VT2 shows the activation pattern of another tachycardia induced in the same heart. Earliest endocardial activation arose at the septal side of the infarct zone. At the base of the septum, spread of activation toward the posterior wall was blocked. However, the wavefront reached the posterior wall by way of the anterolateral wall and apex. The wavefronts merged at a mid posterior level (160 ms isochrone) to arrive 240 ms after the onset at the base of the posterior septal border (site a). Because the CL of the tachycardia is 400 ms, a time gap of 160 ms had to be bridged to close the reentrant circuit that reactivated the "origin." The distance between latest and earliest activated sites was about 1.2 cm, yielding a mean conduction velocity in the presumed return tract of approximately 0.07 m/s.

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Characteristics of the Return Path For both tachycardias shown in Figure 2 the location of the return path of the presumed reentry circuit could be determined from the activation maps; however, only for the tachycardia of VT1 were we able to trace the exact route. After fixation in formalin, the area comprising the earliest and latest activated site was removed and sectioned. Sections of 10-u,m thickness were produced. A total of 500 sections were analyzed. Figure 3 shows a stacking of transparencies made of 10 sections 100 |im apart. In the upper and lower sections, the infarction was transmural. The stacking, however, suggests that a continuous tract (arrow) was present traversing the infarcted area, connecting the septum with the posterior wall. Thus, it could

Figure 3. Schematic drawings of sections of the area harboring the return tract for reentry of VT1 in Figure 2. Black areas are myocardial tissue; white areas are fibrotic. Transparencies of 10 sections have been stacked. The infarction is transmural at the level of sections 1 and 10. The stacking, however, suggests that there is a bridge of surviving myocardial tissue (white arrow) connecting surviving myocardial tissue at either side of the infarcted zone. Note that this tract is located endocardially, almost intramurally. In the same area an epicardially located tract could be traced in the area indicated by the open arrow.

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Figure 4. Three-dimensional reconstruction of a tract of surviving myocardial tissue traversing the infarcted zone as suggested by Figure 3. Surviving myocardium of the sections is indicated in black and that of the tract in gray. Eleven consecutive sections, 100 jim apart, were used for the reconstruction. The tract is connected with remaining healthy tissue of the posterior wall at level d and with the septal wall at level a. The length of the tract is approximately 13 mm. The width varies along the tract, with bottlenecks appearing in both the descending and the ascending parts of the tract. Reproduced from reference 33, with permission.

well be that a surviving bundle of myocardial tissue was present, connecting viable tissue at either side of the infarct zone and possibly forming a return path for reentry.

To prove that the supposed tract was indeed continuous, a 3-dimensional reconstruction of the tract had to be made (Figure 4). The schematic drawings of 10 successive sections (a to k), each 100 um

MAPPING IN EXPLANTED HEARTS apart, show that the tract (gray area) fuses with remaining healthy tissue of the posterior wall at level d. From here, the tract runs down toward level k, and remains horizontal over a distance of about 6 mm in level j before it ascends and finally merges with remaining healthy tissue of the septal wall at level a. Although the tract appears to be continuous, there are a number of narrow passages, especially in the descending and ascending parts of the tract. The smallest width of these bottlenecks was approximately 250 um. One might speculate that unidirectional activation block, necessary for initiating the tachycardia, could preferentially occur at such sites.34-36 The length of the endocardial tract within the infarct zone was approximately 13 mm. The short length of the tract may account for the small delay of activation in this area. It occurred to us that the subendocardial tract did not constitute the only possibility for reentry. The epicardial activation map suggested the presence of a surviving tract in the subepicardial part of the infarct, and an anatomical substantiation for such a tract could be demonstrated by applying the same procedure as described before.37 There was only one other heart in which delay between latest activation of one cycle and earliest activation of the next cycle was less than 30 ms, whereas the distance between the sites was only 1.2 cm. A tract of surviving myocardium, located 1.5 mm from the epicardial surface of the anterior wall, was traced. Its smallest width was approximately 350 |im. Two morphologically different tachycardias could be induced in this heart. In both tachycardias, the return path of the reentry circuit was the same. Because we could trace only one surviving tract in this area, it was likely that this return path was used for activation in both

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tachycardias. The tachycardias revolved in opposite directions, indicating that unidirectional block in this area could occur in either direction. These observations show that surviving tracts may be present throughout the entire infarcted ventricular wall and that return tracts may be used in either direction. The latter gives rise to VTs with different configuration. Direction of Surviving Fibers The area of the return path in VT2 in Figure 2, and in 3 other hearts where the apparent conduction velocity between the site of latest activation of one cycle and earliest activation of the next was low, consisted of a collection of surviving bundles with various diameters, separated from each other by fibrous or fatty tissue. Surviving bundles coursed separately over a few hundred micrometers and then merged into a single bundle (Figure 5). The fiber direction of the bundles was perpendicular to the line connecting the sites of earliest and latest activation, indicating that it was necessary for activation to proceed perpendicular to the fibers. The clusters of surviving muscle bundles separated by fibrous tissue and the repeated fusion and bifurcation of these bundles resembles inhomogeneous anisotropy, which could well account for the delayed conduction.38,39 Because of the complicated architecture of the branching bundles in the infarct, it was impossible to reconstruct a possible return path in either of these hearts. In the remaining hearts, the surviving fibers had no fixed direction, but varied throughout the area of the presumed return path. In the infarcted dog heart too, disorganization of surviving myocardial cells due to the ingrowth of fibrous tissue is a common finding.40

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Figure 5. Photomicrographs of an area revealing slow conduction during tachycardia. The left panel shows that the area consists of a number of surviving myocardial bundles (bright areas), separated from each other by fibrous tissue (dark areas). The photomicrograph at the right shows histological features in a section 100 jj,m beneath the one at the left. Here, the separated bundles have merged into a single bundle. Fiber direction in the area shown was perpendicular to the line connecting earliest and latest activated sites, indicating that activation had to proceed perpendicular to the fiber direction. Modified from reference 37.

slow conduction in healed infarcts. Impaired coupling between cells presents Unraveling the mechanism of con- another option for impaired conduction. duction delays of greater than 100 ms over Several investigators have shown that in distances less than 1 cm, which were compromised myocardium the connecfound in the majority of the tachycardias, tions of cells in side-to-side apposition are presented a challenge. Microelectrode reduced, whereas end-to-end connections recordings of myocardial tissue surviving are virtually unaffected.43,44 This is comin the infarcted zone have shown that patible with our finding that conduction action potentials were close to normal in delay preferentially occurred perpendichealed myocardial infarction.33,40-42 There- ular to the fiber direction. fore, abnormal membrane characteristics Disruption of side-to-side connection were unlikely candidates as the cause of may increase path length. Histology showed Superfused Preparations

MAPPING IN EXPLANTED HEARTS proliferation of fibrous tissue resulting in longitudinally oriented shells of connective tissue, insulating adjacent groups of myocardial fibers. Side-to-side electrical coupling among these fibers could be absent over distances of several millimeters, but interconnections farther away transferred activation to neighboring bundles. Diameter of the surviving bundles ranged from a few millimeters to the diameter of single cells. The small diameter of the isolated bundles together with the large delays over short distances suggested that very high resolution measurements were required to unravel the mechanism of activation delay. Measurements in the isolated hearts were not very suitable for such high-resolution mapping and therefore we studied conduction in and histology of papillary muscles resected from the explanted hearts.45 Muscles were superfused in a tissue bath; this has the advantage that only a rim of subendocardial myocardium 300 to 600 um thick survives. Thus, these preparations were more or less 2 dimensional. Papillary muscles were chosen because bundles of viable myocardial cells that survive in the subendocardial rim remain parallel in orientation.31 In infarcted myocardium, the parallel orientation of the surviving fibers often is not preserved and the surviving fibers appear to course in different directions.38,40 During basic stimulation, spread of activation was determined from recordings made at distances of 200 um from up to 416 sites. Electrograms showed multiple deflection in virtually all preparations (fractionated electrograms). Such electrograms are a common finding in diseased myocardium and point to asynchronous conduction. Electrical separation of myocardial fibers by anatomical barriers such as fibrous or fatty tissue give rise to separated conducting paths, which may result in asynchronous conduction. Separation of

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conducting paths is not exclusively the result of anatomic barriers. Reduced coupling between cells caused by a decrease in the number of gap junctions or reduction of the conduction properties may result in fractionation of electrograms as well. Analysis of activation times revealed that activation in the infarcted papillary muscle spread in myocardial tracts parallel to the fiber direction. Conduction velocity in the tracts was high (0.79 m/s). Tracts were separated by collagenous septa over distances up to 3 mm, but often connected with each other at one or more sites, forming a complex network of merging and diverging tracts. For propagation perpendicular to the fiber direction, delays of up to 36.5 ms over a distance of 1.2 mm were observed. Conduction delay in the direction perpendicular to the fibers was caused mainly by the increase of the route activation had to travel through the branching and merging bundles. Figure 6 shows an example of the complex architecture of merging and diverging bundles in one of the papillary muscles. The preparation was stimulated in the lower left corner (near site A); numbers within the tracts indicate activation times with respect to the stimulus. To reach site B, at a distance of 1.2 mm from site A, activation had to follow the indicated zigzag route. At site B, activation arrived after a delay of 36.5 ms, indicating that the apparent conduction velocity perpendicular to the fiber direction was 0.04 m/s. Note that in a number of tracts activation proceeded from the right to the left, that is toward the site of stimulation. The tracings in Figure 7 are 8 electrograms recorded along a line perpendicular to the fiber direction. The interelectrode distance of the recording electrode was 0.2 mm. All electrograms are highly fractionated because of the asynchronous conduction within the different bundles. The architecture

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Figure 6. Tracts along which activation proceeded in an infarcted papillary muscle from an explanted human heart. The tracts, which were reconstructed using electrograms recorded with a resolution of 200 jim, run parallel to the fiber direction and are separated over distances of several millimeters before they connect to neighboring tracts. The preparation was stimulated at the lower left corner (close to site A). Numbers in the tracts indicate activation times measured with respect to the stimulus. Activation delay between sites A and B along a line perpendicular to the fiber direction is 36.5 ms. Sites A and B are 1.2 mm apart, resulting in an apparent conduction velocity between A and B of 0.04 m/s. The continuous line indicates the tortuous route activation had to travel from A to reach B. Activation delay between A and B is caused mainly by the increase of the route activation must travel. Conduction velocity in the tracts is close to normal (0.78 m/s).

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Figure 7. Eight of 240 unipolar recordings made to determine the tracts in Figure 6. Electrograms are highly fractionated indicating asynchronous activation in the various tracts. Modified from reference 45.

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Figure 8. Photomicrograph of a section of the papillary muscle in Figure 6. A surviving subendocardial rim (bright area) surrounds a core of dense connective tissue (dark area). The surviving subendocardial rim is divided into several bundles of myocytes that are sheathed by septae of fibrous tissue. Reproduced from reference 45, with permission.

of isolated myocardial bundles in the surviving subendocardial rim is shown in Figure 8. A narrow surviving subendocardial rim (bright area) surrounds a core of dense connective tissue (dark area). The surviving subendocardial rim is divided into several bundles of myocytes that are sheathed by septae of fibrous tissue. The infarcted papillary muscle presents the simplest model for studying conduction abnormalities imposed by healed myocardial infarction. As illustrated, very high resolution mapping is required to gain insight into the mechanism of slow conduction. Such recordings are difficult to perform in the isolated Langendorffperfused heart. In addition, superfusion

virtually reduces the 3-dimensional structure to 2 dimensions and fiber direction in the papillary muscles remains almost parallel.

Conduction in Dilated Cardiomyopathy Electrophysiological abnormalities have been observed in various experimental models of dilated cardiomyopathy.7"10 Anderson et al.46 have shown that the severity of abnormal propagation correlates with the amount of myocardial fibrosis in patients with dilated cardiomyopathy who underwent heart transplantation.

MAPPING IN EXPLANTED HEARTS To unravel the mechanism of abnormal conduction in dilated cardiomyopathy, we carried out similar measurements as described before in papillary muscles derived from explanted hearts of patients who underwent heart transplantation while in the end stage of heart failure due to dilated cardiomyopathy.47 Although preparations revealed fractionated electrograms and conduction delay as observed in the infarcted preparations, architecture of the cardiomyopathic papillary muscles differed from that of the infarcted ones. Impaired conduction in dilated cardiomyopathy was indeed associated with collagen infiltration, but the matrix of intermingling myocardial bundles and fibrosis differed. Discernible lines of block consisting of broad strands of fibrosis were present but most often electrical barriers consisted of short stretches of fibrous tissue. Delayed conduction was caused by curvature of activation around the distinct lines of block and by a wavy course of activation between the short barriers. The latter reflects extreme nonuniform anisotropy. Architecture of Interstitial Fibrosis and Conduction Delay The previous observations suggest that the architecture of interstitial fibrosis is an important parameter in determining the amount of conduction delay. To investigate the role of the architecture of fibrosis on conduction, we performed high-resolution mapping in another 8 Langendorff-perfused human hearts.48 Three patients had coronary artery disease (with myocardial infarction), 1 suffered from hypertrophic cardiomyopathy, and 4 had dilated cardiomyopathy. Multiterminal plaque electrodes harbored 105 or 208 terminals consisting of 70-jimdiameter silver wires, isolated except at

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the tip. Terminals were arranged in a 9 x 12 or 16 x 13 matrix at interelectrode distances of 0.8 and 0.5 mm, respectively. Plaque electrodes were positioned over nonfatty epicardial areas. Electrical stimulation was applied with bipolar hook electrodes positioned adjacent to any one of the 4 sides of the multielectrode. Pacing was at twice diastolic current threshold with an 8-pulse drive train (CL 600 ms) and one premature stimulus. Coupling intervals of premature stimuli were from 500 ms down to the refractory period in steps of 10 ms. Tissue at 16 of the 26 positions of the multielectrode was subjected to histological investigation. Mean density of fibrosis in the recording areas ranged from 7% to 43% (mean 18 ± 10%). Three types of fibrosis with regard to architecture were distinguished: • Patchy: patchy fibrosis with long, compact groups of strands • Diffuse: more or less diffusely distributed fibrosis with short strands • Stringy: homogeneously distributed fibrosis with long "single" strands; sometimes local, compact areas of fibrosis were present in this type. Density of fibrosis did not correlate with conduction delay, but the architecture of fibrosis played a major role. Figure 9 shows 2 types of fibrosis, patchy (left panel) and diffuse (right panel) with similar mean density of fibrosis (22% and 33%, respectively). Conduction velocity during basic CL was similar for both types of fibrosis when propagation was parallel to the fiber direction. However, for propagation perpendicular to the fiber direction, conduction velocity, which was 0.24 ± 0.04 m/s during basic CL, reduced to 0.17 ± 0.06 m/s after premature stimulation with a coupling interval 10 ms longer than the refractory period. In contrast, conduction velocity reduced from

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Figure 9. Histological sections showing patchy fibrosis with long strands (left panel) and diffuse fibrosis (right panel). See text for discussion. See color appendix. Adapted from reference 48.

0.28 ± 0.07 m/s to 0.05 ± 0.01 m/s for patchy fibrosis. This is illustrated in Figure 10. Stimulation at site A (panel A) resulted in propagation of activation nearly perpendicular to the fiber direction. Tracings at the left in panel b show a progressive increase in conduction delay during premature stimulation at site A. Activation maps (panel C) during baseline stimulation at site A revealed widely separated isochronal lines, compatible with continuous conduction. Following premature stimulation, however, conduction became irregular with functional lines of conduction block at decreasing coupling intervals. Delay of activation within the recording area increased from 11 ms to 68 ms. Activation patterns resulting from stimulation at site B (lower maps) showed no irregularities after premature stimuli, and only a marginal increase of conduction delay was observed (from 7 to 17 ms). Thus, this study showed that, in chronically diseased human myocardium,

progressive increase of conduction delay during premature stimulation arises in areas with patchy fibrosis having long, compact, groups of strands. Delay strongly depends on the direction of wavefront propagation with respect to fiber direction, the effect during propagation perpendicular to the fiber direction being large as compared to that found upon parallel propagation. Diffusely distributed fibrosis with short strands only marginally affected conduction delay, even at high densities of fibrosis. In summary, mapping of the electrical activity in Langendorff-perfused human hearts allowed detection of the reentry circuit by correlating electrophysiology with anatomy in only a minority of the cases. In these cases, surviving myocardial bundles within the infarct zone constituted a continuous tract that traversed the infarct; activation delay in these tracts was close to normal. In the majority of the cases, activation delay in the area supposed to harbor the return

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Figure 10. a. Histological section of the recording area (rectangle) in a heart showing patchy fibrosis with long strands (red areas). Yellow areas show myocardial tissue. A and B are pacing sites. b. Extracellular electrograms recorded at the center of the recording electrode (asterisks). Numbers are coupling intervals of the premature stimuli, c. Activation maps during stimulation at site A (upper maps) and site B (lower maps) during basic cycle length of 600 ms and premature stimuli at coupling intervals from 500 to 320 ms. Numbers beneath the maps indicate the time in which the recording area was activated. See color appendix. Adapted from reference 48.

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Figure 11. Schematics of delayed conduction in infarcted myocardium. Fibrous tissue separates surviving myocardial bundles within the infarcted zone, although bundles may merge at a number of sites to connect with neighboring tracts. Activation starting at site A must follow the tortuous route indicated by the black line to reach site B. Activation delay between sites A and B is caused mainly by the increase of the route activation must travel.

tract was, however, large and the architecture of the area was too complex to correlate electrophysiology with histology. To reveal the mechanism of conduction delay in the return tract in these cases, refined measurements in papillary muscles superfused in a tissue bath were more appropriate. These measurements showed that slow conduction perpendicular to the fiber direction in infarcted myocardial tissue is caused by zigzag conduction at normal speed due to lengthening of the pathway by branching and merging of surviving myocardial bundles ensheathed by collagenous septae (Figure 11). Impaired conduction in dilated cardiomyopathy is caused, at least in part,

by the development of fibrous tissue as well. In these hearts, delayed conduction was caused by curvature of activation around distinct barriers (Figure 12A) and by the wavy course of activation between short barriers of fibrous tissue (Figure 12B). Finally, architecture of fibrosis plays a major role in determining progressive increase of conduction delay at incremental shortening of the coupling interval of premature stimuli. The effect of long fibrotic strands on conduction was much greater than that of diffuse fibrosis with short strands. The architecture of fibrosis is more important than its density for generating conduction disturbances.

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Figure 12. Schematic representations of activation in myocardium impaired by cardiomyopathy. Conduction delay arises because of curvature of activation around distinct barriers (A) or by the wavy course of activation between short barriers (B). Numbers indicate activation times.

References 1. Harris AS. Delayed development of ventricular ectopic rhythms following experimental coronary occlusion. Circulation 1950;1:1318-1328. 2. Uemura N, Knight DR, Shen J, et al. Increased myocardial infarct size because of reduced coronary collateral blood flow in beagles. Am JPhysiol 1989;257(6 Pt 2): H1798-H1803. 3. El-Sherif N, Scherlag BJ, Lazarra R, et al. Reentrant ventricular arrhythmias in the late myocardial infarction period. 1. Conduction characteristics in the infarcted zone. Circulation 1977;55:686-702. 4. Wit AL, Allessie MA, Bonke FIM, et al. Electrophysiologic mapping to determine the mechanism of experimental ventricular tachycardia initiated by premature impulses. Experimental approach and initial results demonstrating reentrant excitation. Am J Cardiol 1982;49:166-185.

5. Kramer JB, Saffitz JE, Witkowski FX, et al. Intramural reentry as a mechanism of ventricular tachycardia during evolving canine myocardial infarction. Circ Res 1985; 56:736-754. 6. Walker MJA, Cirtis MJ, Hearse DJ, et al. The Lambeth Conventions: Guidelines for the study of arrhythmias in ischemia, infarction and reperfusion. Cardiouasc Res 1988;22:447-455. 7. Hano O, Mitsuoka T, Matsumoto Y, et al. Arrhythmogenic properties of the ventricular myocardium in cardiomyopathic Syrian hamster, BIO 14.6 strain. Cardiovasc Res 1991;25:49-57. 8. Weber KT, Pick R, Silver MA, et al. Fibrillar collagen and remodeling of dilated canine left ventricle. Circulation 1990;82: 1387-1401. 9. Einzig S, Detloff BLS, Borgwardt BK, et al. Cellular electrophysiological changes in "round heart disease" of turkeys: A potential basis for dysrhythmias in myopathic

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ventricles. Cardiouasc Res 1981;15:643— 21. Estes HE Jr, Entman ML, Dixon HB, 651. et al. The vascular supply of the left ven10. Fein FS, Capasso JM, Aronson RS, et al. tricular wall: Anatomic observations, plus a hypothesis regarding acute events in Combined renovascular hypertension in diabetes in rats: A new preparation for coronary artery disease. Am Heart J 1966;71:58-67. congestive cardiomyopathy. Circulation 1984;70:318-330. 22. Gardner PI, Ursell PC, Due Pham T, 11. Poll DS, Marchlinski FE, Buxton AE, et al. Experimental chronic ventricular et al. Sustained ventricular tachycardia in tachycardia: Anatomic and electrophysiopatients with idiopathic dilated cardiomylogic substrates. In Josephson ME, Wellens HJJ (eds): Tachycardias: Mechaopathy: Electrophysiologic testing and lack of response to antiarrhythmic drug therapy. nisms, Diagnosis, Treatment. PhiladelCirculation 1984;70:451-456. phia: Lea and Febiger; 1984:29. 12. Milner PG, DiMarco JP, Lerman BB. Elec- 23. de Bakker JMT, van Capelle FJL, Janse trophysiologic evaluation of sustained MJ, et al. Macroreentry in the infarcted human heart: The mechanism of ventricventricular tachyarrhythmias in idiopathic dilated cardiomyopathy. Pacing ular tachycardias with a "focal" activation pattern. J Am Coll Cardiol 1991; 128: Clin Electrophysiol 1988;ll:562-568. 1005-1015. 13. Barber MJ, Mueller TM, Henry DP, et al. Transmural myocardial infarction in the 24. Josephson ME, Horowitz LN, Farshidi A, dog produces sympathectomy in noninet al. Recurrent sustained ventricular farcted myocardium. Circulation 1983; tachycardia. I. Mechanisms. Circulation 1978;57:431-439. 67:787-796. 14. Zipes DP. Influence of myocardial 25. Horowitz LN, Josephson ME, Harken AM. ischemia and infarction on autonomic Epicardial and endocardial activation innervation of heart. Circulation 1990; during sustained ventricular tachycardia 82:1095-1105. in man. Circulation 1980;61:1227-1238. 15. Brugada P, Waldecker B, Kersschot Y, 26. Mickleborough LL, Harris L, Downar E, et et al. Ventricular arrhythmias initiated al. A new intraoperative approach for by programmed stimulation in four groups endocardial mapping of ventricular tachyof patients with healed myocardial infarccardia. JThorac Cardiouasc Surg 1988;95: 271-280. tion. JAm Coll Cardiol 1986;8:1035-1040. 16. Roy DE, Marchand E, Theroux P, et al. 27. Mason JW, Stinson EB, Oter PE, et al. The mechanism of ventricular tachycardia Programmed ventricular stimulation in survivors of an acute myocardial infarcin humans determined by intraoperative recording of the electrical activation tion. Circulation 1985;72:487-494. 17. Kuck KH, Costard A, Schlulter M, et al. sequence. Int J Cardiol 1985;8:163-172. Significance of timing programmed elec- 28. Josephson ME, Buxton AE, Marchlinski FE, et al. Sustained ventricular tachytrical stimulation after acute myocardial cardia in coronary artery disease— infarction. J Am Coll Cardiol 1986;8: evidence for reentrant mechanism. In: 1279-1288. 18. Downar E, Janse MJ, Durrer D. The effect Zipes DP, Jalife J (eds): Cardiac Electroof acute coronary artery occlusion on physiology and Arrhythmias. Orlando: subepicardial transmembrane potentials Grune & Stratton; 1985:409-418. in the intact porcine heart. Circulation 29. El Sherif N, Smith RA, Evans K. Canine 1977;56:217-224. ventricular arrhythmias in the late 19. Fenoglio JJ, Due Pham T, Harken AM, et myocardial infarction period: Epicardial mapping of reentrant circuits. Circ Res al. Recurrent sustained ventricular tachy1981;49:255-271. cardia: Structure and ultrastructure of subendocardial regions in which tachy- 30. Karagueuzian HS, Fenoglio JJ, Weiss MB, et al. Protracted ventricular tachycardia originates. Circulation 1983; cardia induced by premature stimulation 68:518-533. in the canine heart after coronary artery 20. Fulton WFM. The dynamic factor in occlusion and reperfusion. Circ Res 1979; enlargement of coronary arterial anasto44:833-846. moses, and paradoxical change in the subendocardial plexus. Br Heart J 1964; 31. Mehra R, Zeiler R, Cough WB, et al. Reentrant ventricular arrhythmias in the 26:39-50.

MAPPING IN EXPLANTED HEARTS late myocardial infarction period. 9. Electrophysiologic-anatomic correlation of reentrant circuits. Circulation 1983;67: 11-24. 32. Gessman LJ, Agarwal JB, Endo T, et al. Localization and mechanism of ventricular tachycardia by ice mapping 1 week after the onset of myocardial infarction in dogs. Circulation 1983;68:657-666. 33. de Bakker JMT, van Capelle FJL, Janse MJ, et al. Reentry as a cause of ventricular tachycardia in patients with chronic ischemic heart disease: Electrophysiologic and anatomic correlation. Circulation 1988;77:589-606. 34. De la Fuente D, Sasyniuk B, Moe GK. Conduction through a narrow isthmus in isolated canine atrial tissue: A model of the WPW syndrome. Circulation 1971; 44:803-809. 35. Fast VG, Kleber AG. Cardiac tissue geometry as a determinant of unidirectional conduction block: Assessment of microscopic excitation spread by optical mapping in patterned cell cultures and in a computer model. Cardiovasc Res 1995; 29:697-707. 36. Maglaveras N, de Bakker JMT, van Capelle FJL, et al. Activation delay in healed myocardial infarction: A comparison between model and experiment. Am J Physiol 1995;269(4 Pt 2):H1441-H1449. 37. de Bakker JMT, Coronel R, Tasseron S, et al. Ventricular tachycardia in the infarcted Langendorff-perfused human heart: Role of the arrangement of surviving cardiac fibers. J Am Coll Cardiol 1990;15:1594-1607. 38. Dillon S, Allessie MC, Ursell PC, Wit AL. Influence of anisotropic tissue structure on reentrant circuits in the epicardial border zone of subacute canine infarcts. CircRes 1988;63:182-206. 39. Spach MS, Miller WT, Dolber PC, et al. The functional role of structural complexities in the propagation of depolar-

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ization in the atrium of the dog. Cardiac conduction disturbances due to discontinuities of effective axial resistivity. Circ Res 1982;50:175-191. 40. Ursell PC, Gardner PI, Albala A, et al. Structural and electrophysiological changes in the epicardial border zone of canine myocardial infarcts during infarct healing. CircRes 1985;56:436-451. 41. Meyerburg RJ, Gelband H, Nilsson K, et al. Long-term electrophysiologic abnormalities resulting from experimental myocardial infarction in cats. Circ Res 1977;41: 73-84. 42. Spear JF, Horowitz LN, Hodess AB, et al. Cellular electrophysiology of human myocardial infarction, I: Abnormalities of cellular activation. Circulation 1979;59: 247-256. 43. Luke RA, Saffitz JE. Remodeling of ventricular conduction pathways in healed canine infarct border zones. J Clin Invest 1990;87:1594-1602. 44. Hoyt RH, Cohen ML, Saffitz JE. Distribution and three-dimensional structure of intercellular junctions in canine myocardium. Circ Res 1988;64:563-574. 45. de Bakker JMT, van Capelle FJL, Janse MJ, et al. Slow conduction in the infarcted human heart. 'Zigzag' course of activation. Circulation 1993;88:915-926. 46. Anderson KP, Walker R, Urie P, et al. Myocardial electrical propagation in patients with idiopathic dilated cardiomyopathy. J Clin Invest 1993;92:122-140. 47. de Bakker JMT, van Capelle FJL, Janse MJ, et al. Fractionated electrograms in dilated cardiomyopathy: Origin and relation to abnormal conduction. J Am Coll Cardiol 1996;27:1071-1078. 48. Kawara T, Derksen R, de Groot JR, et al. Activation delay after premature stimulation in chronically diseased myocardium relates to the architecture of interstitial fibrosis. Circulation 2001;104: 3069-3075.

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Chapter 17 Efferent Autonomic Innervation of the Atrium: Assessment by Isointegral Mapping Pierre L. Page, MD and Rene Cardinal PhD

Introduction Autonomic nerves affect heart rate, atrioventricular (AV) conduction, and contractile force through their efferent projections to the sinus node, AV node, and atrial musculature. These parameters have therefore been used as markers for the study of atrial innervation in the canine heart.1"3 From these previous reports, we have learned that parasympathetic postganglionic efferent neurons were localized in the right atrial (RA) ganglionated plexus, a collection of neural elements contained in a triangular fat pad on the ventral aspect of the RA free wall (pulmonary vein fat pad), as well as in a ganglionated plexus located in fatty tissues overlying the junction of the inferior vena cava and inferior left atrium (LA).4"7 Selective stimulation4'8 or surgical removal9"12 of these structures were used to demonstrate the specificity of parasympathetic efferent innervation of the sinus node and AV node that may

occur through the RA and inferior LA ganglionated plexi, respectively. However, little information was available on functional pathways to regions of the atria other than the sinus and AV nodes. In addition, a precise knowledge of the anatomical distribution of autonomic neural elements may have important implications for clinical procedures such as those used in cardiac surgery or during invasive electrophysiological ablation sessions. In this chapter, new information on the autonomic innervation of the atrium resulting from experimental and clinical work based on repolarization mapping is discussed. Atrial Integral Distribution Mapping The repolarization phase of the cardiac action potential is very sensitive to parasympathetic and sympathetic nerve stimulation.13'14 Therefore, refractory

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003. 363

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period determinations have been used to study regional atrial effects in response to stimulation of intrathoracic autonomic nerves. However, the extrastimulus technique commonly used for refractory period measurements is limited by the fact that only one site can be sampled at a time and that each determination requires several seconds to complete. Other parameters—QRST area, activationrecovery interval, QT interval, and T wave amplitude—have been used to determine ventricular recovery properties.15'16 In conjunction with a multichannel recording system and multiple electrode arrays, the QRST area calculated from unipolar electrograms was used to assess ventricular patterns of sympathetic innervation.17 This concept was then applied to atrial unipolar electrograms to assess repolarization properties on a beatto-beat basis, thereby analyzing the spatial distribution of electrical responses induced by stimulation of specific efferent autonomic neural elements with a high degree of spatial and temporal resolution.18 In the studies summarized herein, the integral of the atrial unipolar electrogram waveform was calculated with reference to the isoelectric diastolic baseline. The distribution of integral values measured from multiple simultaneous recordings (Figure 1) was used to detect regional changes in atrial electrical events induced by stimulation of individual intrathoracic and intracardiac neural elements. To allow the analysis of atrial unipolar electrograms without interference made by ventricular QRS complexes usually occurring before the end of the atrial T wave, a complete AV block was induced by the injection of formaldehyde into the His bundle region in all of our canine studies. Unipolar electrograms were simultaneously recorded from 192 sites by means of flexible electrode tern-

Figure 1. A. Unipolar atrial electrogram recorded during control conditions (sinus rhythm, atrioventricular block, no ventricular pacing, no nerve stimulation). B. Atrial unipolar electrogram recorded during stimulation of the right vagosympathetic complex. C. Superimposition of electrograms shown in A and B. Neural stimulation affected primarily the T wave (arrows) of unipolar electrograms. The hatched area represents the integral of changes in the T wave morphology. This value was plotted on the atrial grid for each recording site and used to generate an integral distribution map.

plates sutured to the epicardial surfaces of both atria. The signals were recorded with reference to the Wilson central terminal, and amplified, filtered (0.05 to 200 Hz), multiplexed, digitized at I kHz, and stored on hard disk using a data acquisition system (Institut de Genie Biomedical, Universite de Montreal).18 Data obtained

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365

Figure 2. Integral distribution maps showing effects of neural stimulation in selected preparations (A through C). The grids represent a posterior view of the atria. The left atrium is displayed on the left-hand side of the map. The two upper corners of the maps correspond to the atrial appendages. Isoarea lines delimit color-coded zones including points where integral measurements were within a given 60 mV/ms range of values. Increases in T wave amplitude are shown as positive values (green to blue), whereas reductions of T wave amplitude or inversion are represented as negative values (orange to red). The major effects common to the right (A) and left (B) vagosympathetic stimulation and right atrial ganglionated plexus (C) consisted of a blue shift in the right atrial free wall. The map in panel D was obtained during nerve stimulation after an inverted Y-shaped incision was performed in the right atrium. Compared to map A, the effect of RVSC stimulation was suppressed. RVSC = right vagosympathetic complex; LVCS = left vagosympathetic complex; RAGP =right atrial ganglionated plexus (fat pad). RVSC-Y = RVSC stimulation after a Y-shaped incision in the right atrium. See color appendix.

during each period of neural stimulation were compared to control data obtained prior to stimulation. The net area (integral) under the intrinsic deflection and T wave of each atrial electrogram was computed by an integration process using a modified Simpson's technique and custom software that added the values of sample sectors multiplied by the duration of each sampling period (Institut de Genie Biomedical, Universite de Montreal).17'18 The difference between prestimulation integral and that measured

during stimulation was calculated for each recording site (Figure 1C). This value was plotted on an atrial grid using color-coded zones including points displaying values within a given range (Figure 2). The incidences, among preparations, of specific regional effects were assessed by counting the number of preparations that displayed integral changes beyond a threshold of ±60 mV/ms corresponding to 2 standard deviations of changes obtained when measurements were repeated under basal conditions.

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14

Figure 3. Histogram representing the incidence, in 12 preparations, of electrogram integral changes beyond ±60 mV/ms in each atrial region in response to nerve stimulation. Nerves: LVSC = left vagosympathetic complex; RAGP = right atrial ganglionated plexus; RVSC = right vagosympathetic complex. IAB = interatrial band; LAFW = left atrial free wall; LatRA = lateral right atrial free wall, adjacent to the AV groove; LowRA = lower half of right atrial free wall; SAN = sinus node area.

Stimulation of Autonomic Neural Elements Figure 3 shows the incidence of significant changes (>60 mV/ms) in each region of the RA and LA in a series of 12 preparations. Stimulation of the right vagosympathetic complex induced positive integral changes in the RA free wall in all preparations (Figure 2A). Interanimal variability of responses occurred, as illustrated by the fact that right vagosympathetic complex stimulation induced similar global patterns of effects, albeit with a variable distribution in the RA. The interatrial band and the LA free wall were both affected in half of the preparations. On the other hand, negative integral changes were induced in the LA in approximately half of the animals (Figure 3).

Stimulation of the left vagosympathetic complex also induced positive integral changes in the sinus node area in most preparations (Figure 2B). However, positive changes were also induced in the LA free wall in all animals. Stimulation of loci in the RA ganglionated plexus produced positive changes in the sinus node area and the RA free wall (Figure 2C). These effects were more restricted than those of the right vagosympathetic complex, encompassing smaller regions of the RA (31 ± 13 cm2 and 43 ± 10 cm2, respectively, P< 0.01). Negative integral changes of a lesser amplitude were induced in small regions of the LA free wall in less than 25% of the preparations. Efferent sympathetic neural elements in the RA ganglionated plexus were also identified following atropine administration

EFFERENT AUTONOMIC INNERVATION OF THE ATRIUM in 11 preparations, since the induction of positive integral changes in the RA was inhibited, whereas changes similar to those generated in response to right or left stellate ganglion stimulation were induced. These data indicate that the RA ganglionated plexus may contain neural elements originating from neural structures other than the right vagosympathetic complex, possibly from the right stellate ganglion.

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Effects of the Maze Procedure

Surgical procedures designed to prevent or cure atrial fibrillation must comply with a wide range of electrophysiological conditions. Therefore, the major rationale of the development of the Maze operation led to a global, biatrial approach.22 This operation consists of an arrangement of numerous incisions performed in both the RA and the LA that are meant, first, to eliminate most opportunities for reentrant circuits, and second, to reduce the likeliEffects of Atrial Incisions hood of fibrillation in any remaining single fragment of tissue because of the Incisions in the RA free wall are myocardial mass reduction. As shown in often used in experimental models of the previous section, all parts of the reentry19'20 or during human open-heart atrium are richly innervated by efferent surgery aimed at the correction of intra- parasympathetic elements. Experiments atrial abnormalities. The effect of a Y-- were conducted in canines to determine shaped incision in the RA free wall was whether extensive surgical modification investigated through integral mapping of atrial anatomy lead to parasympathetic during vagal stimulation in 7 anes- denervation.23"26 thetized dogs. Right and left vagal stimIn the experiments with the Maze III ulation and that of the RA ganglionated procedure, the sinus bradycardia induced plexus decreased heart rate by 87 ± 25, by vagal stimulation was suppressed in all 76 ± 17, and 42 ± 15 beats per minute 9 preparations. Isointegral maps (Figure 4) (bpm), respectively, before the incision, indicated that neurally induced repolarand by 25 ± 21, 14 ± 9, and 8 ± 9 bpm, ization changes were suppressed by the respectively, after the incision (P< 0.01).21 Maze procedure in most atrial regions in Figure 2D shows an example of suppres- 7 of 9 preparations. Neural effects induced sion of integral changes induced by right by left vagal stimulation persisted in the vagal stimulation. The incidence of sup- Bachmann's bundle region (4 of 9) and in pression of significant neural effects after the superior RA (3 of 9), and in the supethe incision suggested the following con- rior RA (3 of 9) during right vagal stimuclusions: (1) The denervated area included lation. We concluded that the Maze III the rostral RA encompassing the anterior procedure induces parasympathetic denpart of the tricuspid ring. (2) The supe- ervation of the sinus node in canine rior LA and, to a lesser extent, the infe- preparations. The procedure also interrior LA are innervated directly by the feres with parasympathetic innervation right and/or the left vagal nerve. (3) Post- of atrial regions remote from the sinus ganglionic axons of the RA ganglionated node, mainly the inferior RA and LA. The plexus may innervate the LA by coursing extent to which this effect contributes to through the RA free wall. Thus, incision the antiarrhythmic mechanism of the in the RA induces parasympathetic procedure and whether this effect will denervation of a significant portion of persist over the long term is not yet the RA. established.

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Figure 4. Integral maps during stimulation of the right vagosympathetic complex in a dog experiment before and 90 minutes after a Maze procedure. In this example, neurally induced repolarization changes persisted in the interatrial band but were completely suppressed on the right atrial free wall. See color appendix.

Stimulation of Intrinsic Cardiac Ganglia in Humans The implication of the autonomic nervous system in the occurrence and maintenance of postoperative atrial arrhythmias motivated us to investigate the regional distribution of neural terminations throughout the atrium in human subjects during routine open-heart surgery. In 7 patients scheduled for elective coronary bypass procedures, atrial mapping was performed during normothermic cardiopulmonary bypass.27 Multielectrode templates containing 128 unipolar contacts were sutured onto the epicardial surface of the RA and the LA. In order to allow the analysis of whole atrial activation, a programmed stimulation protocol independently applied to the RA was used to increase the PR interval. This protocol was performed during the control acquisition and during the stimulation of the RA ganglionated plexus (i.e., the pulmonary vein fat pad). The stimulation of the fat pad

decreased the sinus rate from a mean of 73 ± 12 bpm to 52 ± 9 bpm, indicating the recruitment of parasympathetic neural elements within the RA ganglionated plexus. The map shown in Figure 5 shows cumulative data obtained in all 7 patients. The results show that the changes occurred only in the RA and in the RA appendage. The area encompassed by significant changes has been calculated with planimetry of the maps. Neural stimulation induced changes in 32% of the surface of the RA and in 8.5% of the surface of the LA; however, although mathematically significant, changes noted on the LA were always measured on a single, isolated electrode, thus not reflecting an actual local neural effect. These data suggest that the electrophysiological effects of stimulation of the RA ganglionated plexus in humans are parasympathetic, as also demonstrated by others,28 and appear to be more specific to the sinus node region than in the dog. The reasons for these observations are not yet well understood.

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369

Figure 5. Cumulative integral mapping data obtained in 7 patients during electrical stimulation of the right atrial ganglionated plexus. Effects are restricted in the right atrial free wall and the sinus node area. See color appendix.

Summary and Conclusion

The spatial distribution of repolarization changes induced by neural stimulation can be determined using integral distribution maps obtained from multiple atrial recordings.18 The data so obtained indicate that the autonomic nervous system displays a heterogeneity of atrial electrical responses when its various extrinsic and intrinsic neural elements are stimulated electrically. In our experiments, consistent atrial electrogram integral changes were induced in the RA free wall during stimulation of the right and left vagosympathetic com-

plexes as well as the RA ganglionated plexus. Such integral changes were also induced by vagal stimulation in other atrial regions (Figures 2 and 3). Our data also indicate that stimulation of loci in the RA ganglionated plexus induced changes in regions of the RA remote from the sinus node region and, in about a third of the animal preparations, also in the LA, indicating that neural elements in the RA ganglionated plexus project to many more atrial sites than suggested previously.6'9"12'29'30 Other work performed in laboratory used intrapericardial dissections to delineate the contribution of specific neural structure to atrial innervation.31 Interestingly,

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the data from these studies have sugReferences gested that (1) parasympathetic dener1. Randall WC, Priola DV, Ulmer RHG. A vation induced by the ablation of the RA functional study of the distribution of fat pad largely exceeds the region of the cardiac sympathetic nerves. Am JPhysiol sinus node, and (2) the RA fat pad con1963'205' 1227—1231 tains parasympathetic axons from the 2. GeisWP, Kaye MP, Randall WC. Major right vagal nerve that terminate in both autonomic pathways to the atria and S-A and A-V nodes of the canine heart. Am J atria and also contains elements from the Physiol 1973;224:202-208. left vagal nerve that distribute only to 3. Stuesse SL, Wallick DW, Levy MN. Autothe RA, as the LA receives parasympanomic control of right atrial contractile thetic axons directly from the left vagus. strength in the dog. Am JPhysiol 1979;236: In another group of studies, the interaH860-H865. 4. Lazzara R, Scherlag BJ, Robinson MJ, trial septum was mapped using an inflatSamet P. Selective in situ parasympaable balloon electrode array.32'33 These thetic control of the canine sinoatrial and studies demonstrated that the atrial atrioventricular nodes. Circ Res 1973;32: septum is richly innervated by parasym393-401. pathetic efferent pathways coursing near 5. Randall WC, Ardell JL, Calderwood D, et al. Parasympathetic ganglia innervating the the superior vena cava and via the RA canine atrioventricular nodal region. J ganglionated plexus. Tissues near the Autonom Nerv Syst 1986;16:311-323. pulmonary artery or inferior vena cava 6. Randall WC, Ardell JL, Wurster RD, do not appear to play a significant role in Miloslavljevic M. Vagal postganglionic septal innervation. innervation of the canine sinoatrial node. JAuton Nerv Syst 1987;20:13-23. Integral changes identified in the pre7. Gagliardi M, Randall WC, Bieger D, et al. sent study are consistent with heterogeActivity of in vivo canine cardiac plexus neous modifications of repolarization. The neurons. Am JPhysiol 1988;255(4 Pt 2): nonuniform distribution of atrial refracH789-H800. tory period shortening is a well-known 8. Butler CK, Smith FM, Cardinal R, et al. Cardiac responses to electrical stimulaeffect of vagal stimulation.13'14 Using tion of discrete loci in canine atrial and refractory period determinations by the ventricular ganglionated plexi. Am J extrastimulus technique, Zipes et al.14 Physiol 1990;259(5 Pt 2):H1365-H1373. have shown that right vagal stimulation 9. Ardell JL, Randall WC. Selective vagal elicits greater effects in the RA than the innervation of sinoatrial and atrioventricular nodes in canine hearts. Am J LA and that shortening of atrial refracPhysiol 1986;251(4 Pt 2):H764-H773. tory periods is more pronounced during 10. Randall WC, Ardell JL. Selective parasymright than left vagal stimulation. The prepathectomy of automatic and conductile sent study not only supported these findtissues of the canine heart. Am J Physiol ings but also provided information depict1985;248(2 Pt 2):H61-H68. ing the complexity of atrial parasympa- 11. Randall WC, Wurster RD, Duff M, et al. Surgical interruption of postganglionic thetic innervation. Furthermore, the coninnervation of the sinoatrial nodal region. cept of integral distribution mapping JThorac Cardiovasc Surg 1991;101:66-74. based on multiple-site simultaneous record- 12. Mick JD, Wurster RD, Duff M, et al. ings appears to be feasible in humans Epicardial sites for vagal mediation of sinoatrial function. Am JPhysiol 1992;262 during cardiac surgical procedures. This (5 Pt 2):H1401-H1406. new concept opens the way to further 13. Alessi R, Nusynowitz M, Abildskov JA, investigate the functional anatomy of the Moe GK. Nonuniform distribution of vagal cardiac autonomic nervous system in effects on the atrial refractory period. Am humans. JPhysiol 1958;194:406-410.

EFFERENT AUTONOMIC INNERVATION OF THE ATRIUM 14. Zipes DP, Mihalik MJ, Robbins GT. Effects of selective vagal and stellate ganglion stimulation on atrial refractoriness. Cardiovasc Res 1974;8:647-655. 15. Abildskov JA, Evans AK, Lux RL, Burgess MJ. Ventricular recovery properties and the QRST deflection area in cardiac electrograms. Am JPhysiol 1980;239:H227-H231. 16. Millar CK, Kralios FA, Lux RL. Correlation between refractory periods and activationrecovery intervals from electrograms: Effects of rate and adrenergic interventions. Circulation 1985;72:1372-1379. 17. Savard P, Cardinal R, Nadeau RA, Armour JA. Epicardial distribution of ST segment and T wave changes produced by stimulation of intrathoracic ganglia or cardiopulmonary nerves in dogs. JAuton Nerv Syst 1991;34:47-58. 18. Page PL, Dandan N, Savard P, et al. Regional distribution of atrial electrical changes induced by stimulation of extracardiac and intracardiac neural elements. J Thorac Cardiovasc Surg 1995;109:377-388. 19. Frame LH, Page RL, Hoffman BF. Atrial reentry around an anatomic barrier with a partially refractory excitable gap. Circ Res 1986;58:495-511. 20. Derakhchan K, Page P, Lambert C, Kus T. Effects of procainamide and propafenone on the composition of the excitable gap in canine atrial reentry tachycardia. J Pharmacol Exp Ther 1994;270:47-54. 21. Dandan N, Do Q-B, Page P, Cardinal R. The right atrial Y-shaped incision model of atrial flutter affects parasympathetic innervation of the reentry pathway: Assessment by integral distribution mapping. Pacing Clin Electrophysiol 1996; 19 (Pt II): 705. 22. Cox JL, Schuessler RB, DAgostino HJ Jr, et al. The surgical treatment of atrial fibrillation. III. Development of a definitive surgical procedure. J Thorac Cardiovasc Surg 1991;101:569-583. 23. Do Q-B, Page P, Dandan N, Cardinal R. Maze procedure against atrial fibrillation abolishes atrial parasympathetic efferents. Cardiostim '96. Nice, France: June

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19-22, 1996. Eur J Card Pacing Electrophysiol 1996;6(Suppl 5):21. 24. Do Q-B, Page P, Dandan N, Cardinal R. The Maze III procedure for surgical treatment of atrial fibrillation abolishes parasympathetic influences on the atrium. Pacing Clin Electrophysiol 1996;9(Pt II): 628. 25. Do QB, Page P, Dandan N, Cardinal R. Effects of Maze III procedure on atrial parasympathetic innervation. Can J Cardiol 1996;12(Suppl E):145E. 26. Do QB, Page PL, Dandan N, Cardinal R. Influence of the Maze III procedure on atrial autonomic innervation: Assessment by repolarization mapping. Circulation 1996;94(Suppl I):I493-I494. 27. Page P, Corriveau MM, Cardinal R. Atrial parasympathetic innervation in the human: Assessment by intraoperative epicardial isointegral mapping. Can J Cardiol 1998;14(Suppl F):101F. 28. Carlson MD, Geha A, Hsu J, et al. Selective stimulation of parasympathetic nerve fibers to the human sinoatrial node. Circulation 1992;85:1311-1317. 29. Furakawa Y, Narita M, Takei M, et al. Differential intracardiac sympathetic and parasympathetic innervation to the SA and AV nodes in anesthetized dog hearts. Jpn JPharmacol 1991;55:381-390. 30. Wallick DW, Martin PJ. Separate parasympathetic control of the heart rate and atrioventricular conduction of dogs. Am J Physiol 1990;259:H536-H542. 31. Do QB, Page P, Dandan N, Cardinal R. Effect of intrapericardial dissections on atrial innervation: Assessment by integral distribution mapping. Can J Cardiol 1995;ll(Suppl E):95E. 32. Do QB, Page P, Dandan N, Cardinal R. Autonomic innervation of the atrial septum: Assessment by integral mapping. Can J Cardiol 1996;12(Suppl E):112E. 33. Do QB, Dandan N, Cardinal R, Page P. Etude de 1'innervation autonomique du septum interauriculaire par cartographic isointegrale chez le chien. Ann Chir 1996; 50:659-666.

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Chapter 18

Mapping of Atrial Flutter Wolfgang Schoels, MD and Nabil El-Sherif, MD

It is now very well accepted that typical atrial flutter results from single-loop reentry around a large combined functional-anatomical obstacle consisting of the circumference of both caval veins and an arc of functional conduction block in between.1'2 The rim of atrial tissue bounded by the inferior vena cava and the adjacent atrioventricular (AV) ring constitutes a crucial part of the reentrant circuit, since any obstacle within this isthmus linking both boundaries will inevitably stop the circulating wavefront. Accordingly, "isthmus ablation" has now become the treatment of choice for recurrent typical atrial flutter.3"5 It might therefore appear that there is no need for further mapping studies of this particular arrhythmia. There are still, however, several unsettled issues regarding the pathophysiology of typical and atypical atrial flutter that are of relevance for the development of future preventive therapeutic strategies and the selection of current treatment options. This relates, for example, to the nature of functional conduction block in general, to the electrophysiological properties of the intercaval region as a preferential site for extensive

conduction block, to the question on hemodynamic-electrophysiological interactions, and to the value of surface EGG characteristics for the prediction of epicardial activation patterns during atrial flutter. Standard electrophysiological mapping techniques were used to analyze activation and refractory patterns in dogs with right atrial (RA) enlargement,6 to specifically determine conduction properties and gradients of refractoriness within the intercaval region in normal canine hearts, to assess the effects of acute RA pressure load on atrial repolarization, and to correlate surface EGG characteristics and epicardial activation maps in dogs with sterile pericarditis and inducible sustained atrial flutter.7 We used a custom-designed electrode array for simultaneous recording of 127 bipolar epicardial electrograms (interpolar distance 1 to 2 mm, interelectrode distance 3 to 8 mm) from the in situ canine heart. A high-density patch-electrode (10 x 10 bipoles, interelectrode distance 1.5 mm) allowed for more detailed analysis of activation and refractory patterns in the intercaval region. Data were stored and

From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003. 373

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analyzed on a 256-channel computerized multiplexer mapping system. Details of the model preparation, the recording techniques, and the methods for constructing isochronal maps have been described elsewhere.1 Activation and Refractory Patterns in the RA Enlargement Model As in the sterile pericarditis model, atrial flutter in the RA enlargement model generally results from single-loop reentry around combined functional-anatomical obstacles.8 In response to a premature stimulus, an arc of functional conduction block occurs. With an isolated short arc of block, the stimulated wavefront proceeds around both of its ends. The 2 wavelets then collide on the distal side of the arc. For either wavelet, the pathway includes the distance from the site of stimulation to the respective end of the arc and then half of its length distally. Based on the length of this pathway and the conduction velocity within atrial tissue, one might calculate the conduction time required to reach the site of collision. For reentry to occur, this conduction time must exceed the refractory period of the tissue on the proximal side of the arc. Obviously, conduction and repolarization characteristics of the atria imply rather long pathways and, thus, rather long arcs of functional conduction block. Two aspects of the normal atrial anatomy seem to facilitate reentry. The atrial vessels and, especially, the caval veins introduce large discontinuities, which might combine with arcs of block to form large functionalanatomical obstacles. Furthermore, the atrial surface area is relatively small, being electrically isolated from the ventricles by the AV ring. If one end of an arc of block occurring in response to a premature stimulus reaches the AV ring,

bidirectional activation of the tissue on the distal side of this arc is no longer possible. Instead, only one stimulated wavefront might proceed around the free end of the arc, reaching the distal AV ring connection as the last site to be activated. This sudden increase in the length of the effective pathway seems to facilitate reentry, possibly explaining why most reentrant circuits underlying typical and atypical atrial flutter reveal some spatial relationship to the AV ring. Although there is some temporal dispersion of refractoriness even in normal hearts, the transition of areas with relatively long refractory periods, typically located below the superior vena cava and in the lateral RA wall, and areas with shorter refractoriness, predominantly found in the left atrium (LA), is gradual for most of the epicardial surface. Only a few small areas exhibit local gradients of refractoriness reaching 20 ms or more. In response to premature atrial stimulation, short arcs of functional conduction block tend to coincide with respective areas (Figure 1). In enlarged atria, the temporal dispersion of refractoriness is not much different. However, the refractory pattern appears to be much more inhomogeneous, with areas of short and long refractoriness being commonly located next to each other. This spatiotemporal dispersion of refractoriness seems to underlie the occurrence of regional conduction block, since there is generally a compelling correlation between the location of these arcs of block and the isochrones of refractoriness (Figure 2). At individual sites, a lack of correlation might indicate that anisotropic conduction properties are also of some relevance. Thus, our interpretation would be that the long arcs of functional conduction block seen during atrial flutter are primarily based on local inhomogeneities in repolarization with anisotropic conduction properties serving as a modifying factor.

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375

Figure 1. Epicardial refractory map (left panel) and endocardia! activation map during premature atrial stimulation (right panel) in a normal dog. The site of stimulation is indicated by E. Here and in all subsequent figures in this chapter, the epicardial atrial surface is displayed as a planar projection of a posterior view. The atria are separated from the ventricles along the atrioventricular ring, the atrial appendages are incised inferiorly and unfolded. The refractory map shows a gradual transition from areas of short refractoriness to areas with longer refractoriness. Only at a few sites, local gradients in refractoriness of 20 ms occur. During S2 stimulation, short arcs of functional conduction block (the heavy solid lines) occur at those very sites.

Figure 2. Epicardial refractory map (left panel) and endocardial activation map during premature atrial stimulation (right panel) in a dog with right atrial enlargement. The refractory pattern appears to be much more complex, with local gradients in refractoriness occurring at several sites and over a considerable distance. With S2 stimulation, long arcs of functional conduction block in the activation map coincide with respective isorefractory lines in the refractory map.

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sists mainly of the pectinate muscles and a thin overlying epicardial muscle layer. The pectinates run more or less perpenThe fact that typical atrial flutter is dicular to the intercaval axis before they so uniform in cycle length and ECG mor- reach the crista terminalis. Within the phology from patient to patient and from free RA wall, apparent conduction velocepisode to episode already suggests some ities reach 1.5 ± 0.5 m/s in the direction involvement of well-defined anatomical perpendicular and 0.5 ± 0.2 m/s in the structures. The finding of a common cen- direction parallel to the intercaval axis. tral obstacle consisting of the circumfer- While this could explain anisotropic conence of both caval veins and a long arc of duction block perpendicular to the interfunctional conduction block in between caval axis, one would then have to expect fits very well with this expectation. Still, this type of block anywhere within the one might wonder why the intercaval free RA wall. It seems, however, tempting region is so obviously prone to functional to speculate that the directional changes conduction block. Theoretically, the local in fiber orientation supposedly occurring tissue could be particularly sensitive to any at the junction of the pectinate muscles type of pathology associated with atrial with the crista terminalis increase the likeflutter. It would, however, seem more likely lihood for anisotropic conduction block. that the normal anatomy provides a phys- Obviously, this hypothesis must be subiological basis for the occurrence of con- stantiated by future studies. duction block. The intercaval region, as RA Pressure and Local described by epicardial activation maps, Refractory Patterns roughly coincides with the location of the crista terminalis seen endocardially. This Clinically, an increase in LA or RA compact strand of atrial muscle fibers runs parallel to the intercaval axis. pressure, as seen, for example, with mitral Accordingly, the crista terminalis exhibits valve stenosis, pulmonary embolism, or marked anisotropic conduction proper- hypertension, is frequently associated ties, with fast, longitudinal conduction with atrial tachyarrhythmias.10 Once iniparallel and slow, transverse conduction tiated, atrial tachyarrhythmias also cause perpendicular to the intercaval axis. an increase in atrial pressure, and this Thus, conduction block across the crista might in turn facilitate their perpetuaterminalis could not be easily explained tion, provided there is some sort of hemoon the basis of current concepts on dynamic/electrophy siological interaction. In normal dogs, hemodynamically tolanisotropy, claiming faster conduction but a reduced safety factor for impulse erated acute banding of the pulmonary propagation along the long axis, and artery results in a slight but significant slower conduction but a higher safety increase in mean RA pressure in the range factor for impulse propagation along the of 2 to 4 mm Hg. At the same time, atrial short axis of myocardial muscle fibers.9 flutter and particularly atrial fibrillaHigh-density refractory patterns in tion might easily be induced. The overall normal dogs, on the other hand, also do activation pattern remains unchanged. not reveal any systemic decrease or Accordingly, total RA or LA activation increase in local refractoriness within the time is also unaffected. There is, however, intercaval region (Figure 3). This also a significant decrease in mean RA refracrelates to the free RA wall, which con- toriness (from 129 ± 17 ms to 119 ± 16 ms), Electrophysiological Properties of the Intercaval Region

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377

Figure 3. Local refractory periods across the intercaval axis in normal dogs. A systemic decrease or increase in local refractoriness is not evident; the maximum gradient in refractoriness is 30 ms.

which is not evident in the LA (110 ± 18 versus 114 ± 21 ms). Even within the RA, the changes in local refractoriness reveal regional inhomogeneities, so that the refractory pattern appears to be more irregular and discontinuous with elevated pressure. Unhanding and consecutive restitution of baseline hemodynamic conditions also results in restitution of baseline refractory patterns. Thus, hemodynamic changes seem to be of relevance for local electrophysiological properties, potentially leading to an increase in the dispersion of refractoriness. It is not clear at the moment whether this reflects direct hemodynamic-electrophysiological coupling or an indirect effect based on autonomic counter-regulation. The fact

that increased RA pressure affects RA but not LA refractory patterns would favor a direct interaction. Characteristics of the Surface EGG and Epicardial Activation Patterns Comparable to the clinical situation, the electrocardiographic manifestation of experimental atrial flutter in both the canine sterile pericarditis model and the RA enlargement model is characterized by either undulating F waves without isoelectric intervals ("typical" atrial flutter) or by discrete P waves separated by

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isoelectric intervals (" atypical" atrial flut- circuits in P wave atrial flutter, the ter).11 Undulating F waves suggesting requirement of a revolution time exceedcontinuous atrial activation are very well ing the longest refractory period within compatible with a reentrant activation the circuit might only be fulfilled by a pattern. Discrete P waves with interven- reduction in conduction velocity. Typiing, seemingly isoelectric, intervals, on cally, this is achieved through a marked the other hand, would rather suggest a area of very slow conduction, with normal focal mechanism. When comparing epi- conduction in the remainder of the reencardial activation maps and surface ECG trant pathway. Propagation of the reencharacteristics during sustained atrial trant wavefront within the area of slow flutter, it becomes quite evident that F conduction results in activation of very wave atrial flutter is almost invariably little tissue per 10-ms interval, and thus associated with single-loop reentrant acti- the electromotive force is not sufficient to vation around the combined functional- be depicted by the surface ECG. Accordanatomical obstacle mentioned above. The ingly, conduction time within the area of polarity of the F waves in the inferior slow conduction corresponds to the isoleads (II, III, and aVF) is determined by electric interval between subsequent P the direction of rotation, with a cranio- waves, whereas the P wave duration caudal activation of the LA resulting in reflects the activation time of atrial tissue positive F waves and a caudocranial acti- outside the slow zone. vation in negative F waves (Figure 4). P wave atrial flutter might actually reflect Clinical Implications a focal activation pattern with rapid activation of the epicardial atrial surface and The uniform activation pattern of an interval of electrical silence preceding subsequent activations. However, P wave typical atrial flutter has already led to atrial flutter might also be associated with the development of ablative strategies reentrant activation, the underlying reen- that can be easily applied without extentrant circuits being variable in size and sive mapping procedures. The relevance location from dog to dog (Figure 5). P wave of refractory patterns for the occurrence reentrant circuits are typically relatively of functional conduction block not only small. A possible explanation for the strik- forms the basis for pharmacological intering difference in the electrocardiographic ventions, but should also encourage preappearance of reentrant P wave atrial ventive pacing strategies that modify the flutter and F wave atrial flutter emerges sequence of activation and repolarization. when comparing the amount of atrial Even though anisotropy rather than distissue being activated during each 10-ms persion of refractoriness seems to conisochronal interval of respective circus tribute to the preferential occurrence of movements. With the large reentrant cir- conduction block along the intercaval cuits in F wave atrial flutter, the circu- axis, premature activation of the tissue on lating impulse spreads at a relatively fast, either side of this arc, potentially through more or less uniform conduction velocity. septal stimulation, might prevent reenA marked area of slow conduction is not try. Since hemodynamic-physiological evident. Thus, at any given time during interactions seem to be of relevance for each cycle, a relatively large amount of the initiation and perpetuation of atrial atrial tissue is being activated, accounting tachyarrhythmias, interventions aiming for some undulation of the baseline on the at a reduction in atrial pressure should be insurface ECG. For the smaller reentrant corporated more vigorously into therapeutic

MAPPING OF ATRIAL FLUTTER

379

Isochronal Intervals (10 msec)

Figure 4. A. Electrocardiographic leads II, III, and aVF together with an atrial electrogram during sustained atrial flutter in a dog with typical F waves. The epicardial activation map illustrates the activation sequence for one tachycardia cycle. B. Number of electrode sites activated during each 10-ms isochronal interval of 4 consecutive tachycardia cycles. Note that for most 10-ms intervals of each cycle, at least 5 electrode sites are being activated. This accounts for the continuous undulations of the baseline on the surface EGG.

and preventive strategies. The surface EGG characteristics of typical and atypical atrial flutter are already used as a guide to anatomically guided or mappingguided ablative interventions. A more

detailed analysis of the P wave morphology in atypical atrial flutter may help to direct therapeutic approaches for this particular arrhythmia prior to any invasive evaluation.

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Figure 5. A. Electrocardiograph^ leads II, III, and aVF together with an atrial electrogram during sustained atrial flutter in a dog with typical P waves. The epicardial activation map illustrates the activation sequence for one tachycardia cycle. B. Number of electrode sites activated during each 10-ms isochronal interval of 4 consecutive tachycardia cycles. For more than 50% of each cycle, less than 5 electrode sites are being activated per 10-ms isochronal interval, due to propagation of the circulating wavefront within the area of slow conduction. This corresponds to the seemingly isoelectric interval between P waves on the surface ECG.

MAPPING OF ATRIAL FLUTTER

References 1. Cosio FG, Arribas F, Palacios J, et al. Fragmented electrograms and continuous electrical activity in atrial flutter. Am J Cardiol 1986;57:1309-1314. 2. Scheols W, Gough WB, Restivo M, et al. Circus movement atrial flutter in the canine sterile pericarditis model. Activation patterns during initiation, termination, and sustained reentry in vivo. Circ Res 1990;67:35-50. 3. Saoudi N, Atallah G, Kirkorian G, et al. Catheter ablation of the atrial myocardium in human type I atrial flutter. Circulation 1990;81:762-771. 4. Cosio FG, Lopez-Gil M, Goicolea A, et al. Radiofrequency modification of the critical isthmus in atrial flutter. Eur Heart J1991;21:369. 5. Feld FK, Fleck P, Chen PS, et al. Radiofrequency catheter ablation for the treatment of human type 1 atrial flutter. Identification of a critical zone in the reentrant circuit by endocardial mapping techniques. Circulation 1992;86:12331240. 6. Boyden PA, Hoffman BF. The effects on atrial electrophysiology and structure of surgically induced right atrial enlarge-

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ment in dogs. Circ Res 1981;49:13191331. 7. Page PL, Plumb VJ, Okumura K, et al. A new animal model of atrial flutter. J Am Coll Cardiol 1986;8:872-879. 8. Schoels W, Kiibler W, Yang H, et al. A unified functional/anatomic substrate for circus movement atrial flutter: Activation and refractory patterns in the right atrial enlargement model. J Am Coll Cardiol 1993;21:73-84. 9. Spach MS, Dolber PC, Heidlage JF. Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle: A model of reentry based on anisotropic discontinuous propagation. Circ Res 1988;62:811-832. 10. Henry WL, Morganroth J, Pearlman AS, et al. Relation between echocardiographically determined left atrial size and atrial fibrillation. Circulation 1976; 53:273-279. 11. Schoels W, Offner B, Brachmann J, et al. Circus movement atrial flutter in the canine sterile pericarditis model. Relation of characteristics of the surface electrocardiogram and conduction properties of the reentrant pathway. J Am Coll Cardiol 1994;23:799-808.

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Chapter 19

Mapping of Normal and Arrhythmogenic Activation of the Rabbit Atrioventricular Node Jacques Billette, MD, PhD, Jun Wang, MD, PhD, Karim Khalife, BSc, and Li-Jen Lin, MD

Introduction

may help understand its circuitry.7"12 This chapter briefly summarizes current knowledge of nodal function and the contribution of different mapping techniques to its understanding.

The slow conduction and filtering properties of the atrioventricular (AV) node largely control the ventricular response during supraventricular tachyarrhythmias. Despite this strategic role and Rate-Dependent Nodal abundant study, underlying mechanisms Functional Properties remain debated. Among the questions are the exact intranodal origin of nodal delay The activation of the AV node varies and its rate-dependent variations, the nature of compact node conduction, sub- widely with the underlying functional strate of nodal dual pathway physiology conditions, and the understanding of its and reentry, and the role of nodal inputs physiology is essential for an accurate in nodal function. New optical technology interpretation of mapping results. The may help resolve these issues, but further following is a summary of its basic and development will be needed to achieve rate-dependent function. The AV node cell-level resolution in AV nodal mapping conduction time (AH interval = atrial-His such as achieved in cultured cells.1"6 interval) accounts for nearly 50% of the Other recent developments in surface PR interval and provides time for the potential recording have also improved atrial contraction to contribute to venaccess to critical intranodal events that tricular filling. The AV node also filters Supported by the Medical Research Council of Canada, the Heart and Stroke Foundation of Quebec, and the Fonds de la recherche en sante du Quebec. From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; e2003. 383

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impulses during supraventricular tachyarrhythmias to achieve a ventricular rate compatible with effective pumping. Resulting AH intervals vary widely and form different patterns of response. A typical example is the response to a constant fast atrial rate. At the beginning of the fast rate the AH interval is prolonged, but each atrial beat is conducted to His bundle (1:1 nodal conduction). However, the AH interval increases further with fast rate duration until Wenckebach cycles develop. During these cycles, the AH interval increases from beat to beat until an atrial beat is blocked and resets the process. Different A:H ratios may then be observed. The most intricate case of nodal filtering occurs during atrial fibrillation that results in a highly irregular ventricular response characterized by a nearly random distribution of RR intervals (ventricular cycle lengths [CLs]). The main factors involved in these rateinduced AV nodal responses and blocks were recognized early.13 They are now described as 3 functional rules, known as recovery, facilitation, and fatigue, which can be independently characterized with specifically designed premature protocols (Figure 1A) and represented with recovery curves (Figure 1B).14~17 As the transitional, compact node, posterior extension, and lower bundle tissues are important determinants of the AH interval, they are all considered parts of the AV node.8"10'18"20 This functional definition of the AV node is also best suited for correlation between clinical and experimental data. The recovery property reflects the nonlinear increase in AH interval with increasing prematurity (Figure IB). It can be independently characterized with a premature protocol performed at a slow basic rate (Figure 1A). Its contribution to AH interval, however, is the same at any basic rate.21 This contribution is similar during nodal slow and fast pathway conduction.22 The facilitation property can

be selectively characterized by the introduction of a short cycle before the premature test cycle during a slow basic rate (Figure 1A). The resulting curve is tilted down and left with respect to the control curve in the short coupling interval range (Figure IB); premature AH intervals are shorter and nodal block occurs at a shorter recovery time under facilitation. Facilitation develops after one beat of a fast rate, remains unchanged during a constant fast rate, and dissipates after one long cycle.23 For a given recovery time and level of facilitation, the AH interval increases progressively with the duration of a fast rate, a change that is attributed to fatigue.13'21-24'25 Fatigue can be selectively characterized by overdriving the atrium for 5 minutes to reach a steady state, and then introducing a facilitationdissipating long cycle (L) and a premature cycle (Figure 1A).25 The resulting curve is bodily shifted upward with respect to the control curve (Figure IB). The fatigue induction and dissipation can also be selectively characterized from changes in AH interval observed during a fast rate imposed with a constant Hisstimulus interval and ensuing return to the control rate. The combined facilitation and fatigue effects present during a fast rate can also be determined by simply omitting the facilitation-dissipating long cycle from the fatigue protocol (Figure 1A). While identical to the fatigue curve in long coupling interval range, the combined effect curve is tilted to the left in short coupling interval range (Figure IB). This tilting may result in a crossing with the control curve; beyond the crossing point, AH intervals are shorter (faster conduction) during the fast rate than at control (Figure IB). This occurs because the nevertheless present fatigue is then overcome by greater facilitation. The 3 nodal properties persist after autonomic blockade26 and can also be demonstrated while controlling the interstimulus interval

ELECTRICAL ACTIVATION OF AV NODE

385

Figure 1. Characterization of nodal functional properties with premature stimulation protocols (A) and resulting recovery curves (B) in a rabbit heart preparation. The control recovery protocol shows the last of a series of 20 long cycles (L, slightly shorter than spontaneous cycle length) followed by a premature cycle (P). The selective facilitation protocol differs from the control one only by a facilitationinducing short cycle (SC) introduced between the long and premature cycle. The steady-state selective fatigue protocol shows the last of a series of 20 short cycles followed by one facilitation-dissipating long cycle and a premature cycle. Testing of premature cycles is started after 5 minutes of short cycles. The combined effects of facilitation and fatigue produced by a fast rate are obtained by repeating the fatigue protocol while omitting the facilitation-dissipating long cycle. All stimuli are imposed with controlled HS intervals. S2 identifies the test premature beat. For simplicity, all other beats are marked Si regardless of protocol and cycle length. B. The 4 recovery curves obtained when plotting the premature nodal conduction time (A2H2 interval) against the corresponding recovery time (H^ interval).

in a standard fashion.27'28 The beat-tobeat variations in the contribution of recovery, facilitation, and fatigue to the AH interval have been shown to account for Wenckebach cycles, response to incremental pacing, hysteresis, alternans, and retrograde conduction.29"35 Autonomic

modulations and drug effects can also be explained in this context.36"38 A much debated issue is whether the PP or RP (AA or HA in our context) should be used to assess the nodal recovery time.13-39"44 For a given protocol, the shape of the recovery curve, i.e., nodal recovery

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pattern, is identical when the AH intervals are plotted against the preceding atrial or His-atrial interval.41 However, the difference between recovery curves obtained in different conditions varies markedly with the chosen recovery parameter, which, by definition, does not affect nodal function (same nodal responses in the 2 formats). Our data indeed suggest that the 2 formats similarly reflect nodal function. Their difference arises entirely from changes in the AH interval of the last beat that affects the nodal recovery time preceding a premature beat and invalidates the assumption that similar AA reflects similar nodal recovery time. One particular data point of the recovery curve corresponds to the nodal functional refractory period or minimum interval reached between 2 consecutive His bundle activations. This parameter is important because it reflects the capacity of the node to impose a minimum ventricular CL during supraventricular tachyarrhythmias. The functional refractory period was found to vary predictably under the influence of facilitation and fatigue.45 The interaction between these properties during a fast rate can result in shortening, prolongation, or no change in the functional refractory period depending upon the duration of the fast rate. The functional refractory period also controls the minimum RR interval during atrial fibrillation.46'47 However, the beat-to-beat variations in the contribution of nodal properties to the gross irregularity of the ventricular response observed during atrial fibrillation remain to be established. In summary, the nodal properties of recovery, facilitation, and fatigue can be individually characterized and their contribution to rate-induced responses can be established with specifically designed stimulation protocols. Consistent characterization of nodal function can be obtained with different recovery measures.

Nodal Inputs, Dual Pathway Physiology, and Reentry The AV node frequently generates echo beats and reentrant rhythms. These phenomena are unanimously attributed to the presence of a slow and a fast AV nodal pathway the substrate of which remains debated. The authors of 5 chapters addressing this question in a recent book proposed a number of mechanisms. The functional asymmetry underlying dual pathways was postulated to arise from (1) different properties of crista terminalis and interatrial septum input48; (2) different properties of the inputs with their compact node prolongation49; (3) 2 posterior input limbs connecting through the proximal compact node and a fast conducting anterior input11; 4) a slow posterior input and anterior shortcut track bypassing or only traveling through a portion of the compact node49; 5) a slow and fast portion in dissociated compact node and perhaps some nearby transitional cells50; and 6) different properties of compact node and its posterior extension.17 Further investigation will likely be required in order to sort out these hypotheses. The current thoughts are strongly influenced by the fact that the slow or fast pathway can be altered by crista terminalis or interatrial septum input ablation, respectively.51"55 Because such lesions leave the compact node intact, the asymmetry seems to arise within inputs. However, no differences in local input conduction and refractory properties have been found that could account for dual pathways.7'56"62 Optical dye mapping has not revealed the existence of an independent input-based fast pathway either.1 Diverging results have also been reported.63'64 No specific anatomical input features have been identified in patients suffering from AV nodal reentrant tachycardia.65 The possibility of multiple nodal inputs has also been reported.11'66'67 There is

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Figure 2. Atrioventricular node landmarks and structures of the recently proposed reentrant circuit.8"10 For practical purposes, orientation is relative to a horizontal septal baseline rather than to the real intrathoracic position. S = superior; I = inferior; P = posterior; A = anterior; DA = upper atrium; CT = crista terminalis; IAS = interatrial septum; HIS = His bundle; TT = tendon of Todaro; TV = tricuspid valve; CS = coronary sinus; TC = transitional cell zone; CN = compact node; LNC = lower nodal cell bundle; PNE = posterior extension of AVN.

equally convincing evidence that the compact node plays a determinant role in the reentrant circuit.50'68"70 In our recently proposed model (Figure 2), slow pathway and fast pathway correspond to the posterior extension and compact node, respectively.8"10'71 Perinodal and lower nodal tissues provide a common proximal and distal pathway, respectively. During very early premature beats, the impulse is blocked at the perinodal compact node junction but can nevertheless reach the His bundle by means of posterior extension propagation. The resulting long delay allows for recovery of transitional tissues, which may then support reentry. The reentrant retrograde perinodal activation may break at different positions of the junction between compact node and transitional tissues and, whatever its breakthrough point, always forms a broad perinodal wavefront.9 These studies also show that the conventional

nodal structures impose the functional refractory period while the posterior extension accounts for the nodal effective refractory period.9'10 The slow pathway and the fast pathway can be selectively interrupted with discrete lesions of the posterior extension and transitional compact node junction, respectively.10'71 Despite their neighborhood, connection, and overlap near the tricuspid annulus, anatomical and functional properties of the posterior extension and input differ markedly. The posterior input is made of rapid transitional cells that cover the region from tricuspid annulus to tendon of Todaro and establish a broad contact with working atrial myocardium.19'72 Its activation time covers 25% of the AH interval and is largely independent of CL.7~10 The posterior extension is a small bundle of compact-node-like tissues.8'73 Along the AV axis at a position just posterior to the compact node, the posterior

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extension measures approximately 600 um. It progressively decreases to about 100 um along its 2.5-mm length.8 This thin structure (38 have classified the AH interval. Furthermore, during premaanisotropic properties of cardiac muscle ture stimulation, the increase of conducas uniform and nonuniform. Anisotropy is tion delay in the AV junctional area was said to be nonuniform when side-to-side only 10% of the increase of the AH interelectrical coupling of adjacent groups of val. Thus, the increase in the AH interval parallel fibers is absent because of the can only be partly due to the increase in interposition of strands of connective the conduction delay in the superficial tissue.44 This connective tissue may be a layers of the AV junction. It is therefore normal component of the heart in regions unlikely that anisotropic conduction in the such as the crista terminalis, or can result subendocardial layers of the AV junction from aging or pathological changes. Prop- plays an important role in slow AV conducagation of activation transverse to the tion. However, activation of the AV nodal long axis is interrupted, such that adja- area is by nature a complex 3-dimensional cent bundles are excited in an irregular event, and is certainly not confined to sequence that results in slow conduction. superficial layers alone. Conduction delay The irregular activation is evident in the must have occurred in deeper layers and extracellular electrograms, which are highly escaped our attention. Thus, we cannot fractionated. Propagation parallel to the rule out the possibility that anisotropic fibers is still fast, and electrograms are conduction in deeper layers plays a role in smooth with single deflections. Our anatom- the increase in the AH interval after preical as well as electrophysiological data mature stimulation. are compatible with such nonuniform anisotropic characteristics. An additional The Reentrant Pathway During complicating factor for the spread of actiVentricular Echoes is Confined vation arises, nonetheless, because of the changing direction of fibers in the anteto the AV Node rior aspect of the triangle of Koch. Atrial Activation Sequence During Relation with the Transitional Ventricular Stimulation Cell Zone Sixteen canine hearts were studied. In the rabbit, transitional cells con- All hearts revealed 2 distinct atrial exit stitute the most superficially located group sites. One was located in the anterior of fibers.8 In the pig and dog, however, as area of the AV junction, the other was in the human, the superficial fibers are located posteriorly between the tricusmade up of cells that, histologically, are pid valve annulus and the orifice of the

MAPPING OF AV NODE IN THE EXPERIMENTAL SETTING coronary sinus. In 5 of the 16 hearts, earliest atrial activation was found at the anterior site during pacing at long cycle lengths (CLs) (>600 ms). During incremental pacing, the sequence of atrial activation changed gradually until earliest atrial activation was recorded at the posterior site during pacing at shorter CLs.

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Figure 4 shows the change of the atrial activation pattern during incremental ventricular pacing in 1 of these 5 hearts. Although the change in the activation pattern suggests a shift from retrograde fast (panel A) to retrograde slow pathway conduction, earliest atrial activation was delayed by only 4 ms (panel C). Likewise,

Figure 4. Activation maps during incremental ventricular pacing. The dashed lines indicate the anatomical landmarks of the mapped area. Isochrones are drawn at 4-ms intervals (A and C) and 2-ms intervals (B), respectively, with the ventricular stimulus as time zero. For maps A and C, 24 of 94 recorded atrial electrograms are shown in the approximate position of recording. A. Cycle length (CL) = 600 ms; earliest atrial activation is at the anterior site with initial negativity of the corresponding unipolar atrial electrogram (marked with an asterisk*). B. CL = 460 ms; conduction to the anterior exit delays by 6 ms. A second endocardial breakthrough manifests at a posterior site with an SA interval of 114 ms. C. CL = 360 ms; earliest atrial activation is now at the posterior site with an initially negative unipolar atrial electrogram (marked with an asterisk*). Note that the electrogram at the site of the anterior exit reveals a positive deflection (marked with #). CS = coronary sinus orifice; TVA = tricuspid valve annulus; TT = tendon of Todaro.

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Figure 5. Activation map in a heart with 2 atrial exit sites after ventricular pacing at a cycle length of 1000 ms. The dashed lines indicate the anatomical landmarks of the mapped area. Isochrones are drawn at 4-ms intervals with the ventricular stimulus as time zero. Sixty-four of 94 recorded atrial electrograms are shown in the approximate position of recording. The tracing in the lower right part shows a His bundle recording with the stimulus artifact (S), a retrograde His deflection (H), the ventricular (V) depolarization, and the atrial depolarization (A). See text for discussion. CS = coronary sinus orifice; TVA = tricuspid valve annulus; TT = tendon of Todaro.

sudden changes in the ventriculoatrial (VA) conduction time consequent upon the alteration of the retrograde atrial activation sequence were not observed in the remaining 4 hearts. In 1 of the 16 hearts, a spontaneous switch from the anterior to the posterior exit site was recorded during baseline stimulation at a CL of 600 ms. In contrast to the other 5 hearts, this change in the retrograde atrial activation sequence was associated with an increase of the Hisatrial conduction time from 168 ms to 260 ms, suggesting a VA "jump." In 10 hearts, the retrograde impulse activated the atrium using both exit sites concurrently over a wide range of paced CLs. The activation maps revealed 2 early

sites with intrinsic negative deflections (indicative of areas where activation arises) separated by recording sites with later local activation times. An example is shown in Figure 5. The site of earliest atrial activation (signal marked with *) was recorded in the posterior area close to the tricuspid valve annulus. A second exit site, activated 12 ms after the posterior exit site, was in the anterior area near the apex of the triangle of Koch (signals marked with #). Atrial Activation Sequence During Ventricular Echoes Although single ventricular echoes were consistently induced in all hearts,

MAPPING OF AV NODE IN THE EXPERIMENTAL SETTING sustained AVNRT was never observed. None of the hearts investigated showed discontinuous AV nodal function curves during baseline study. A critical delay in VA conduction achieved by means of programmed ventricular extrastimulation was mandatory for the appearance of ventricular echoes. Surprisingly, the sequence of atrial activation and the signal morphology did not differ between baseline ventricular stimulation and retrograde atrial activation followed by ventricular echoes. Figure 6 shows the atrial activation pattern and the morphology of the unipolar atrial

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electrograms preceding a ventricular echo in the same heart as in Figure 5. VA conduction delay compared to Figure 5 is 25 ms. Note that the activation pattern and the signal morphology match those in Figure 5. The tracings in the lower right part show His bundle electrograms of the ventricular echo (a), and baseline atrial stimulation (b). The retrograde His deflection in a appeared before the ventricular electrogram. The He-Ve interval and the morphology of the ventricular electrogram of the echo (Ve) match those during normal antegrade conduction, indicating that the

Figure 6. Activation map in the heart of Figure 5 after a premature ventricular extrastimulus (S1S2 = 520 ms) at a basic cycle length of 800 ms, followed by a ventricular echo (Ve). Isochrones are drawn at 4-ms intervals with the premature ventricular extrastimulus (S2) as time zero. Sixty-four of 94 recorded atrial electrograms are shown in the approximate position of recording. The anterior exit was close to the site where antegrade His deflections were recorded during reciprocation (marked with H). See text for discussion. S = stimulus artifact; V = ventricular electrogram; A = atrial electrogram; He and H = His bundle electrogram during echo and during baseline atrial stimulation, respectively. Other abbreviations as in Figure 5.

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closely coupled ventricular extrastimuli, the preferential route of atrial activation was via the posterior exit site, suggesting functional differences between the 2 areas. The exit sites observed in our study correspond to the sites of earliest atrial activation described in both animal studies and clinical settings. The studies of Sung et al.26 and of McGuire et al.46'47 suggest that during VA conduction, strands of Histology of the Exit Sites atrial cells that connect the compact node with the endocardial exit sites are the The anterior and the posterior exit site underlying substrate of fast and slow were found to be lying in atrial myocardium, pathway conduction. The observations of well away from the compact AV node and our study, however, clearly show that: (1) the transitional cell zone. The myocardium ventricular echoes occurred irrespective between the sites of endocardial breakof the atrial activation pattern; (2) synthrough and the compact AV node or the chronous retrograde activation of both transitional cells was not specialized in exit sites often preceded ventricular echoes; terms of histological characteristics, nor and (3) ventricular echoes occurred after were histologically discrete or insulated chemical destruction of the endocardial tracts identified. and subendocardial tissue. These findings limit the reentrant circuit to the AV Phenol Application node. In an attempt to further restrict the reentrant circuit, surgical dissection Ventricular echoes were still inducible of the AV nodal area was performed.5 In after application of phenol on the endo- these experiments, the perinodal atrial cardium within the triangle of Koch, on tissue, including both endocardial exit the perinodal area, and on the floor of the sites, could be disconnected from the AV coronary sinus. Retrograde and ante- node without abolishing dual-pathway grade AV nodal conduction parameters physiology. did not differ before and after phenol application. Light microscopy of histological sections cut from the anterior and Canine Dual AV Nodal Physiology the posterior AV junction revealed a mean zone of necrosis to a depth of 475 |im Although dual AV nodal pathways (range 350-600 jim). manifested as ventricular echoes in all

antegrade limb of the circuit used the AV node-His-Purkinje system. Mapping was also performed with the high-resolution, quasiunipolar electrode. Although this electrode was specifically designed to unveil low-frequency signals, no distinct potentials were discerned that could be attributed to activation of the compact node or the transitional cell zone.

Dual Atrial Exit Sites Versus Dual Pathways In the canine hearts, activation of the right atrium following ventricular stimulation occurred via 2 distinct endocardial exit sites in the anterior and posterior right AV junction. During ventricular pacing with short CLs or after

hearts, none of the hearts showed discontinuous AV nodal function curves during baseline electrophysiological study. Since discontinuous AV nodal conduction can be observed in the majority of patients undergoing electrophysiological study,48 this might indicate a substantial difference between human and canine AV nodal physiology. The explanation for this apparent discrepancy might be simple: if

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in humans with AVNRT suggest that damage to the AV node is not a prerequisite for cure.27'54"56 There are several possible explanations for this discrepancy: (1) The persistence of single echo beats after selective slow pathway ablation in patients with AVNRT is a common finding. If successful ablation for AVNRT could only be achieved by complete destruction of the circuit, this should equate with eradication of the echo beat. Radiofrequency or surgical lesions, even if placed well away from the compact AV node, certainly modify the complex architecture of the AV junction. Modulation of the atrial input to the AV node might disturb the delicate balance that seems to be necessary to sustain circus movement, Where is the Site of AV while the circuit is still intact and allows single echoes. (2) The success of radiofreNodal Reentry? quency ablation in abolishing AVNRT The observations made in our study at sites well away from the compact AV excluded the atrial tissue outside the AV node can be attributed to remote effects nodal area from the reentrant circuit on the transitional cells or the compact during ventricular echoes. Early studies node itself. It has been shown that already demonstrated that the anatomi- sequences of 60-second, 25-W radiofrecal and functional potentials for a dual quency pulses rise myocardial temperatransmission system within the AV node ture to greater than 50°C at distances as do certainly exist. In their original study, large as 10 mm.57 (3) Recent concepts Mendez and Moe suggested that "...the suggest intranodal "microreentry" as the upper region of the node was functionally basis for single AV nodal echoes, whereas and spatially split into two effective some forms of AVNRT are ascribed to pathways..."53 This early observation is "macroreentry" with the participation of strongly supported by a recent report by atrial tissue well outside the AV nodal Patterson and Scherlag,31 who studied area.58 (4) The mechanism of the ventricAVNRT in the superfused rabbit heart ular echoes induced in the dog hearts is preparation. They suggested longitudi- different from the mechanism of AVNRT nal dissociation within the posterior AV in humans. Despite the fact that dual AV nodal nodal area as a substrate for AV nodal reentry. physiology seems to be a normal propOur findings limit the reentrant cir- erty of the dog heart, sustained AVNRT cuit during ventricular echoes to the AV could not be induced. Although it has node. Since it is generally thought that been shown that the conduction system atrial and ventricular echoes represent a in dogs and in humans is basically simi"single-beat expression" of AVNRT, they lar,14 extrapolation of our observations might be in contradiction to findings in to the pathophysiology of human hearts humans with AVNRT: recent results of with AVNRT should be considered with surgical and catheter ablation techniques care. the differences in conduction velocities between the retrograde dual pathways are not sufficiently distinct, block in the pathway with the longer effective refractory period will not yield discontinuous conduction. The occurrence of ventricular echoes with smooth AV nodal function curves is a common finding in experimental and clinical settings,49'50 and patients presenting with AVNRT do not necessarily demonstrate discontinuous AV conduction.51'52 Thus, conduction delay due to decremental conduction properties, rather than differences in conduction velocities, is essential for AV nodal reentry to occur.

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CARDIAC MAPPING Double Component Action Potentials in the Posterior Approach to the AV Node

Action potentials with double components were preferentially recorded in the area between the coronary sinus orifice and the tricuspid valve annulus almost up to the middle of the triangle of Koch (posterior approach to the AV node). During basic stimulation, delay between the 2 components could be as large as 60 ms, but it could increase to 150 ms after premature stimulation. As illustrated in Figure 7, progressive shortening of the 8^2 interval yielded action potentials with increasing delay between the 2 components (lower tracings). The tracings in the middle panel show action potentials during basic stimulation (Si) and after an early coupled extrastimulus (S2). The amplitude of the action potentials decreased with increasing prematurity of the extrastimulus. Double-component action potentials could be recorded in cells located superficially directly beneath the endocardium, as well as in cells from deeper layers. In those cases, the earliest component was recorded from cells directly beneath the endocardium, whereas late components were always generated by depolarization of cells in deeper layers (Figure 8). Histological investigation at these sites revealed a subendocardial zone of mainly transitional cells, arranged in clusters and single strands interspersed with connective tissue. Changes in the site of stimulation from posterior to anterior only marginally affected the configuration of the doublecomponent action potentials. The delay between the 2 components was always less during stimulation from a posterior site. The effectiveness of posterior stimulation was always greater than that of anterior stimulation, as evidenced by conduction block toward His occurring at

shorter coupling intervals of the premature stimulus. The first upstroke of the doublecomponent action potential always occurred before the His deflection. The upstroke of the second deflection, however, often ensued after the His deflection during basic stimulation (26% of registrations) and after premature stimulation (50% of registrations). This suggests that the activation generating that second component did not participate in AV conduction in these cases. Cooling of the Anterior Exit Site To study the nature of doublecomponent action potentials, the anterior region was cooled at the site where the atrial exit site was located during retrograde conduction in 3 hearts. The cooling probe consisted of a stainless steel tube with a diameter of 3 mm and a length of 10 cm, and could be cooled to a temperature of 4°C. Cooling of the anterior exit site resulted in an increase of the delay between the stimulus artifact and the second component of the double-component action potential (Figure 9). The interval between the stimulus and the first component did not change. The delay increased with decreasing temperature. During cooling, incremental pacing often resulted in Wenckebach periodicity of the AV conduction, whereas 1:1 conduction was still present in both components of the action potential of the cell impaled in the posterior approach to the compact AV node. Double-Component Action Potentials Our observation that the delay between the 2 components increases after premature stimulation suggests that doublecomponent action potentials are caused

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Figure 7. Top tracing: Extracellular recording from the His bundle region. Middle tracing: Action potentials with a double upstroke recorded in the posterior aspect of the atrioventricular node during basic stimulation (S1) with a cycle length of 500 ms followed by an early coupled stimulus (S2). The heart was stimulated from a posterior site. Bottom tracing: Action potentials recorded after a premature stimulus with a coupling interval of (1) 310, (2) 290, and (3) 280 ms. Delay between the first and the second components of the action potential increased and the amplitude of the second component decreased with increasing prematurity. Delay between the stimulus and the first upstroke remained virtually the same. Activation evoked after the extrastimulus of 280 ms was blocked toward His. Inset: Schematic drawing of the atrioventricular junctional area, showing the recording site. A = atrial deflection; H = His deflection; V = ventricular deflection; TVA = tricuspid valve annulus; CS = coronary sinus orifice; TT = tendon of Todaro; ME = microelectrode; CFB = central fibrous body.

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Figure 8. Top tracing: Extracellular electrogram from the His bundle region. Lower tracings: Action potentials recorded from the same endocardial site after the last basic stimulus (S1) and an early coupled extrastimulus (S2). The tracing marked "superficial" shows the action potential from a cell located in a superficial layer (directly beneath the endocardium). The tracing marked "deep" shows the action potential from a cell located at a deeper level. Both tracings show double components during basic stimulation (S1), but the notch in the superficial tracing (bold arrow) becomes more distinct after the premature stimulus (S2). The main (first) component of the action potential of the superficial tracing has a low upstroke velocity. The timing corresponds to the first, low-amplitude deflection of the action potentials from the deeper tracing. The main (second) component of the deeper tracing has a high amplitude and fast upstroke velocity. The timing corresponds to the notches marked by the bold arrow in the superficial tracing. The inset shows the endocardial location of the microelectrode. The dips following the bold arrows are artifacts caused by the reference of the microelectrode. Abbreviations as in Figure 7.

by activation arriving at discontinuities, e.g., electrotonic impulse transmission over an inexcitable or high resistance gap (Figure 10, panel a) or transmission of activation at isthmus sites, where a small bundle inserts into a large bundle

(panel b). The large bundle represents a high load for the relatively weak wavefront generated by the small bundle that results in activation delay.20 If propagation occurs at the discontinuity, at least one of the deflections in the action potential

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Figure 9. Tracings are intracellular recordings made during cooling of the anterior area of the atrioventricular junction. This area was the atrial exit site during retrograde conduction. Recordings were made during posterior stimulation at 3 instants during the cooling procedure: (1) baseline, no cooling; (2) 30 seconds of cooling; (3) 60 seconds of cooling. A double component is present during baseline (tracing 1). Delay between the first and second components of the action potential increases with cooling. Delay between the stimulus and the first component remains unchanged. The inset shows the location of the cooling probe and the recording microelectrode. The distance between the center of the cooling probe and the endocardial site where the microelectrode was impaled was 5 mm. Abbreviations as in Figure 7.

will reach threshold (panel c). In case of activation block, only single deflections remain (panel d). The observation that in virtually all cases the amplitude of both components becomes less than 20 mV with increasing prematurity, however, does not fit with the discontinuity concept and favors the concept of asynchronous arrival of activation due to discontinuous propagation between poorly coupled sheets of transitional cells (Figure 10, panel e), or the asynchronous arrival of converging wavefronts (panel f). In these instances, both components may become subthreshold (panel h). Relation with Slow Pathway Conduction Arguments in favor of the hypothesis that double-component action potentials in the posterior approach to the compact

AV node reflect activation delay are as follows: (1) in 74% of the recordings, the second component preceded the His bundle deflection during basic stimulation and in 50% during premature stimulation. (2) With premature stimulation, delay of the second component and delay of the His bundle potential increased more or less equally; however, in 26% of the recordings during basic stimulation and in 50% during premature stimulation, the second component occurred after activation of the His. In these cases, the second component did not participate in AV conduction and was most likely recorded from a dead-end pathway. In our view, this argues against the notion that these potentials arise in the slow pathway, which is supposed to ensure atrium-His conduction of premature impulses that are blocked in the fast pathway. However, since we were unable to find an animal with demonstrable dual

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Figure 10. Schematic drawings illustrating how double-component action potentials may arise. An activation front (arrows) that passes a discontinuity, being a high-resistance gap (a) or a site with impedance mismatch (b), generates double-component action potentials at sites before (1) and after (2) the discontinuity (c). Because this process is active, at least one of the components has a large (suprathreshold) amplitude. When activation blocks at the discontinuity, only one deflection remains (d). A weak coupling between bundles (e) or summation of activation in branching structures (f) also gives rise to double-component action potentials. When the wavefronts (arrows) are propagating in these structures (g), the configuration of the generated action potentials is similar to those that arise at high-resistance gaps or sites with a load mismatch. When, however, wavefronts are dying, double-component action potentials with subthreshold amplitudes may arise (h). 1 and 2 indicate recording sites.

MAPPING OF AV NODE IN THE EXPERIMENTAL SETTING antegrade AV nodal pathways, we could not link activation in the posterior approach to the compact AV node to slow pathway conduction. Whereas cooling of the posterior area hardly affected the timing of the 2 components, cooling of the anterior area delayed the second component that was recorded in the deeper layers. These observations suggest asynchronous arrival of a second wavefront from the anterior area through deeper layers. Summary and Prospects In this chapter, the anatomical, electrophysiological, and functional aspects of the AV node in normal conduction and in arrhythmogenesis have been briefly discussed. Prerequisites for the initiation of reentry in the AV nodal area are 2 pathways or areas with different functional properties, allowing unidirectional block, slow conduction, and early restoration of excitability in the area of unidirectional block. The substrate and the precise location of this reentrant circuit, however, have not been identified. Functional dissociation resulting from dual pathways or nonuniform anisotropic conduction because of morphological aspects of the AV nodal area could provide the functional basis for AV nodal reentry. Experiments were performed in isolated, Langendorff-bloodperfused dog and pig hearts: 1. To characterize anisotropic conduction in the triangle of Koch, the endocardial activation sequence was determined by multichannel mapping and was related with fiber orientation: fibers were parallel to the tricuspid valve annulus in the posterior part of the triangle of Koch, and changed to a perpendicular direction in the anterior area. Activation patterns correlated well with the arrangement

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of the superficial atrial fibers, supporting the concept of anisotropic conduction. However, the increase in AH delay after premature stimulation was only partly caused by activation delay in the superficial layers within the AV junction. This disproves that anisotropy in these layers plays an important role in the initiation of reentry. 2. Multiterminal electrodes were used to map electrical activity in the Koch's triangle after ventricular stimulation and during ventricular echoes. In some hearts the subendocardial cell layers were chemically destroyed with phenol. Retrograde atrial activation occurred via 2 distinct endocardial exit sites. Ventricular echoes were induced in all hearts, irrespective of the atrial activation pattern. Simultaneous retrograde activation of both exit sites often preceded reciprocation. Ventricular echoes could be induced after chemical destruction of the endocardial and subendocardial tissue as well as after surgical dissociation of the atrial exit sites of the putative dual pathways from the AV node, indicating that the reentrant pathway is confined to the AV node. 3. Double-component action potentials in the posterior approach to the compact AV node are often associated with activation delay and might reflect slow pathway conduction. Microelectrode recordings showed that the double-component action potentials in the posterior approach to the compact node are the result of the asynchronous arrival of activation fronts in superficial and deeper layers. Indications for and against an association with slow pathway conduction were found.

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The observations in our studies sug- cells might play an important role in the gest that the reentrant circuit during 'AV origin of reentry. nodal' reentry is indeed confined to the AV node. It cannot be excluded that a rim of perinodal atrial cells might participate in References the reentrant circuit, but the atrial exit sites of the putative dual pathways could 1. Paes de Carvalho A, Almeida DF. Spread be disconnected from the AV node without of activity through the atrioventricular node. Circ Res 1960;8:801-809. any effect on ventricular echoes. Atrial 2. Anderson RH, Janse MJ, van Capelle echoes and sustained AVNRT could not FJL, et al. A combined morphological and be induced in the isolated hearts. Obvielectrophysiological study of the atrioously, the question of whether single echoes ventricular node of the rabbit heart. Circ Res 1974;35:909-922. and sustained AV nodal reentry employ 3. Janse MJ, van Capelle FJL, Freud GE, the same substrate remains to be eluciDurrer D. Circus movement within the dated. Comprehensive understanding of AV node as a basis for supraventricular the arrhythmogenesis in the AV junction tachycardia as shown by multiple microis still hampered by the lack of an accurate electrode recording in the isolated rabbit heart. Circ Res 1971;28:403-414. model of AVNRT in an experimental set4. Hocini M, Loh P, Ho SY, et al. Anisotropic ting and by the lack of appropriate techconduction in the triangle of Koch of mamniques to study AV nodal activation. malian hearts: Electrophysiology and Recently, techniques such as optical anatomic correlations. J Am Coll Cardiol imaging using a voltage-sensitive dye 1998;31:629-636. 5. Loh P, De Bakker JMT, Hocini M, et al. have established their role in AV nodal Reentrant pathway during ventricular mapping.32'34 Considering its limitations, echoes is confined to the atrioventricular optical mapping was largely restricted to node: High-resolution mapping and disthe study of electrical activation in thin, section of the triangle of Koch in isolated, 2-dimensional cell layers. Wu et al.32 perperfused canine hearts. Circulation 1999; 100:1346-1353. formed optical mapping of AV nodal con6. De Bakker JMT, Loh P, Hocini M, et al. duction and reentry in a perfused canine Double potentials in the posterior approach heart preparation, and suggested that the to the AV node: Do they reflect activation inferior AV nodal extension might be the in the slow pathway? J Am Coll Cardiol anatomical substrate of the slow path1999;34:570-577. 7. Tawara S. The Conduction System in way and that unidirectional block occurs the Mammalian Heart—AnAnatomicoat the interface between the AV node and Histological Study of the Atrioventricular the connecting atrial tissue. Bundle and the Purkinje Fibers (transIn our laboratory, we succeeded in lated by K. Suma and M. Shimada). mapping AV nodal potentials after careful London: Imperial College Press; 2000. 8. Anderson RH, Becker AE, Brechenmacher resection of the overlying atrial endoC, et al. The human atrioventricular junccardium.59 Programmed electrical stimutional area: A morphological study of the lation before and after endocardial resection A-V node and bundle. Eur J Cardiol showed that the resection did not change 1975;3:ll-25. the functional characteristics of the AV 9. McGuire MA, De Bakker JMT, Vermeulen JT, et al. Atrioventricular junctional node. First results after high-resolution tissue: Discrepancy between histological mapping of AV nodal activation during and electrophysiological characteristics. ventricular and atrial echoes and histoCirculation 1996;94: 571-577. logical correlation suggested that tissue 10. Inoue S, Becker AE. Posterior extensions architecture and the contact zones between of the human compact atrioventricular node: A neglected anatomic feature of atrial, transitional, and compact nodal

MAPPING OF AV NODE IN THE EXPERIMENTAL SETTING potential clinical significance. Circulation 1998;97:188-193. 11. Mazgalev TN, Ho SY, Anderson RH. Anatomic-electrophysiological correlations concerning the pathways for atrioventricular conduction. Circulation 2001;103: 2660-2667. 12. Medkour D, Becker AE, Khalife K, Billette J. Anatomic and functional characteristics of a slow posterior AV nodal pathway: Role in dual-pathway physiology and reentry. Circulation 1998;98:164-174. 13. Tawara S. Das Reizleitungssystem des Herzens. Jena: Gustav Fischer; 1906. 14. Ho SY, Kilpatrick L, Kanai T, et al. The architecture of the atrioventricular conduction axis in dog compared to man: Its significance to ablation of the atrioventricular nodal approaches. J Cardiovasc Electrophysiol 1995;6:26-39. 15. Becker AE, Anderson RH. Morphology of the human atrioventricular junctional area. In: Wellens HJJ, Lie KI, Janse MJ (eds): The Conduction System of the HeartStructure, Function and Clinical Implications. Philadelphia: Lea and Febiger; 1976:263-286. 16. Janse MJ, van Capelle FJL, Anderson RH, et al. Electrophysiology and structure of the atrioventricular node of the isolated rabbit heart. In: Wellens HJJ, Lie KI, Janse MJ (eds): The Conduction System of the Heart: Structure, Function and Clinical Implications. Philadelphia: Lea and Febiger; 1976:296-315. 17. Zipes DP, Mendez C, Moe GK. Evidence for summation and voltage dependency in rabbit atrioventricular nodal fibers. Circ Res 1973;32:170-177. 18. Kleber A, Kucera JP, Rohr S. Principles of slow and discontinuous conduction: Experimental observations. In: Mazgalev TN, Tchou PJ (eds): Atrial-AVNodal Electrophysiology: A View from the Millennium. Armonk, NY: Futura Publishing Co.; 2000:73-88 19. van Kempen MJA, Fromaget C, Gros D, et al. Spatial distribution of connexin-43, the major gap-junction protein, in the developing and adult rat heart. Circ Res 1991;68:1638-1651. 20. Rohr S. Determination of impulse conduction characteristics at a microscopic scale in patterned growth heart cell cultures using multiple site optical recording of transmembrane voltage. J Cardiovasc Electrophysiol 1995;6:551-568.

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21. Maglaveras N, De Bakker JMT, van Capelle FJL, et al. Activation delay in healed myocardial infarction: A comparison between model and experiment. Am J Physiol 1995;38(4 Pt 2):H1441-H1449. 22. Cabo C, Pertsov AM, Baxter WT, et al. Wave-front curvature as a cause of slow conduction and block in isolated cardiac muscle. Circ Res 1994;75:1014-1028. 23. Jalife J. The sucrose gap preparation as a model of AV nodal transmission: Are dual pathways necessary for reciprocation and AV nodal "echoes"? Pacing Clin Electrophysiol 1983;6:1106-1122. 24. van Capelle FJL, Janse MJ. Influence of geometry on the shape of the propagated action potential. In: Wellens HJJ, Lie KI, Janse MJ (eds): The Conduction System of the Heart: Structure, Function and Clinical Implications. The Hague: Martinus Nijhoff Medical Division; 1978:316-335. 25. linuma H, Dreifus LS, Mazgalev T, et al. Role of the perinodal region in atrioventricular nodal reentry: Evidence in an isolated rabbit heart preparation. J Am Coll Cardiol 1983;2:465-473. 26. Sung RJ, Waxman HL, Saksena S, Juma Z. Sequence of retrograde atrial activation in patients with dual atrioventricular nodal pathways. Circulation 1981;64: 1059-1067. 27. Jackman WM, Beckman KJ, McClelland JH, et al. Treatment of supraventricular tachycardia due to atrioventricular nodal reentry by radiofrequency catheter ablation of slow-pathway conduction. N Engl JMed 1992;327:313-318. 28. Josephson ME, Miller JM. Atrioventricular nodal reentry: Evidence supporting an intranodal location. Pacing Clin Electrophysiol 1993;16:599-614. 29. Janse MJ, Anderson RH, McGuire MA, Ho SY. AV nodal' reentry: Part I: AV nodal' reentry revisited. J Cardiovasc Electrophysiol 1993;4:561-572. 30. McGuire MA, Janse MJ, Ross DL. AV nodal' reentry: Part II: AV nodal, AV junctional, or atrionodal reentry? J Cardiovasc Electrophysiol 1993;4:573-586. 31. Patterson E, Scherlag BJ. Longitudinal dissociation within the posterior AV nodal input of the rabbit: A substrate for AV nodal reentry. Circulation 1999;99:143155. 32. Wu J, Wu J, Olgin J, et al. Mechanisms underlying the re-entrant circuit of atrioventricular nodal re-entrant tachycardia

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in isolated canine atrioventricular nodal preparation using optical mapping. Circ Res 2001;88:1189-1195. 33. Yamabe H, Shimasaki Y, Honda 0, et al. Demonstration of the exact anatomic tachycardia circuit in the fast-slow form of atrioventricular nodal reentry tachycardia. Circulation 2001; 104:1268-1273. 34. Nikolski V, Efimov IR. Fluorescent imaging of a dual-pathway atrioventricularnodal conduction system. Circ Res 2001; 88:e23-e30. 35. Spach MS, Josephson ME. Initiating reentry: The role of nonuniform anisotropy in small circuits. J Cardiovasc Electrophysiol 1994;5:182-209. 36. Spach MS, Miller WT III, Geselowitz DB, et al. The discontinuous nature of propagation in normal canine cardiac muscle: Evidence for recurrent discontinuities of intracellular resistance that affect the membrane currents. Circ Res 1981;48: 39-54. 37. Spach MS, Dolber PC, Heidlage JF, et al. Propagating depolarization in anisotropic human and canine cardiac muscle: Apparent directional differences in membrane capacitance. Circ Res 1987;60:206-219. 38. Spach MS, Miller WT III, Dolber PC, et al. The functional role of structural complexities in the propagation of depolarization in the atrium of the dog: Cardiac conduction disturbances due to discontinuities of effective axial resistivity. Circ Res 1982;50:175-191. 39. Roberts DE, Hersh LT, Scher AM. Influence of cardiac fiber orientation on wavefront voltage, conduction velocity and tissue resistivity in the dog. Circ Res 1979;44:701-712. 40. Wit AL, Dillon S, Ursell PC. Influences of anisotropic tissue structure on reentrant ventricular tachycardia. In: Brugada P, Wellens HJJ (eds): Cardiac Arrhythmias: Where To Go From Here? Mount Kisco, NY: Futura Publishing Co.; 1987:27-50. 41. McGuire MA, De Bakker JMT, Vermeulen JT, et al. Origin and significance of double potentials near the atrioventricular node: Correlation of extracellular potentials, intracellular potentials, and histology. Circulation 1994;89:2351-2360. 42. Veenstra RD, Joyner RW, Rawling DA. Purkinje and ventricular activation sequences of canine papillary muscle. Effects of quinidine and calcium on the

Purkinje-ventricular conduction delay. Circ Res 1984;54:500-515. 43. Lack W, Lang S, Brand G. Necrotizing effect of phenol on normal tissues and on tumors. A study on postoperative and cadaver specimens. Acta Orthop Scand 1994;65:351-354. 44. Spach MS, Dolber PC, Heidlage JF. Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle: A model of reentry based on anisotropic discontinuous propagation. Circ Res 1986;62:811-832. 45. Truex RC, Smythe MQ. Comparative morphology of the cardiac conduction tissue in mammals. Ann NY Acad Sci 1965;127: 19-33. 46. McGuire MA, Robotin M, Yip ASB, et al. Electrophysiologic and histologic effects of dissection of the connections between the atrium and posterior part of the atrioventricular node. J Am Coll Cardiol 1994;23:693-701. 47. McGuire MA, Bourke JP, Robotin MC, et al. High resolution mapping of Koch's triangle using sixty electrodes in humans with atrioventricular junctional (AV nodal) reentrant tachycardia. Circulation 1993;88:2315-2328. 48. Denes P, Wu D, Dhingra R, et al. Dual atrioventricular nodal pathways: A common electrophysiological response. Br Heart J 1975;37:1069-1076. 49. Moe GK, Preston JB, Burlington H. Physiological evidence for a dual A-V transmission system. Circ Res 1956;4:357— 375. 50. Schuilenburg RM, Durrer D. Further observations on the ventricular echo phenomenon elicited in the human heart: Is the atrium part of the echo pathway? Circulation 1972;45:629-638. 51. Sheahan RG, Klein GJ, Yee R, et al. Atrioventricular node reentry with 'smooth' AV node function curves: A different arrhythmia substrate? Circulation 1996;93:969-972. 52. Goldreyer BN, Damato AN. The essential role of atrioventricular conduction delay in the initiation of paroxysmal supraventricular tachycardia. Circulation 1971;43: 679-687. 53. Mendez C, Moe GK. Demonstration of a dual A-V nodal conduction system in the isolated rabbit heart. Circ Res 1966;19:378-393. 54. Haissaguerre M, Gaita F, Fischer B, et al. Elimination of atrioventricular nodal reentrant

MAPPING OF AV NODE IN THE EXPERIMENTAL SETTING tachycardia using discrete slow potentials to guide application of radiofrequency energy. Circulation 1992;85:2162-2175. 55. Keim S, Werner P, Jazayeri M, et al. Localization of the fast and slow pathways in atrioventricular nodal reentrant tachycardia by intraoperative ice mapping. Circulation 1992;86:919-925. 56. Sanchez-Quintana D, Davies W, Ho SY, et al. Architecture of the atrial musculature in and around the triangle of Koch: Its potential relevance to atrioventricular nodal reentry. J Cardiovasc Electrophysiol 1997;8:1396-1407.

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57. Wittkampf FHM, Simmers TA, Hauer RNW, et al. Myocardial temperature response during radiofrequency catheter ablation. Pacing Clin Electrophysiol 1995; 18: 307-317. 58. Scherlag BJ, Patterson E, Nakagawa H, et al. Changing concepts of A-V nodal conduction: Basic and clinical correlates. Primary Cardiol 1995;21:13-21. 59. Loh P, de Bakker JM, Borggrefe M, Janse MJ. High resolution mapping of reentrant activation in the AV node during ventricular echoes. Circulation 1999;100(Suppl): 4412. Abstract.

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Part 4 nONINVASIVE Methods

of Cardiac Mapping

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Chapter 21 Mapping of Atrial Arrhythmias: Role of P Wave Morphology Arne SippensGroenewegen, MD, PhD, Franz X. Roithinger, MD, and Michael D. Lesh, MD

Introduction The pioneering experimental work by Lewis in the early days of clinical electrocardiography provided the fundamental basis for the paradigm that the morphology of the P wave on the surface ECG is uniquely related to the location of the underlying focal origin.1 Observations during canine and human atrial flutter by the same author and his co-workers have initiated our understanding of the mechanism of this arrhythmia and the genesis of the flutter wave on the torso surface.2,3 Many scientists have subsequently studied the value of the surface ECG to localize ectopic atrial rhythms or to characterize reentrant atrial activity, particularly after the introduction of programmed stimulation, direct intracardiac mapping, and radiofrequency catheter ablation. Fueled by the ongoing evolution in the electrophysiological study and ablation of atrial arrhythmias, it seems timely to reassess

the clinical role of the surface ECG and to consider the development of novel methods to improve its noninvasive diagnostic performance. This chapter features a historic overview of the clinical electrocardiography in this field and presents newly developed ECG applications that are aimed at providing a higher spatial resolution to localize focal atrial activity, obtaining more reliable classification of atrial flutter, and improving characterization of atrial fibrillation. The Surface ECG of Ectopic Focal Atrial Activity Early investigations using atrial pacing in humans to study the variations in scalar morphology and vector loop of the P wave with varying sites of focal origin were primarily geared toward the differentiation of left-sided rhythms from right-sided rhythms.4–6 Despite several

This study was supported in part by the Royal Netherlands Academy of Arts and Sciences, the National Institutes of Health (HL09602-01), and the Fonds zur Foerderung der Wissenschaftlichen Forschung, Vienna, Austria. From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; ®2003.

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attempts to develop a set of morphological ECG criteria specific to a left-sided origin of an ectopic atrial rhythm, different algorithms were proposed and consensus appeared difficult to attain. Mirowski7 initially suggested that a negative P wave polarity in lead I and a "dart and dome" configuration in V1 was related to a leftsided origin, and later added that a negative P wave in V6 was more specific particularly when the aforementioned features were absent. Although these findings were partly underlined by others,6 Harris et al.5 contested the importance of P wave inversion in leads I and V6 for a left-sided rhythm and alternatively proposed that a terminally positive P wave in V1 was a more specific finding for a left atrial origin. Conversely, Massumi and Tawakkol4 noted a profound variability in P wave morphology when stimulating from similar left atrial sites in different patients, and did not believe that distinct ECG criteria specific to areas of ectopic impulse formation could be developed. Using temporarily implanted pacing wires following cardiac surgery, Maclean et al.8 subsequently performed a comprehensive study in 69 patients by stimulating both atria at a total of 12 epicardial regions. Overall, the results of this study were disappointing in that only a few specific correlations between P wave morphology and site of origin could be made: (1) a negative P wave in the inferior leads with pacing of the inferior regions in either atrium; (2) a negative P wave in lead I with left atrial pacing near the left pulmonary veins; and (3) a positive bifid P wave in V1 with pacing near the lower pulmonary veins and coronary sinus. Therefore, these investigators, and more recently others using contemporary multisite endocardial catheter pace mapping techniques,9 underlined the complexity of visual analysis of the lowvoltage P wave and concluded that the 12-lead ECG was of limited clinical value in localizing ectopic atrial foci.

The successful treatment of focal atrial tachycardia using catheter ablation has resulted in a renewed interest in the design of ECG algorithms capable of regionalizing the arrhythmia origin prior to invasive catheter mapping.10,11 Tang et al.10 showed that the P wave morphology in aVL and V1 allows separation of left from right atrial tachycardia foci while the P wave polarity in the inferior leads enables discrimination of tachycardias with an inferior or superior origin. Using the polarity of the P wave in aVR, Tada and collegues11 were able to distinguish atrial tachycardias arising from the terminal crest from those originating from the tricuspid annulus. In accordance to the findings of Tang et al.,10 they found that right atrial tachycardias with an inferior or superior origin could be discriminated by the P wave polarity in the inferior leads. They additionally found that inferior right-sided tachycardias could be further separated into a medial or lateral origin based on the P wave polarity in V5 and V6. There have also been attempts to localize the atrial insertion site of an accessory pathway during orthodromic atrioventricular (AV) reentrant tachycardia.12–14 Farshidi et al.12 initially demonstrated that a negative retrograde P wave in lead I was associated with a left-sided atrial insertion of the accessory pathway. Garcia Civera et al.13 were able to separate free wall accessory pathway locations in the left atrium and right atrium using the retrograde P wave polarity in leads I and V1. Other investigators later studied the localization resolution of the 12-lead ECG for this particular application by confining pace mapping to the annular regions of the left atrium and right atrium.15,16 However, despite a more directed pace mapping approach, the paced P wave morphology only allowed a gross separation of pacing sites in terms of a left- versus right-sided

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origin, an inferior origin in either atrium, performing ECG signal analysis.26–28 In or an origin in the right free wall. In con- our opinion, these features of the surface trast, Tai et al.14 recently reported that mapping technique are of paramount the polarity of the retrograde P wave in importance to increase the resolving power leads I, II, III, aVF, and V1 obtained of the surface ECG in localizing ectopic during AV reentrant tachycardia allows atrial activation. accessory pathway localization to 9 possiTo assess the localization perforble annular regions with an overall accu- mance of ECG mapping in discriminatracy of 88% provided a clearly visible P ing various sites of right atrial ectopic wave could be discriminated. It must be impulse formation, we performed endocarrealized with this application of the sur- dial pace mapping in 9 patients with echoface ECG that visual analysis of the low- cardiographically demonstrated normal voltage retrograde P wave is frequently biatrial anatomy.20 Body surface maphampered by the simultaneous occur- ping was carried out using a 62-lead rence of the preceding cardiac cycle's high- radiotransparent electrode array during voltage T-U wave. bipolar pacing with a roving catheter at Triggered by the limited clinical util- a total of 86 widely distributed endocarity of the 12-lead ECG in localizing dial sites. Pacing was executed at a slow ectopic atrial rhythms, there have been a rate to ensure adequate separation of few experimental17,18 and some more the P wave and the preceding T-U wave. recent clinical reports19–22 on the use of Integral maps of the excitation component multiple surface ECG lead mapping to of the P wave were computed for each obtain improved spatial resolution in dis- paced sequence (Figure 1). The pacing site criminating focal atrial activity. These location was carefully documented using studies were carried out based on the biplane fluoroscopic imaging and right notion that ECG sampling over the entire atrial angiography. This information was torso surface provides a more compre- used to compute the 3-dimensional locahensive electrocardiographic blueprint tion of each pacing site relative to anaof the cardiac electrical activity and its tomical fiducial points, and to extrapolate distribution on the chest.23–25 An instan- the location of each pacing site to an endotaneous or time-interval—related presen- cardial diagram of the right atrium. 29 tation of the entire set of electrical All 86 paced P wave integral maps information on the body surface offers showed a dipolar voltage distribution and the unique advantage over lead-by-lead were visually grouped into 17 subsets scalar ECG interpretation that informa- with nearly identical map patterns. tion obtained at all electrode sites can be Spatial map pattern analysis used prejudged simultaneously. This presentation viously reported concepts, which include approach not only enables one to appre- an assessment of the position and ciate the intricate spatial voltage rela- mutual orientation of the extremes and tionships between the various electrode the zero line contour.30,31 Subset selecsites but also allows a more intuitive and tion was statistically supported by condirect interpretation of the signals in firming an adequate level of intragroup terms of the underlying cardiac source. pattern correspondence and intergroup Furthermore, the use of surface mapping pattern variability. After a mean P wave techniques allows application of inverse integral map was computed for every modeling to compute the location of subset of paced P wave integral maps, ectopic activation and, thus, provide a the stimulus sites corresponding to each more accurate mathematical means of subset were indicated as segments in

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CARDIAC MAPPING Figure 1. A. Torso anatomy with superimposed location of the 62 lead sites, which include standard precordial leads V1 to V6. Electrodes are applied as 14 vertical straps on the chest surface and secured in place using double adhesive tape. B. P wave integral map obtained in a 54year-old male patient during pacing at the middle lateral wall of the right atrium using a stimulation cycle length of 700 ms. The integral map was computed over the excitation component of the P wave (duration of 106 ms), which is depicted by the shaded gray area between the 2 vertical bars in the scalar V1 tracing below the map. Note the discrete stimulus artifact prior to the P wave onset in the ECG tracing. The 2-dimensional map format relates to a 3-dimensional representation of the chest as a cylinder that is cut open at the level of the right posterior axillary line. The schematic locations of the sternum (left) and spine (right) are shown at the top of the map. Positive, negative, and zero isointegral lines are indicated by solid (shaded gray area), dashed, and dotted lines, respectively. The scaling between isointegral lines varies linearly according to the absolute magnitude of each positive or negative voltage distribution. The spatial position and amplitude of the maximum and minimum are shown within (plus and minus sign) and below the map, respectively. Notice that this particular paced P wave integral map displays leftward directed electromotive forces consequent to the right atrial origin of activation onset.

the anatomical diagram of the right atrium. Figure 2 demonstrates the complete atlas of 17 mean paced P wave integral maps (panel A) together with the location of the right atrial endocardial segments at which pacing was performed (panel B). It may be noted that quite apparent as well as more subtle spatial differences exist between the various mean P wave integral map patterns. For instance, pacing at superior (segments 2 to 5) versus distant inferior (segments 13 to 15) locations in the right atrium results in maps with diametrically opposed voltage patterns. Also, stimulation at adjacent segments in the lower regions of the posterior (segment 10), lateral (segment 11), and inferior (segment 12) right atrium produces clear pattern differences that feature a major

spatial shift in P wave forces. Conversely, subtle differences in zero line contour and extreme orientation with fairly comparable extreme locations may be observed with pacing at segments in the superior vena cava (segments 2 and 3) and sinus node region (segment 4). Using the quantitative fluoroscopic technique to assess the 3-dimensional stimulus site location, we approximated the spatial resolution of body surface mapping to discriminate right atrial ectopic impulse formation. This resulted in a mean right atrial segment size of 3.5 ± 2.9 cm2. In a preliminary clinical study, Kawano and Hiraoka19 showed that endocardial pacing at 1 right (low) and 3 left (low, middle, and high) atrial locations produced characteristic P wave body surface potential map patterns. The map pattern that they obtained

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Image Not Available

Figure 2. Atlas of 17 different mean paced P wave integral maps (A) shown in combination with the endocardial locations of the associated segments of ectopic impulse formation indicated in a schematic diagram of the right atrium (B). Maps are depicted without isointegral lines to delineate the discriminating spatial map parameters, i.e., location of maximum (plus sign) and minimum (minus sign), mutual orientation of maximum and minimum, and zero line contour (solid lines).30,31 The encircled numbers relate each map to its corresponding endocardial segment. The endocardial diagram features an anteroposterior (AP) and posteroanterior (PA) view of the right atrial endocardium and includes the major anatomical structures: superior (SVC) and inferior (IVC) vena cava; right atrial appendage (RAA); smooth (SRA) and trabeculated (TRA) right atrium; crista terminalis (CT); fossa ovalis (FO); eustachian valve (EV); coronary sinus os (CSO); tricuspid valve (TV); left atrium (LA); aorta; and right (RPA) and left (LPA) pulmonary arteries. See to text for discussion. Reproduced from reference 20, with permission.

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during low right atrial stimulation compares favorably with the mean P wave integral map pattern that we noted during pacing at the inferior wall of the right atrium in the subeustachian isthmus (segment 12) (Figure 2). Initial results of the clinical application of the atlas of 17 mean paced P wave integral maps to localize right atrial tachycardia were obtained in 8 patients who underwent catheter activation sequence mapping and subsequent radiofrequency ablation of their ectopic focus.22 Compared to activation mapping, body surface mapping was able to predict the correct or an adjacent segment of origin in 5 of 8 and 3 of 8 tachycardias, respectively. Figure 3 includes an example of a right atrial tachycardia that was correctly localized to the medial part of the subeustachian isthmus close to the coronary sinus os (segment 13) using the atlas of 17 mean paced P wave integral maps. These preliminary data demonstrate that a spatial presentation of the P wave morphology using ECG mapping techniques allows discrete localization of right atrial tachycardia foci and may be useful in targeting invasive mapping prior to ablative interventions. At present, however, we are not able to report on the ability of body surface mapping to discriminate right-sided ectopic atrial rhythms from left-sided ectopic atrial rhythms. The limited role of the standard 12lead ECG in distinguishing right atrial from left atrial focal activity has already been reported using pace mapping techniques8,9 and also, more recently, during ablation of atrial tachycardia guided by intracardiac echocardiography.32 Kalman et al.32 reported that the P wave morphology on the 12-lead ECG of tachycardias arising from the upper part of the crista terminalis in the right atrium or from the right upper pulmonary vein in

the left atrium demonstrate considerable overlap because of the anatomical proximity of both structures. However, Tang et al.10 suggested previously that a change in P wave morphology in lead V1 from biphasic during sinus rhythm to completely positive during tachycardia would be helpful in discriminating foci arising from the superior portion of the crista terminalis and the right upper pulmonary vein. The latter finding was found to be predictive for right upper pulmonary vein tachycardia foci even when lead aVL would demonstrate a positive instead of a negative P wave. Figure 4 displays 12lead ECG recordings obtained during sinus rhythm (panel A) and atrial tachycardia with a focal origin at the right upper pulmonary vein (panel B). Although lead aVL displays a negative P wave during atrial tachycardia indicative of a left-sided origin, one may note that the morphology of the P wave in lead V1 remains biphasic during both sinus rhythm and atrial tachycardia and, thus, is not helpful in providing additional evidence to support a focal origin in the right upper pulmonary vein. Nevertheless, it should also be stated that analysis of the P wave morphology on the 12-lead ECG does not always lead to a disputable result and can indeed be clinically helpful in providing a global impression of the origin of ectopic atrial activity. For instance, panel A of Figure 5 is a 12-lead ECG recording of an atrial premature beat with an endocardial origin at the middle section of the crista terminalis. The positive P wave in lead aVL and negative P wave in lead Vl that are noted in this recording are features compatible with a right-sided focal origin.10 Also, the negative P wave in aVR is found to be consistent with an origin at the crista terminalis.11 Panel B of Figure 5 displays the 12-lead ECG of an atrial premature beat where the focal activity was found to arise from the left upper

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Figure 3. P wave integral map (A) and 12-lead ECG (B) obtained during atrial tachycardia (cycle length 590 ms) in a 43-year-old male patient who did not have any concomitant structural cardiac disease. The schematic diagram of the right atrial endocardium (C) features the focal tachycardia origin, which was determined by catheter activation sequence mapping (CM) and was found to be situated just inferior to the coronary sinus os in the medial part of the subeustachian isthmus. See legend of Figure 2 for explanation of abbreviations. Correlation of the atrial tachycardia P wave integral map (see legend of Figure 1 for further explanation) with the atlas of 17 mean paced P wave integral maps (Figure 2) revealed that the paced map pattern obtained at segment 13, also located at the inferior border of the coronary sinus os, demonstrated the best morphological match. Note the negative P wave polarity in the inferior leads of the 12-lead ECG corresponding with an inferior atrial origin of the tachycardia focus. See text for further discussion.

pulmonary vein. In this example, the P wave appears negative in aVL and positive in V1—criteria indicative of a left-sided origin.10 It may also be appreciated that the positive P wave in V1 contains a distinct

M-shaped pattern; we have found this morphological feature to be specific for a focal origin at the left upper pulmonary vein provided the polarity of the P waves in the inferior leads is also positive.

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Figure 4. Twelve-lead ECG recordings acquired during sinus rhythm (A) and atrial tachycardia (cycle length 410 ms) (B) in a 42-year-old female patient with no structural heart disease. The tachycardia was localized using catheter activation sequence mapping and was found to arise from the right upper pulmonary vein. Note that the atrial tachycardia is associated with 2:1 atrioventricular conduction resulting in both an obscured and unobscured P wave. See text for further discussion.

In a preliminary attempt to study the resolving power of ECG mapping in localizing left atrial ectopic activity, we performed trans-septal pace mapping of the left atrium and observed a mean of

5.0 ± 1.4 P wave integral map patterns per patient after pacing at up to 7 different endocardial locations.21 Figure 6 comprises 3 P wave integral maps that were produced during pacing at the left atrial

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Figure 5. Standard 12-lead ECG tracings of 2 different spontaneous atrial premature beats where activation mapping by catheter identified a focal origin at the middle part of the crista terminalis in a 29-year-old male patient (A) and at the os of the left upper pulmonary vein in a 33-year-old female patient (B). Both patients did not have any associated organic heart disease. See text for further discussion.

appendage (panel A), the lateral mitral annulus (panel B), and the posterior mitral annulus close to the septum (panel C). It may be appreciated that the first 2 map patterns (panels A and B) are clearly

different from any of the 17 right-sided mean paced P wave integral maps shown in Figure 2. The map pattern displayed in panel C, however, does demonstrate features comparable to the mean P wave

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Figure 6. Three distinct P wave integral maps obtained during trans-septal left atrial pacing in a 39-year-old female patient who underwent ablation of a left anterolateral accessory pathway. See legend of Figure 1 for further explanation. Bipolar pacing (cycle length 650 ms) was performed with a roving catheter positioned in a stable location at the left atrial appendage (A), the lateral mitral annulus (B), and the posterior mitral annulus close to the septum (C). One may notice the profound morphological differences between these 3 map patterns. See text for further discussion.

integral map produced at an opposing atrial rhythms as well as its spatial reslocation in the right atrium (i.e., segment olution in the left atrium will have to 15 situated at the low right atrial septum) await the results of ongoing and future (Figure 2). Similar findings with regard investigations. to the spatial correspondence of QRS integral maps were previously noted during The Surface ECG of Typical pace mapping at spatially opposed locations in the left and right ventricular Atrial Flutter septum.30 Although the aforementioned results clearly underscore the potential The first ECG recording of human utility of body surface P wave integral atrial flutter was reported more than 90 mapping in providing detailed nonin- years ago by Jolly and Ritchie,33 who used vasive localization of ectopic right atrial the Cambridge model of Einthoven's foci, its clinical performance in separat- string galvanometer. This was followed ing left-sided from right-sided ectopic by a series of clinical and experimental

MAPPING OF ATRIAL ARRHYTHMIAS 439 publications by Lewis et al.,2,3,34 who described the uniform configuration and continuous nature of the classic counterclockwise "sawtooth" flutter wave pattern in leads II and III at rate of 260 to 335 beat per minute. Based on experimental extrapolations, these authors attributed the electrocardiographic flutter wave pattern to a wavefront rotating around the superior and inferior caval veins. Furthermore, they suggested that the main upstroke or positive deflection in lead II was caused by craniocaudal propagation of the impulse along the right atrial free wall. Kato et al.35 performed a similar comparison of the human lead II recording of counterclockwise atrial flutter with canine endocardial and esophageal mapping data obtained during experimental atrial flutter, and showed that the negative deflection of the flutter wave in lead II coincided with caudocranial activation of the left atrium. Subsequently, in 1970, Puech et al.36 reported the clinical results of endocardial and esophageal recordings by catheter combined with complete 12lead ECG tracings that were obtained during common or counterclockwise typical atrial flutter. These authors demonstrated the distinct surface morphology of counterclockwise typical flutter with predominantly negative flutter waves in the inferior leads and V6 in conjunction with a predominantly positive flutter wave in V1.They showed that the positive part of the flutter wave in the inferior leads was indeed associated with craniocaudal impulse propagation along the right atrial free wall, while the negative part of the flutter wave was found to relate to caudocranial impulse conduction along the right atrial septum and left atrium. More recent multisite catheter mapping and entrainment studies have shown that the aforementioned characteristic 12-lead ECG pattern is caused by macroreentrant counterclockwise wavefront propagation around the tricuspid annulus of

the right atrium in a circuit that is confined by natural anatomical barriers.37–46 This right atrial reentrant circuit has also been demonstrated to be capable of impulse propagation in a reverse clockwise direction giving rise to a 12-lead ECG pattern that has led to more ambiguous opinions with regard to its particular appearance. Cosio et al.37,40 reported that clockwise typical atrial flutter was characterized by positive deflections in the inferior leads. Kalman et al.46 also noted the presence of predominantly positive deflections in the inferior leads, but additionally demonstrated that these positive deflections were preceded by a negative deflection of variable magnitude. Additionally, they mentioned that a positive deflection in V6 was a highly specific marker to distinguish clockwise from counterclockwise flutter. Conversely, Saoudi et al.42 noted a high incidence of the sawtooth pattern in the inferior leads during clockwise flutter albeit that the negative deflection was lower in magnitude than during counterclockwise flutter. Thus, these authors concluded that a short plateau phase and a wide negative component in the inferior leads, as well as a negative flutter wave in V1, were more specific in characterizing clockwise flutter wave rotation. Figure 7 features the 12-lead ECG, leads II and aVF with a set of right atrial endocardial electrograms, and the presumed anatomical location of the reentrant circuit of counterclockwise, clockwise, and atypical atrial flutter obtained in the same patient.41 Correlation of the deflections in the inferior leads of the surface ECG and the intracardiac activation sequence during counterclockwise flutter (panel A) confirms the aforementioned findings described in the original report by Puech et al.36 With clockwise flutter, it may be observed that the predominantly positive flutter wave component is caused by craniocaudal activation of the right atrial septum, while the negative flutter

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Image Not Available

Figure 7. Recordings of the 12-lead ECG, leads II and aVF (at higher gain and paper speed) with bipolar endocardial electrograms obtained around the atrial circumference of the tricuspid annulus (TA) and coronary sinus (CS) os of counterclockwise (A) and clockwise (B) typical atrial flutter as well as atypical atrial flutter (C) obtained in a 65-year-old male patient. Each panel also features the anatomical location of the macroreentrant circuit shown in a schematic diagram of the exposed right atrial endocardium previously reported by Anderson and Becker.47 See legend of Figure 2 for explanation of abbreviations. The endocardial electrograms are ordered according to their locations respective to the left anterior oblique fluoroscopic view (2:00 and 7:00 refer to a position at the high right atrial septum and inferior right posterolateral atrium, respectively). See text for discussion. Reproduced from reference 41, with permission.

wave component is the result of caudocranial activation of the right atrial free wall (panel B). The atypical flutter shown in panel C, on the other hand, demonstrates an intracardiac right atrial free wall activation sequence compatible with counterclockwise wavefront rotation around the tricuspid annulus in combination with a "clockwise appearance" of the surface ECG featuring predominantly positive flutter waves in the inferior leads.

One may also appreciate from Figure 7 that visual assessment of the low-voltage flutter waves on the scalar 12-lead ECG is not a trivial matter, particularly when standard gain settings and paper speeds are used. The lack of a clear isoelectric interval in a continuously undulating signal impedes evaluation of the polarity of the individual flutter wave components.37,44 Also, the flutter waves may be partly or completely obscured by the QRST segment when a low degree of AV

MAPPING OF ATRIAL ARRHYTHMIAS block is present (Figure 7, panels A and B)42 or when there is significant QRST prolongation because of antiarrhythmic drug use with or without associated abnormalities in ventricular conduction. Saoudi et al.42 also noted that clockwise atrial flutter may not be recognized and considered for ablative therapy due to a 12-lead ECG pattern that is not "close to classic." In addition, Kalman et al.46 mentioned that the surface ECG morphology of atypical or non-isthmusdependent flutter may resemble the morphology of counterclockwise or clockwise typical atrial flutter, particularly when visual ECG analysis is restricted to the inferior leads only. These authors emphasized the importance of including both activation and entrainment mapping data to obtain a reliable distinction between these 2 forms of flutter. These factors clearly limit the role of the 12lead ECG to classify the various types of clinical atrial flutter, and should be taken into consideration when corroborative invasive mapping procedures are not available. In a recent study, we used 62-lead ECG mapping to study the temporal changes in the spatial surface map pattern of typical atrial flutter and develop improved electrocardiographic criteria to classify the 2 directions of flutter wave rotation.48 Body surface mapping and simultaneous multisite endocardial catheter mapping were performed during 17 counterclockwise and 7 clockwise flutter wave episodes in 20 patients with or without associated structural cardiac abnormalities. Adenosine was delivered intravenously when a low degree of AV block ( yellow), and finally turn transverse to fibers again (red region). As the wavefront pivots conduction slows (i.e., crowding of isochrones) paradoxically as propagation turns parallel to fibers. Action potential upstrokes recorded from 5 evenly spaced sites around the pivot point are shown to the right. While the wavefront enters the pivot point (A,B) conduction is relatively fast and upstrokes are sharp. However, as the wavefront pivots (C,D) action potential upstrokes become increasingly slowed. After pivoting is complete (E), conduction and action potential upstroke velocity are again normal. See color appendix. Reprinted from Girouard et al. Circulation •\996;93:6Q3-6J\3.

normal propagation (i.e., the sink). Other experimental67'68 and theoretical69 studies have supported this finding. Summary Using high-resolution optical action potential mapping with voltage-sensitive dye, we have demonstrated how systematic, beat-to-beat changes in the spatial and temporal dynamics of ventricular repolarization influence the initiation and maintenance of reentrant arrhythmias. Due to limitations of conventional electrophysiological recording techniques, the influence such heterogeneities of repolarization have on arrhythmia vulnerability in the intact heart has not been well appreciated. We demonstrated that because

of spatial heterogeneities in electrical properties between cells, during premature stimulation repolarization gradients are modulated in a systematic and predictable manner that is highly dependent on premature coupling interval. Importantly, such changes critically influence the substrate for unidirectional block and reentry. Thus, a premature stimulus serves not only as a "trigger" of arrhythmias, but also importantly modulates the electrophysiological substrate for reentry. Spatial heterogeneities of repolarization also appear to play a critical role in the development of arrhythmogenic substrates during repolarization alternans. Heterogeneous ion channel function, as manifest by regional variation in cellular restitution properties, produces a situation in which cellular repolarization within separate regions

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of myocardium alternates with differing amplitude and phase. Regional differences in the phase of alternans (i.e., discordant alternans) produce critical gradients of repolarization that form a suitable substrate for unidirectional block, leading to the initiation of VF. Equally important are changes in the electrophysiological substrate that occur during reentry, as they determine the ultimate stability of the arrhythmia. Using optical mapping to directly measure dynamic changes in wavelength at any point in time, we were able to demonstrate heterogeneity of wavelength within a single reentrant beat. Moreover, high-resolution optical action potential recordings at the pivot points suggest that the underlying mechanism of wavelength heterogeneity is related to conduction slowing associated with wavefront curvature. These findings demonstrate the complexity of arrhythmogenic substrates and indicate that the electrophysiological substrate for reentry is not necessarily static but can potentially form, disappear, and reform in a predictable fashion during the initiation and maintenance of reentry. Obviously, the factors that determine dispersion of repolarization in the heart are dependent on the specific pathophysiological substrate involved. Further studies are required to increase our understanding of how heterogeneities of repolarization in the presence and absence of cardiac pathology influence the electrophysiological substrate for reentry. Undoubtedly, optical mapping will play an important role in these investigations. References 1. Allessie A, Bonke FI, Schopman FJG. Circus movement in rabbit atrial muscle as a mechanism of tachycardia: The role of nonuniform recovery of excitability in the occurrence of unidirectional block as studied with multiple microelectrodes. CircRes 1976;39:169-177.

2. Han J, Moe G. Nonuniform recovery of excitability in ventricular muscle. Circ Res 1964;14:44-60. 3. Gough W, Mehra R, Restivo M, et al. Reentrant ventricular arrhythmias in the late myocardial infarction period in the dog: 13. Correlation of activation and refractory maps. Circ Res 1985;57:432-442. 4. Allessie MA. Circus movement in rabbit atrial muscle as a mechanism of tachycardia. III. The "leading circle" concept: A new model of circus movement in cardiac tissue without the involvement of an anatomic obstacle. CircRes 1977;41:9-18. 5. Litovsky SH, Antzelevitch C. Transient outward current prominent in canine ventricular epicardium but not endocardium. CircRes 1988;62:116-126. 6. Furukawa T, Myerburg RJ, Furukawa N, et al. Differences in transient outward currents of feline endocardial and epicardial myocytes. CircRes 1990;67:1287-1291. 7. Fedida D, Giles WR. Regional variations in action potentials and transient outward current in myocytes isolated from rabbit left ventricle. J Physiol (Lond) 1991;442:191209. 8. Sicouri S, Antzelevitch C. A subpopulation of cells with unique electrophysiological properties in the deep subepicardium of the canine ventricle: The M cell. Circ Res 1991;68:1729-1741. 9. Drouin E, Charpentier F, Gauthier C, et al. Electrophysiologic characteristics of cells spanning the left ventricular wall of human heart: Evidence for presence of M cells. JAm Coll Cardiol 1995;26:185-192. 10. Sicouri S, Quist M, Antzelevitch C. Evidence for the presence of M cells in the guinea pig ventricle. J Cardiovasc Electrophysiol 1996;7:503-511. 11. Laurita KR, Girouard SD, Rosenbaum DS. Modulation of ventricular repolarization by a premature stimulus: Role of epicardial dispersion of repolarization kinetics demonstrated by optical mapping of the intact guinea pig heart. CircRes 1996;79:493-503. 12. Curran ME, Splawski I, Timothy KW, et al. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995;80:795-803. 13. Wang Q, Shen J, Splawski I, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995;80:805-811. 14. Spach MS, Dolber PC, Heidlage JF. Interaction of inhomogeneities of repolarization with anisotropic propagation in dog atria:

OPTICAL MAPPING OF REPOLARIZATION A mechanism for both preventing and initiating reentry. CircRes 1989;65:1612-1631. 15. Lammers WJEP, Wit AL, Allessie MA: Effects of anisotropy on functional reentrant circuits: Preliminary results of computer simulation studies. In: Sideman S, Beyar R, (eds): Activation, Metabolism, andPerfusion of the Heart: Simulation and Experimental Models. Zoetermeer, The Netherlands: Martinus Nijhoff; 1987:133-149. 16. Kuo C, Munakata K, Reddy CP, Surawicz B. Characteristics and possible mechanisms of ventricular arrhythmia dependent on the dispersion of action potential durations. Circulation 1983;67:1356-1357. 17. Rosenbaum DS, Kaplan DT, Kanai A, et al. Repolarization inhomogeneities in ventricular myocardium change dynamically with abrupt cycle length shortening. Circulation 1991;84:1333-1345. 18. Rosenbaum D, Jalife J, (eds): Optical Mapping of Cardiac Excitation and Arrhythmias. Armonk, NY: Futura Publishing Co.; 2001. 19. Windisch H, Muller W, Tritthart H. Fluorescence monitoring of rapid changes in membrane potential in heart muscle. Biophys J 1985;48:877-884. 20. Loew LM. Design and characterization of electrochromic membrane probes. JBiochem Biophys Methods 1982;6:243. 21. Slavik J. Measurement of Membrane Potential. Fluorescent Probes in Cellular and Molecular Biology. Boca Raton: CRC Press; 1994:155-166. 22. Laurita KR, Singal A. Mapping action potentials and calcium transients simultaneously from the intact heart. Am J Physiol 2001;280:H2053-H2060. 23. Fast VG, Ideker RE. Fast co-local optical recordings of transmembrane potential and intracellular calcium in myocyte cultures. Pacing Clin Electrophysiol 1999;22:702. Abstract. 24. Loew LM, Cohen LB, Dix J, et al. A naphthyl analog of the aminostyryl pyridinium class of potentiometric membrane dyes shows consistent sensitivity in a variety of tissue, cell, and model membrane preparations. JMembrBiol 1992;130:1-10. 25. Baxter WT, Davidenko JM, Loew LM, et al. Technical features of a CCD video camera system to record cardiac fluorescence data. Ann Biomed Eng 1997;25:713-725. 26. Dillon SM, Morad MA. A new laser scanning system for measuring action potential propagation in the heart. Science 1981; 214:453-456.

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27. Knisley SB, Blitchington TF, Hill BC, et al. Optical measurements of transmembrane potential changes during electric field stimulation of ventricular cells. Circ Res 1993;72:255-270. 28. Pastore JM, Rosenbaum DS. Role of structural barriers in the mechanism of alternans-induced reentry. Circ Res 2000;87: 1157-1163. 29. Laurita KR, Rosenbaum DS. Interdependence of modulated dispersion and tissue structure in the mechanism of unidirectional block. Circ Res 2000;87:922-928. 30. Akar FG, Roth BJ, Rosenbaum DS. Optical measurement of cell-to-cell coupling in intact heart using subthreshold electrical stimulation. Am J Physiol (Heart Circ Physiol) 2001;281(2):H533-H542. 31. Eloff BC, Lerner DL, Yamada KA, et al. High resolution optical mapping reveals conduction slowing in connexin43 deficient mice. Cardiovasc Res 2001;51(4):681-690. 32. Laurita K, Libbus I. Optics and detectors used in optical mapping. In: Rosenbaum D, Jalife J (eds): Optical Mapping of Cardiac Excitation and Arrhythmias. Armonk, NY: Futura Publishing Co.; 2001:61-78. 33. Bass BG. Restitution of the action potential in cat papillary muscle. Am J Physiol 1975;228:1717-1724. 34. Carmeliet E. Repolarization and frequency in cardiac cells. J Physiol (Paris) 1977;73:903-923. 35. Girouard SD, Laurita KR, Rosenbaum DS. Unique properties of cardiac action potentials recorded with voltage-sensitive dyes. J Cardiovasc Electrophysiol 1996;7: 1024-1038. 36. Qu Z, Garfinkel A, Chen P, Weiss J. Mechanisms of discordant alternans and induction of reentry in simulated cardiac tissue. Circulation 2000; 102:1664-1670. 37. Kanai A, Salama G. Optical mapping reveals that repolarization spreads anisotropically and is guided by fiber orientation in guinea pig hearts. CircRes 1995;77:784-802. 38. El-Sherif N, Caref EB, Yin H, Restivo M. The electrophysiological mechanism of ventricular arrhythmias in the long QT syndrome—tridimensional mapping of activation and recovery patterns. Circ Res 1996;79:474-492. 39. Akar FG, Yan GX, Antzelevitch C, Rosenbaum DS. Unique topograpical distribution of m cells underlies reentrant mechanisms of torsade de pointes in the long-QT syndrome. Circulation 2002;105: 1247-1253.

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with alcoholism and hypomagnesemia. 40. Antzelevitch C, Sicouri S. Clinical releAmJCardiol 1984;53:390-391. vance of cardiac arrhythmias generated by afterdepolarizations. Role of M cells in 53. Platt SB, Vijgen JM, Albrecht P, et al. Occult T wave alternans in long QT synthe generation of U waves, triggered activdrome. J Cardiovasc Electrophysiol 1996;7: ity and torsade de pointes. JAm Coll Car144-148. diol 1994;23:259-277. 41. Yuan S, Wohlfart B, Olsson SB, Blomstrom- 54. Rosenbaum DS, Albrecht P, Cohen RJ. Predicting sudden cardiac death from T Lundqvist C. The dispersion of repolarization wave alternans of the surface electrocarin patients with ventricular tachycardia a diogram: Promise and pitfalls. J Cardiostudy using simultaneous monophasic vasc Electrophysiol 1996;7:1095-1111. action potential recordings from two sites in the right ventricle. Eur Heart J 1995;16: 55. Rubenstein DS, Lipsius SL. Premature beats elicit a phase reversal of mechanoelectrical 68-76. alternans in cat ventricular myocytes: A 42. Vassallo J, Cassidy D, Kindwall E, et al. possible mechanism for reentrant arrhythNonuniform recovery of excitability in the mias. Circulation 1995;91:201-214. left ventricle. Circulation 1988;78:136556. Saitoh H, Bailey J, Surawicz B. Alternans 1372. of action potential duration after abrupt 43. Myerburg RJ, Kessler KM, Castellanos A. shortening of cycle length: Differences Sudden cardiac death: Structure, function, between dog Purkinje and ventricular and time-dependent risk. Circulation 1992; muscle fibers. CircRes 1988;62:1027-1040. 85(SupplI):I-2-I-10. 44. Moe GK, Childers RW, Merideth J. An 57. Karagueuzian HS, Khan SS, Hong K, et al. Action potential alternans and irregappraisal of supernormal A-V conduction. ular dynamics in quinidine-intoxicated Circulation 1968;38:5-28. ventricular muscle cells: Implications for 45. Laurita KR, Girouard SD, Akar FG, ventricular proarrhythmia. Circulation Rosenbaum DS. Modulated dispersion 1993;87:1661-1672. explains changes in arrhythmia vulnerability during premature stimulation of the 58. Kleber AG, Janse MJ, van Capelle FJL, et al. Mechanism and time course of S-T heart. Circulation 1998;98:2774-2780. and T-Q segment changes during acute 46. Boyett MR, Jewell BR. A study of the facregional myocardial ischemia in the pig tors responsible for rate-dependent shortheart determined by extracellular and ening of the action potential in mammalian intracellular recordings. CircRes 1978; 42: ventricular muscle. J Physiol 1978;285:359603-613. 380. 47. Girouard SD, Pastore JM, Laurita KR, et al. 59. Dilly SG, Lab MJ. Electrophysiological alternans and restitution during acute regional Optical mapping in a new guinea pig model ischemia in myocardium of anesthetized pig. of ventricular tachycardia reveals mechJ Physiol (Lond) 1988;402:315-333. anisms for multiple wavelengths in a single reentrant circuit. Circulation 1996;93: 60. Kurz RW, Mohabir R, Ren X-L, Franz MR. Ischaemia induced alternans of action poten603-613. tial duration in the intact heart: Dependence 48. Rosenbaum DS, Jackson LE, Smith JM, on coronary flow, preload, and cycle length. et al. Electrical alternans and vulnerabilEur Heart J 1993;14:1410-1420. ity to ventricular arrhythmias. N Engl J 61. Sutton PMI, Taggart P, Lab M, et al. Med 1994;330:235-241. Alternans of epicardial repolarization as 49. Cheng TC. Electrical alternans: An assoa localized phenomenon in man. Eur ciation with coronary artery spasm. Arch Heart J 1991;12:70-78. Intern Med 1983;143:1052-1053. 50. Salerno JA, Previtali M, Panciroli C, et al. 62. Shimizu W, Yamada K, Arakaki Y, et al. Monophasic action potential recordings Ventricular arrhythmias during acute during T-wave alternans in congenital long myocardial ischemia in man. The role and QT syndrome. Am Heart J 1996;132:699significance of R-ST-T alternans and the prevention of ischemic sudden death by medical 701. 63. Pastore JM, Girouard SD, Laurita KR, et al. treatment. Eur Heart J 1986;7:63-75. Mechanism linking T-wave alternans to the 51. Wayne VS, Bishop RL, Spodick DH. Exergenesis of cardiac fibrillation. Circulation cise-induced ST segment alternans. Chest 1999;99:1385-1394. 1983;83:824-825. 52. Reddy CVR, Kiok JP, Khan RG, El-Sherif 64. Hohnloser SH, Klingenheben T, Zabel M, et al. T wave alternans during exercise N. Repolarization alternans associated

OPTICAL MAPPING OF REPOLARIZATION and atrial pacing in humans. J Cardiovasc Electrophysiol 1997;8:987-993. 65. Konta ,Ikeda K, Yamaki M, et al. Significance of discordant ST alternans in ventricular fibrillation. Circulation 1990;82: 2185-2189. 66. Hirata Y, Toyama J, Yamada K. Effects of hypoxia or low pH on the alteration of canine ventricular action potentials following an abrupt increase in driving rate. Cardiovasc Res 1980; 14:108-115.

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67. Cabo C, Pertsov AM, Baxter WT, et al. Wave-front curvature as a cause of slow conduction and block in isolated cardiac muscle. Circ Res 1994;75:1014-1028. 68. Spach MS, Miller W, Geselowitz D, et al. The discontinuous nature of propagation in normal canine cardiac muscle. Circ Res 1981;48:39-54. 69. Quan W, Rudy Y. Unidirectional block and reentry of cardiac excitation: A model study. Circ Res 1990;66:367-382.

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Chapter 39

Techniques for Mapping Ventricular Fibrillation and Defibrillation William M. Smith, PhD and Raymond E. Ideker, MD, PhD

fibrillation,11 using monophasic action potential electrodes to estimate transmembrane Ventricular fibrillation (VF) and potentials generated by external electrical defibrillation have been studied in a vari- sources applied to intact hearts or isolated ety of ways. For example, the efficacy of tissue preparations,12 applying high temimplantable defibrillators has been greatly poral and spatial resolution techniques to increased by measuring defibrillation estimating transmembrane currents,13-14 thresholds and probability of success curves and attempting to control arrhythmic activfor different electrode configurations, shock ity in isolated tissues15 or the intact heart.16-17 waveforms, and animal models.1-5 Simi- The introduction of high-resolution electrical larly, substantial indirect information about and optical mapping technologies has opened VF has been gleaned from the application the door for intense investigation into the of sophisticated signal processing algo- underlying bioelectrical phenomena associrithms to surface ECGs.6-8 In spite of their ated with fibrillation and defibrillation. great value, these techniques have revealed A complete understanding of fibrillalittle about the mechanisms of either fib- tion and defibrillation will perhaps require rillation or defibrillation, or the determin- a characterization of the transmembrane ing factors for the success or failure of potentials at all points in the myocardium defibrillation shocks. Approaches to more during the arrhythmia and during internal mechanistic investigations include filming or external countershock. Unfortunately, the the surface of the heart at high speeds to instrumentation that will allow that level of record the changes in mechanical contrac- detail will not be available in the foreseeable tion during VF,9 recording from microelec- future. Recent developments in electrical trodes in myocardial cell aggregates during and optical mapping, however, provide a fibrillation-like states10 or in vivo during means for a beginning understanding of the

Introduction

This work is supported in part by research grants HL-33637, HL-28429, HL-42760 from the National Heart, Lung and Blood Institute of the National Institutes of Health. From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; ®2003. 729

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electrophysiological events associated with fibrillation and defibrillation. The introduction of specialized recording techniques has allowed the extension of traditional electrical mapping methods to the study of the electrophysiological events during fibrillation and successful and unsuccessful defibrillation shocks. New technology has allowed the determination of the nature of cardiac activation during fibrillation before and after shocks and the distribution of currents, potentials, and gradients in the myocardium from externally applied fields. Optical mapping, a complementary approach, exploits the characteristics of voltage-sensitive dyes to acquire signals that are approximations of the action potentials in the myocardium. Optical techniques provide information about electrical recovery of the tissue and the change in transmembrane potential caused by shocks, and are impervious to contamination by shock artifact. Because of the instability of fibrillation, activation mapping must be performed by recording simultaneously from many sites. A single-channel system could hypothetically be used to map the distribution of fields during shocks by making measurements during repeated trials during diastole, but the changes in the tissue with repeated shocks dictate the use of multiple channels. In this chapter we discuss the hardware and software developments that have opened the way to new understandings and hypotheses about these electrophysiological phenomena, we describe the way in which mapping studies have been combined with other electrophysiological techniques to broaden the range of questions that can be addressed, and we discuss some developments that might be important in the design of future mapping systems.

Instrumentation Transducers The first step in electrical or optical mapping of VF is the conversion of the

physiological currents and voltages into forms that are accessible to the analog and digital instrumentation. In the case of electrical mapping, the transducers are simply electrodes that are applied to the intercellular space to convert ionic currents into a flow of electrons that can be processed by standard electrical components or to sense the potentials generated in the tissue by extrinsic stimuli of shocks. Optical mapping requires staining the tissue with a voltage-sensitive dye that can be excited to yield a waveform that is typically an estimate of the intracellular action potential in the underlying tissue. The simplest sensors used in electrical mapping studies are electrodes to record electrograms directly from the cardiac tissue. These are structures of many shapes and materials that can be applied to the epicardium,12,18 the endocardium,19 or intramurally.20-24 The application of electrodes with spacing close enough to determine mechanisms of fibrillation and defibrillation throughout the extent of the myocardium is an unsolved problem. There is evidence to indicate that spatial resolution of approximately 1 mm is adequate for mapping fibrillation wavefronts.25 This spacing might be necessary to resolve some of the questions that are currently unanswered about the nature of fibrillation and the events that occur when defibrillation shocks are unsuccessful.26-27 However, to map the entire myocardial volume of a canine heart with this resolution would require more than 100,000 electrodes. This density of plunge needles would obviously cause unacceptable damage to the tissue, perturbing the activation sequences and potential gradients under measurement in addition to placing demands on the data acquisition system that are currently not technologically feasible. In addition, there is evidence that the very presence of either epicardial28 or intramural 29

MAPPING VF AND DEFIBRILLATION electrode arrays can distort the fields under measurement. An extensive literature exists on the electrochemical characteristics of metals and their interfaces with biological tissue.30 The nature of the metal from which the electrodes are made is less important when measurements are limited to the signals arising from the cardiac generators than when it is necessary to measure potentials resulting from large, externally applied fields, as in defibrillation shocks, either simultaneously or within milliseconds. High-level defibrillation potentials recorded by highly polarizable materials can cause large offsets that saturate the input system. Recovery can take up to seconds, causing loss of information about the nature of the response of the tissue to the shock. Electrodes made of chloridized silver, sintered silver-silver chloride, or other nonpolarizable materials are among the most practical available for recording fibrillation/defibrillation episodes.26 There are several possible configurations of the electrodes, and the choice is largely independent of the electrode material. Unipolar electrodes measure the electrical potential in the heart with respect to a distant point, either on the body surface31 or on a common point within the chest wall.26 When measuring externally generated potentials, it is necessary to refer all of the signals to a common level, so unipolar recording is used. Bipolar recordings are made by referring the signal from one electrode to another electrode very close to it. A unipolar or a bipolar configuration can be used to acquire signals generated by the heart for the purpose of mapping the activation sequence (Figure 1). The morphology of the local activation waveforms in unipolar electrograms is more consistent than in bipolar recordings. Electrical activity from sites distant from the electrode is largely suppressed in bipolar waveforms,

731

Figure 1. Cardiac electrograms recorded after 8 seconds of ventricular fibrillation in a canine heart. The signals were recorded from a plunge needle with multiple recording sites along its length. The most distal electrode was just inside the endocardial surface and was always one of the bipolar pairs. For the signals shown, the other electrode of the pair was spaced from 50 microns to 1 cm from the distal point, as indicated. The top tracing is lead II of the EGG.

but the automatic detection of local activation complexes is complicated by the lack of consistent morphology.32 It has been proposed that the distribution of the potential gradient in the myocardium is an important determinant of the success or failure of defibrillation attempts.33,34 Some, but not all, mathematical models indicate that the transmembrane potentials may be predicted from the value of the gradient in the tissue.35'36 If the gradient is a critical variable, it is important to measure its value during a shock with precision and accuracy. Closely spaced triangular arrays have been developed to measure the gradient on the epicardium.26 This is a difficult measurement to make, since the value of the gradient is highly sensitive to errors in the value of the measured voltage and the determination of the coordinates of the electrodes.37 Other mathematical

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models indicate that the derivative of the shock field potential gradient is one of the variables determining the resulting change in transmembrane potential.38 This is an even more difficult measurement to make than the gradient. Other electrode configurations can be used for specialized measurements. For example, very closely spaced electrodes and a data acquisition system with a very high sampling rate have been used to estimate transmembrane ionic currents from extracellular potential gradients.14 A tetrapolar electrode composed of two bipolar pairs39 that has been used for vector mapping of activation in a hand-held probe has been adapted for multichannel use.40 Taccardi et al.41 have developed an intracavitary probe that can be used to identify early sites on the endocardium during arrhythmias. This configuration has been tested to determine whether it is possible to predict shock potentials on the endocardium from those measured in the cavitary blood and vice versa,42-43 and has been used in clinical situations.44 Several groups have developed arrays of electrodes mounted on balloons19,45-47 or extensible baskets48-50 for mapping endocardial activation or ablating endocardial tissue. For repetitive rhythms, a system that uses a hand-held probe has been developed that can map endocardial anatomy and activation sequences.51 The introduction of electrodes fabricated from thin film technologies offers interesting possibilities for very small plunge needles or surface arrays of arbitrary shapes with precise and repeatable electrode arrangements.20-52 These structures have been used successfully in neurophysiological studies53 and there has been some success in incorporating active electronics on the structure.54 Because of the motion of the beating heart and the consistency of the myocardial wall, the use of such needles is more complicated for in vivo cardiac studies than in

neurological tissue. This is an area of active investigation. In optical mapping, the transducer includes the dye, which is sensitive to voltage or other analyte, the light source used to excite the dye, and the instrumentation for converting the photons from the tissue to a voltage or current proportional to the underlying variable. These elements vary from system to system and depend on the desired variable. A typical dye for myocardial staining in optical mapping experiments is di4-ANEPPS.55 This dye binds to the cell membrane in such a way that excitation by light of wavelength less than 520 nanometers induces fluorescence at a wavelength that is proportional to the membrane voltage of myocytes in the underlying tissue. The fluoresced light can be separated from the incident light by filters. The fluorescence shift related to a 100-mV change in action potential can be as much as 10%.56,57 The light to excite the stained tissue can be directed to the area to be mapped by optical fibers58,59 or by a laser beam steered to individual epicardial spots.56,60,61 Spatial resolution is achieved through the manipulation of the laser beam, and the light is collected through a photomultiplier tube56,60 or a single photodiode.61 Alternatively, the tissue can be illuminated by a light source, with spatial information provided by an array of photodiodes62-64 or charged coupled devices.65,66 The use of video imaging systems allows the acquisition of anatomical images at the same time that electrophysiological data are gathered.67 Sampling rates, number of sensor sites, and noise levels differ for the various types of optical mapping systems. Data Acquisition The basic concepts of data acquisition are the same for optical and electrical

MAPPING VF AND DEFIBRILLATION mapping of fibrillation and defibrillation. The primary difference is that optical mapping systems are immune to the effects of shock artifact, while the inputs of electrical mapping systems must accommodate large differences (several orders of magnitude) in input voltage. Conversely, optical mapping does not provide information about the electrical potentials and gradients generated in the myocardium by external or internal shocks. The acquisition of intramural information is more straightforward with electrical mapping than with optical techniques. Acquisition of data during VF and, especially, defibrillation for electrical mapping purposes has required the application of techniques not generally used in biomedical instrumentation. Much has been learned about the response of tissue to countershocks simply by disconnecting the inputs from the amplifiers during the shocks68 or by measuring gradients generated by low-voltage external sources and extrapolating to defibrillation voltage levels.69 For the most complete characterization, it is necessary to provide adequate dynamic range in the inputs for simultaneous, or almost simultaneous, recording of electrograms with amplitudes on the order of millivolts and shock potentials that might be hundreds of volts at the locations of the sensing electrodes. There are currently 2 approaches to this problem in electrical mapping systems. Witkowski et al.26 use parallel input channels for acquiring, respectively, electrograms and shock potentials. Each sensing electrode is directly coupled to 2 amplifiers. One set of amplifiers has a dynamic range of ±130 mV and the other has a dynamic range of ±500 V. This system measures 240 signals from 120 sites. The advantage of this technique is its simplicity and lack of reliance on communications between the defibrillator and the data acquisition system. In addition, the parallel inputs allow each amplifier to

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be operated at a fixed gain, further simplifying system design. A major disadvantage is the fact that only half of the input channels provide useful data at any time. The second method used for electrically mapping fibrillation and defibrillation provides rapid context switching, so that the parameters of the mapping system can be switched between those suitable for recording electrograms and those suitable for recording shock potentials very quickly.70 In one such system, up to 528 electrograms during fibrillation are recorded simultaneously in unipolar or bipolar mode with an appropriate set of gains and input filter settings. Within one sampling period, normally before a shock is to be delivered, the inputs are converted to unipolar mode if not already so set, another set of gains is applied to the variable gain amplifiers, the signals are directly coupled to the inputs, and a voltage divider is switched into each channel. After the shock, the mapping system reverts to its original state to resume recording electrograms. Figure 2 shows an electrogram recorded during a fibrillation/defibrillation episode by one channel of a 128-channel mapping system designed for studying defibrillation. Even though this system is more complicated than the first one described, it has additional flexibility as well as the feature that all channels are recording data from distinct electrode positions. In principle, the 2 approaches provide equivalent information and both have been productively applied to the study of ventricular defibrillation.26,27 Other data can be acquired that can enable or improve the interpretation of mapping data. It is desirable to provide automated, computerized storage of information about the shocks when measuring thresholds or probability of defibrillation curves. These data include the shock voltage, current, and energy of the delivered

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Figure 2. An electrogram recorded from an episode of fibrillation and defibrillation by a specially constructed mapping system. Each channel of the mapping system is capable of rapidly switching from conditions suitable for measuring electrograms to those appropriate for recording shock potentials, then reverting to the original state. The labeled events in the figure are as follows: (A) normal bipolar electrogram recording during fibrillation, with full-scale voltage ±50 mV. (B) Relays inserting voltage dividers into the system are switched on, gains on each channel are modified, and recording mode is switched from bipolar to unipolar. (C) Amplifier settling time. (D) Shock voltage turned on. Full-scale voltage is ±250 V. (E) Shock duration. The amplitude of the generated potential can be measured at each electrode during this period. (F) Trailing edge of the shock. (G) Input restored to bipolar mode with original gain setting. (H) Electrogram recording with transient recovery.

impulses in particular. It is also useful to record the status of the system dynamically within the data stream71 to resolve any uncertainties about the status of the data acquisition system at the time the data are recorded. Another desirable characteristic of mapping systems for fibrillation and defibrillation is the ability to record data continuously for extended periods.72 Since the time of onset of VF is often unpredictable,73 it is often necessary to record the data continuously until an event of interest is identified. In many data acquisition systems, the data acquisition process is controlled by one or more computers.

The amount of data that can be continuously recorded is then limited by the amount of available high-speed computer memory or the speed with which the data can be transferred to a larger storage medium. A simpler approach is to record the data without computer intervention until an event of interest is detected, at which time the data can be transferred to the computer for analysis.74 The high data rates and volumes associated with modern mapping systems impose severe constraints on the hardware and software used for data acquisition. In general, for real time data input, it is not feasible to use operating systems

MAPPING VF AND DEFIBRILLATION that allow many simultaneous users because the computer must be able to respond in a predictable way to external events. In networked computing environments, a machine can be dedicated to the task of controlling acquisition, making the data available for users at other network nodes.75 In this way, the high-speed data acquisition is isolated from the computing demands of data analysis and display. The data acquisition for optical mapping systems can be simpler in some ways, because as stated above, they are generally not constrained to accommodate large voltages associated with shocks. On the other hand, depending on the amount of tissue stained and excited, optically sensed transmembrane potentials can have low signal-to-noise ratios. These issues have been addressed by signal averaging in the time domain56 or by spatially filtering.66 Some of the video imaging systems have been limited by the video rates available,66 but new technology promises to improve substantially the time resolution available.76-78 One limit on achievable noise levels is the occurrence of photobleaching, which limits the time that the light source can illuminate the tissue without undesirable effects.58 Signal Processing The selection of signal processing algorithms that are applied to data from the study of fibrillation and defibrillation depends on the nature of the study and the conditions under which the signals are acquired. It is often necessary to analyze signals recorded from the heart as well as the waveforms delivered to the shocking or defibrillation electrodes. The unique capabilities of optical mapping, in particular the ability of optical systems to measure tissue recovery, create a need for different signal analysis techniques from those used in electrical mapping.

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For complete isochronal and isogradient mapping studies using electrical mapping, the electrograms from bipolar or unipolar sensing electrodes must be analyzed for detection of local activations in each channel and for determination of the field strength at the electrode location during the external shock. VF is of such variability and high rate, especially in smaller experimental animals, that electrograms recorded in the arrhythmia are often confusing. It is sometimes difficult to distinguish conduction block from slow conduction across abnormal tissue and deflections in the electrograms from distant generators can cause ambiguities in the detection and timing of local electrical events. Complicating the analysis is the fact that there are often multiple wavefronts simultaneously existing in the myocardium during fibrillation,73 giving rise to waveform deflections that do not represent local activity and that make grouping activations into beats difficult. Because of the consistent morphology of unipolar electrograms during local activation, some investigators prefer recording in unipolar rather than bipolar mode. The detection of local activations is then limited to comparison of the first derivative of the signal to a threshold, with time of activation determined by the minimum value (maximum absolute value) of the derivative.26,31,79 Unipolar electrodes are subject to more contamination from distant electrical activity than bipolar recordings,80 complicating the selection of a threshold value for the derivative. Bipolar electrograms, while less susceptible to distant electrical generators than unipolar,81 are dependent on the angle of incidence of the wavefront to the axis between the bipolar pair,82 which increases the variability of the waveform morphology. Thus, analysis algorithms for bipolar electrograms are more complex

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for activation detection and determination of activation times than their unipolar counterparts.32 Other algorithms can provide limited information about repolarization from extracellular unipolar electrograms.83 When local activity is difficult to identify, as it often is during fibrillation, it is preferable to study the activation sequence of the myocardium during VF without explicitly identifying and timing local activations.84 This can be accomplished by animating the potential recorded during time of interest. The values of the potentials or their first derivatives are color coded according to their level and displayed dynamically at varying rates. This technique avoids the ambiguities of activation detection and grouping of beats for isochronal displays.85 Figure 3 is adapted from such a display. The potentials generated during a shock or stimulus must be recorded in unipolar mode. To determine the potential in the tissue during the shock, a decision must be made about where in the shock waveform to make the measurement. If the waveform is a truncated exponential, it is possible to fit an exponential to the digitized points and then make a measurement at any desired point along the curve.86 If the signal delivered is a square wave (from a constant voltage source), it is desirable to compute average voltage across several sample points for noise reduction purposes. Activation sequences during fibrillation and after external shocks are also measured in optical mapping studies. Because the optical waveform is a representation of the underlying action potential, the time of activation is generally estimated by the maximum positive derivative of the signal62,76 or a fixed percentage of the action potential upstroke.66 A powerful capability of the optical technique is the ability to estimate repolarization times. These times can be determined

by the return of the action potential to some point near baseline66 or by the point of maximum second derivative during repolarization.62 This measurement becomes problematic during VF because the short cycle lengths often prevent a return to baseline of the signal.87 It is convenient to analyze the signal coming from the defibrillating device by inputting the attenuated and isolated defibrillation waveform into a waveform analyzer or digital oscilloscope instead of dedicating a channel of the mapping system to that signal.88 Waveform analyzers are generally programmable, so that the peak or average voltage and current can be measured and from them impedance, energy, and other defibrillation parameters can be computed. New signal processing algorithms have improved our understanding of fibrillation and defibrillation as studied by both electrical and optical mapping systems, and have added exciting new approaches to extracting the most information possible from the data. One development has been the application of quantitative analysis techniques to multichannel mapping data. These have included assessment of the organizational level of ventricular arrhythmias,76,89,91 estimation of the conduction velocity of propagating wavefronts,92 and automatic and semiautomatic identification of fibrillatory wavefronts and extraction of significant electrophysiological parameters.93,95 The analysis of the phase of the action potential during VF mapped by optical techniques has provided new insight into the mechanisms of VF.96 Many of these techniques have been developed for regular geometric grid patterns in 2 dimensions but are extensible to irregular 3-dimensional arrays.97 As new instrumentation is introduced, it will be necessary to develop new signal processing methods to interpret quantitatively and accurately the new kinds of data acquired.

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Image Not Available

Figure 3. Frames from an animation of activation fronts proceeding across the epicardium beneath a recording plaque with a 22 x 23 array of electrodes with interelectrode spacing of 1.12 mm. The purpose of the study was to electrically capture myocardium during ventricular fibrillation using a pair of pacing electrodes beneath the center of the recording array. Normally the pixels would be color coded according to the value of the derivative of the electrogram at each electrode site, but in this adaptation pixels with a derivative value greater than 0.5 v/s are shaded and others are white. A. The electrogram recorded from the position marked by the circled x. The asterisk marks the spot at which the stimuli begin to capture the myocardium. B, C, and D show, respectively, activation sequence before pacing is begun, after pacing has begun but before the myocardium is captured, and during capture, and correspond to the times indicated by the labels below A. The frames should be read in the top then bottom rows, from left to right. Reprinted with permission from KenKnightetal.16

Visualization Visualization in cardiac mapping encompasses everything from simply plotting electrophysiological waveforms in an intuitive and informative manner to superimposing electrophysiological data on realistic 3-dimensional renderings of the cardiac anatomy.98 As discussed above,

when the sensed sites are from a regularly space 2-dimensional array, animated isopotential or isoderivative maps can be highly effective in either electrical16 or optical76 systems. The most challenging visualization tasks in cardiac mapping arise from electrical mapping studies in which data are acquired within the myocardium.

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These data are inherently 3-dimensional and are superimposed on anatomical structures that are irregular and variable. The electrophysiological quantities are sparsely sampled, at least with the current level of mapping technology, so that interpolation is often needed for interpretation of results. Even though computer software for scientific visualization has improved dramatically over the last several years, there is currently no single solution for the display of data from mapping studies." In addition, accurate and meaningful visualization requires imaging the heart and determining sensor positions, either on a per study basis or in order to define a representative anatomy. Acquisition of anatomy and electrode geometry has progressed from physically slicing and photographing the heart, with data entry using digitizing tablets,88,100 to imaging the whole heart with magnetic resonance imaging techniques and interactively determining boundaries and electrode positions.101 There is a continuing research effort to segment the heart automatically, separating ventricular cavities from myocardium, and to characterize tissue types—normal, fibrotic, ischemic, or acutely infarcted. A rapid, accurate technique for imaging and segmenting the heart either clinically or in experimental studies would improve the quality of results. Anatomical displays can be either surface based or volume based. Surface techniques102 require the extraction of a surface of interest from a 3-dimensional structure. The surface must be defined interactively or automatically on the basis of some characteristic of the image. Surface renderers are capable of providing extremely high-quality visualizations of complex anatomies. For true 3-dimensional visualization, volume rendering techniques are available103 that allow the direct display of volume data without preliminary extraction of a surface.

Volume rendering algorithms often allow exploration of anatomical structures, but are computationally demanding. Surface- and volume-based techniques provide different perspectives on the anatomical data at different costs in processing time and realism. For example, with surface rendering techniques it is possible to display the values of potentials, gradients, or activation times on the epicardial or endocardial surfaces and rotate the heart for different perspective views. Volume rendering preserves information about the interior of the myocardial wall and allows exploration of the data throughout the tissue in a more flexible way (Figures 4 and 5). Because of the sparseness of sensing points, traditional contour maps require interpolation of the variable to be viewed. Often linear interpolation between points is adequate for 2-dimensional displays,104 but discrete smooth interpolation is a robust and flexible method that is readily applied to volumetric data.105-106 The interpolated data can be combined with the anatomy and electrode geometry to display the results realistically107 (Figures 4 and 5), and can incorporate biophysical principles.108 In other instances, presenting the data dynamically can clarify the interactions between variables as the events in fibrillation and defibrillation occur. We have developed software for displaying multivariate data as a function of time and for defining the display parameters quickly and flexibly.98 For example, it is possible with this system to render an activation surface shaded by another variable moving through the cardiac tissue. The surface shading can be derived from the local conduction velocity, from the potentials and gradients generated by a previous defibrillation shock, or by any other measured or computed variable. The goal of the visualization technique chosen is to provide methods of presenting the data from these complex studies that

MAPPING VF AND DEFIBRILLATION 737

Figure 4. Displays of activation sequence of the first beat following a failed defibrillation shock. The times of activation, measured from an arbitrary reference, are shown in the color code at the right of each panel. The top panel shows the epicardial and endocardial sequences separately from a roughly anterior perspective. The epicardial surface is on the left and the left and right ventricular cavities are shown on the right. The left ventricle is to the right and just below the right ventricle and right ventricular outflow tract. The earliest activation is on the apical left ventricle, almost hidden in this 3-dimensional view. The left ventricular epicardium and left atrial appendage are the areas of latest activation. The lower panel shows the same epicardial and endocardial activation sequences, but with the endocardium and epicardium in the proper location with respect to each other. The epicardial surface has been rendered translucent to allow the cavities to be visible. The anatomy and electrode locations for this figure and Figure 5 were derived from magnetic resonance images. The electrophysiological quantities were interpolated using discrete smooth interpolation. See color appendix.

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Figure 5. Potential gradients induced in the same heart as in Figure 4 by a defibrillation shock between an anode in the left ventricular apex and a cathode in the right ventricular outflow tract. The gradients in volts per centimeter are represented by the colors shown in the scale at the right. The 3-dimensional representation allows tissue to be removed for inspection of gradients within the wall. The cubes with X's indicate the recording electrodes. In this view the left and right ventricles have been exposed, with the high-gradient area appearing in the left ventricular apex. See color appendix.

build intuition, increase insight, and lead to new hypotheses about the electrophysiological events of interest. Conclusion Ventricular fibrillation and defibrillation are complex phenomena and the study of their mechanisms can require commensurately complex instrumentation. The tools needed to adequately map these events include sensors for transducing the ionic signals into electronic ones, highspeed electronics for converting the signals into a form that can be analyzed, and modern computers for processing signals, transforming data, and visualizing results. Commercial mapping systems, while adequate for many clinical applications, are limited in mapping defibrillation shocks

and the immediate response of the tissue to the shocks because of their limited dynamic range. Currently, mapping instrumentation appropriate for these studies requires a substantial investment in hardware and software development, but the decreasing cost-to-performance ratio of electronics and computers should lead to the proliferation of electrical and optical mapping systems, and the studies will be limited largely by our imagination and persistence. References I. Chang MS, Inoue H, Kallok MJ, et al. Double and triple sequential shocks reduce ventricular defibrillation threshold in dogs with and without myocardial infarction. J Am Coll Cardiol 1986;8: 1393-1405.

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26. Witkowski FX, Penkoske PA, Plonsey R. Mechanism of cardiac defibrillation in open-chest dogs with unipolar DC-coupled simultaneous activation and shock potential recordings. Circulation 1990;82:244260. 27. Chen P-S, Wolf PD, Melnick SD, et al. Comparison of activation during ventricular fibrillation and following unsuccessful defibrillation shocks in open chest dogs. Circ Res 1990;66:1544-1560. 28. Patel SG, Roth BJ. How electrode size affects the electric potential distribution in cardiac tissue. IEEE Trans Biomed Eng 2000-41:1284-1287. 29. Langrill DM, Roth BJ. The effect of plunge electrodes during electrical stimulation of cardiac tissue. IEEE Trans Biomed Eng 2001;48:1207-1211. 30. Neuman MR. Biopotential electrodes. In: Webster JG (ed): Medical Instrumentation Application and Design. Boston: Houghton Mifflin Co.; 1992:227-287. 31. Durrer D, van der Tweel LH. Spread of activation in the left ventricular wall of the dog: II. Activation conditions at the epicardial surface. Am Heart J 1954;47: 192-203. 32. Simpson EV, Ideker RE, Cabo C, et al. Evaluation of an automatic cardiac activation detector for bipolar electrograms. Med Biol Eng Comput 1993;31:118-128. 33. Lepeschkin E, Jones JL, Rush S, et al. Local potential gradients as a unifying measure for thresholds of stimulation, standstill, tachyarrhythmia and fibrillation appearing after strong capacitor discharges. Adv Cardiol 1978;21:268-278. 34. Wharton JM, Wolf PD, Smith WM, et al. Cardiac potential and potential gradient fields generated by single, combined, and sequential shocks during ventricular defibrillation. Circulation 1992;85:15101523. 35. Krassowska W, Pilkington TC, Ideker RE. Periodic conductivity as a mechanism for cardiac stimulation and defibrillation. IEEE Trans Biomed Eng 1987; 34:555-560. 36. Sepulveda NG, Roth BJ, Wikswo JP Jr. Current injection into a two-dimensional anisotropic bidomain. Biophys J 1989;55: 987_999 37. Idriss SF, Wolf PD, Smith WM, et al. Errors in calculating the epicardial potential gradient field from unipolar voltage measurements during cardiac

defibrillation. In: Nagel JH, Smith WM (eds): Proc 13th Annu Int Conf IEEE Eng Med Biol Soc. Piscataway, NJ: Institute of Electrical and Electronics Engineers, Inc.; 1991:692-693. 38. Sobie EA, Susil RC, Tung L. A generalized activating function for predicting virtual electrodes in cardiac tissue. Biophys J 1997;73:1410-1423. 39. Kadish AH, Spear JF, Levine JH, et al. Vector mapping of myocardial activation. Circulation 1986;74:603-615. 40. Kanaan N, Robinson N, Roth SI, et al. Ventricular tachycardia in healing canine myocardial infarction: Evidence for multiple reentrant mechanisms. Pacing Clin Electrophysiol 1997;20:245-260. 41. Taccardi B, Arisi G, Macchi E, et al. A new intracavitary probe for detecting the site of origin of ectopic ventricular beats during one cardiac cycle. Circulation 1987;75:272-281. 42. Derfus DL, Pilkington TC. Assessing the effect of uncertainty in intracavitary electrode position on endocardial potential estimates. IEEE Trans Biomed Eng 1992;39:676-681. 43. Oster HS, Taccardi B, Lux RL, et al. Electrocardiographic imaging: Noninvasive characterization of intramural myocardial activation from inversereconstructed epicardial potentials and electrograms. Circulation 1998;97:14961507. 44. Peters NS, Jackman WM, Shilling RJ, et al. Human left ventricular endocardial activation mapping using a novel noncontact catheter. Circulation 1997;95: 1658-1660. 45. de Bakker JMT, Janse MJ, van Capelle FJL, et al. Endocardial mapping by simultaneous recording of endocardial electrograms during cardiac surgery for ventricular aneurysm. J Am Coll Cardiol 1983;2:947-953. 46. Fann JI, Loeb JM, LoCicero J III, et al. Endocardial activation mapping and endocardial pace-mapping using a balloon apparatus. Am J Cardiol 1985;55: 1076-1083. 47. Harris L, Mickleborough LL, Shaikh N, et al. Electrical ablation with a balloon electrode array: Chronic electrophysiologic response. Pacing Clin Electrophysiol 1988;11:1262-1266. 48. Triedman JK, Jenkins KJ, Colan SD, et al. Multipolar endocardial mapping of

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and display of defibrillation and electrocardiographic potentials. In: Murray A, Arzbaecher R (eds): Proc Comput Cardiol. Piscataway, NJ: The Institute of Electrical and Electronics Engineers, Inc.; 1993:125-128. 71. Wolf PD, Ideker RE, Smith WM. A data stream formatter for a cardiac mapping system. In: Kondraske GV, Robinson CJ (eds): Proc 8th Annu Int ConflEEE Eng Med Biol Soc. Piscataway, NJ: Institute of Electrical and Electronics Engineers, Inc.; 1986:491-493. 72. Smith WM, Wharton JM, Blanchard SM, et al. Direct cardiac mapping. In: Zipes DP, Jalife J (eds): Cardiac Electrophysiology: From Cell to Bedside. Philadelphia: W.B. Saunders Co.; 1990:849-858. 73. Ideker RE, Klein GJ, Harrison L, et al. The transition to ventricular fibrillation induced by reperfusion following acute ischemia in the dog: A period of organized epicardial activation. Circulation 1981;63:1371-1379. 74. Wolf PD, Danieley ND, Ideker RE, et al. A digital tape recorder for electrophysiologic waveforms. In: Ann Confon Eng in Med and Biol. 1985:124. 75. Danieley N, Wolf PD, Ideker RE, et al. A workstation network for cardiac electrophysiology. In: Murray A, Ripley KL (eds): Proc Comput Cardiol. Piscataway, NJ: The Institute of Electrical and Electronics Engineers, Inc.; 1988:469-472. 76. Witkowski FX, Leon LJ, Penkoske PA, et al. Spatiotemporal evolution of ventricular fibrillation. Nature 1998;392:78-82. 77. lijima T, Witter MP, Ichikawa M, et al. Entorhinal-hippocampal interactions revealed by real-time imaging. Science 1996;272:1176-1179. 78. Banville I, Gray RA, Ideker RE. Optimization of high-resolution video imaging system to study cardiac spatiotemporal patterns. Ann Biomed Eng 1998;26:S-19. Abstract. 79. Spach MS, Barr RC, Serwer GA, et al. Extracellular potentials related to intracellular action potentials in dog Purkinje system. Circ Res 1972;30:505-519. 80. Blanchard SM, Damiano RJ, Asano T, et al. The effects of distant cardiac electrical events on local activation in unipolar epicardial electrograms. IEEE Trans Biomed Eng 1987;34:539-546. 81. Blanchard SM, Hendry PJ, Kabas JS, et al. Local and distant components of

bipolar cardiac electrograms. In: Kim Y, Spelman FA (eds): Proc 11th Annu Int ConflEEE Eng Med Biol Soc. Piscataway, NJ: Institute of Electrical and Electronics Engineers, Inc.; 1989:220-221. 82. DeCaprio V, Hurzeler P, Furman S. A comparison of unipolar and bipolar electrograms for cardiac pacemaker sensing. Circulation 1977;56:750-755. 83. Millar CK, Kralios FA, Lux RL. Correlation between refractory periods and activation-recovery intervals from electrograms: Effects of rate and adrenergic interventions. Circulation 1985;72:13721379. 84. Parson ID, Downar E. Cardiac mapping instrumentation for the instantaneous display of endocardial and epicardial activation. IEEE Trans Biomed Eng 1987;34:468-472. 85. Berbari EJ, Lander P, Scherlag BJ, et al. Ambiguities of epicardial mapping. J Electrocardiol 1991;24(Suppl):16-20. 86. Idriss SF, Melnick SB, Wolf PD, et al. Predicting the potential gradient field in ventricular fibrillation from shocks delivered in paced rhythm. Am J Physiol 1995;268:H2336-H2344. 87. Zhou X, Guse P, Wolf PD, et al. Existence of both fast and slow channel activity during the early stage of ventricular fibrillation. Circ Res 1992;70:773786. 88. Tang ASL, Wolf PD, Claydon FJ III, et al. Measurement of defibrillation shock potential distributions and activation sequences of the heart in threedimensions. Proc IEEE 1988;76:11761186. 89. Ropella KM, Sahakian AV, Baerman JM, et al. The coherence spectrum. A quantitative discriminator of fibrillatory and nonfibrillatory cardiac rhythms. Circulation 1989;80:112-119. 90. Bayly PV, Johnson EE, Wolf PD, et al. A quantitative measurement of spatial order in ventricular fibrillation. J Cardiovasc Electrophysiol 1993;4:533-546. 91. Bayly PV, KenKnight BH, Rogers JM, et al. Spatial organization, predictability, and determinism in ventricular fibrillation. Chaos 1998;8:103-115. 92. Bayly PV, KenKnight BH, Rogers JM, et al. Estimation of conduction velocity vector fields from epicardial mapping data. IEEE Trans Biomed Eng 1998;45: 563-571.

MAPPING VF AND DEFIBRILLATION 93. Rogers JM, Usui M, KenKnight BH, et al. A quantitative framework for analyzing epicardial activation patterns during ventricular fibrillation. Ann Biomed Eng 1997;25:749-760. 94. Rogers J, Usui M, KenKnight B, et al. Recurrent wavefront morphologies: A method for quantifying the complexity of epicardial activation patterns. Ann Biomed Eng 1997;25:761-768. 95. Rogers JM, Huang J, Smith WM, et al. Incidence, evolution and spatial distribution of functional reentry during ventricular fibrillation in pigs. Circ Res 1999;84:945-954. 96. Gray RA, Pertsov AM, Jalife J. Spatial and temporal organization during cardiac fibrillation. Nature 1998;392:675-678. 97. Barnette AR, Bayly PV, Zhang S, et al. Estimation of 3-D conduction velocity vector fields from cardiac mapping data. In: Murray A, Swiryn S (eds): Proc Comput Cardiol. Piscataway, NJ: The Institute of Electrical and Electronics Engineers, Inc.; 1998:605-608. 98. Palmer TC, Simpson EV, Kavanagh KM, et al. Visualization of bioelectric phenomena. In: Pilkington TC, Loftis B, Thompson JF, et al (eds): High-Performance Computing in Biomedical Research. Boca Raton: CRC Press Inc.; 1993:429-446. 99. Carlbom I, Chakravarty I, Hsu WM. SIGGRAPH '91 Workshop Report: Integrating computer graphics, computer vision, and image processing in scientific applications. Comput Graphics 1992;26: 8-17. 100. Witkowski FX, Penkoske PA. A new technique for three-dimensional localization of transmural electrodes. Biomed Inst Technol 1989;23:396-402.

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101. Laxer C, Johnson GA, Kavanagh KM, et al. An interactive graphics system for locating plunge electrodes in cardiac MRI images. In: Kim Y (ed): Image Capture, For matting and Display. 1991:190— 195. 102. Lorensen WE, Cline HE. Marching cubes: A high resolution 3D surface construction algorithm. Comput Graphics 1987;21:163-169. 103. Drebin RA, Carpenter L, Hanrahan P. Volume rendering. Comput Graphics 1988;22:65-74. 104. Barr RC, Gallie TM, Spach MS. Automated production of contour maps for electrophysiology: III. Construction of contour maps. Comput Biomed Res 1980;13:171-191. 105. Mallet J-L. Discrete smooth interpolation. ACM Trans Graphics 1989;8:121144. 106. Simpson EV, Ideker RE, Kavanagh KM, et al. Discrete smooth interpolation as an aid to visualizing electrical variables in the heart wall. In: Murray A, Arzbaecher R (eds): Proc Comput Cardiol. Piscataway, NJ: The Institute of Electrical and Electronics Engineers, Inc.; 1991:409412. 107. Simpson EV, Wolf PD, Ideker RE, et al. Three-dimensional visualization of electrical variables in the ventricular wall of the heart. In: Proc 1st Conf Visualization Biomed Comput. Atlanta: The Institute of Electrical and Electronics Engineers, Inc.; 1990:190-194. 108. Ni Q, MacLeod RS, Lux RL, et al. A novel interpolation method for electric potential fields in the heart during excitation. Ann Biomed Eng 1998;26:597607.

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Chapter 40 Disorders of Cardiac Repolarization and Arrhythmogenesis in the Long QT Syndrome Nabil El-Sherif, MD and Gioia Turitto, MD

Introduction The congenital and acquired forms of the long QT syndrome (LQTS) both result from abnormalities (intrinsic, acquired, or both) of the ionic currents underlying repolarization. Prolongation of the repolarization phase acts as a primary step for the generation of early afterdepolarizations (EADs).1 EAD-induced triggered beats arise predominantly from the Purkinje network.1 In LQTS, prolonged repolarization is associated with increased spatial dispersion of repolarization.2,3 The focal EAD-induced triggered beat(s) can infringe on the underlying substrate of inhomogeneous repolarization to initiate polymorphic reentrant ventricular tachycardia (VT).3 Torsades de pointes (TdP) is an ear-pleasing term that describes an eye-catching form of polymorphic VT. The term was first coined by Dessertenne,4 who described its electrocardiographic

pattern of continuously changing morphology of the QRS complexes that seem to twist around an imaginary baseline. The quasi-musical term (Figure 1) and the intriguing electrocardiographic pattern have caught the attention of electrophysiologists for years and have been, to some extent, a driving force behind the recent focused interest into the value of genetics and cardiac ion channelopathy in cardiac arrhythmias in general.5 More importantly, they are helping to refocus attention on the role of dispersion of ventricular repolarization in the genesis of malignant ventricular tachyarrhythmias. There is more than one electrophysiological mechanism for polymorphic VT, and an understanding of these mechanisms can be valuable in the proper care of individual patients. The most appropriate manner in which to classify polymorphic VT is whether it is associated with normal or prolonged QT (or QTU) segment. The electrophysiological

Supported in part by Veterans Administration REAP program. From Shenasa M, Borggrefe M, Breithardt G (eds): Cardiac Mapping, Second Edition. Elmsford, NY: Blackwell Publishing, Inc./Futura Division; ®2003. 747

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Figure 1. The daily utterance of the term "torsade" in French refers to different bakery items including bread loaves with characteristic twisting configuration. The above card is an advertisement for such products. Reproduced from reference 40, with permission.

mechanisms of these 2 types of polymorphic VT may be different. The term TdP should be reserved for use with LQTS. However, not all patients with LQTS have polymorphic VT with a characteristic TdP configuration,6 and this classic configuration can be seen in some cases without a prolonged QT interval.7 A Paradigm of TdP from Ion Channels to ECG (Figures 2 through 4) An in vivo canine model of LQTS and TdP was developed using the neurotoxins anthopleurin-A (AP-A)8 or ATX-II.9 These agents act by slowing Na channel inactivation resulting in a sustained inward current during the plateau and prolongation of the action potential duration (APD).10,11 The model anticipated the more recent discovery of a genetic mutation of the Na channel a subunit (SCN5A) in

patients with LQT3.12 The mutant channels were shown to generate a sustained inward current during depolarization quite similar to the Na channel exposed to AP-A or ATX-II.13 Although the model is a surrogate of LQTS, which is a relatively uncommon form of congenital LQTS, the basic electrophysiological mechanism of TdP in this model seems to apply, with some necessary modifications, to all forms of congenital and acquired LQTS. In a series of reports, a paradigm of the mechanisms of TdP that extends from an ion channel abnormality to an arrhythmia with a characteristic ECG morphology was elucidated.3,8,14-16 Figures 2 to 4 illustrate this paradigm in a logical, uninterrupted sequence. Figure 2A illustrates the behavior of single Na channels exposed to AP-A. Figure 2B demonstrates the effects of AP-A on the action potential of a canine Purkinje fiber from an endocardial preparation and a midmyocardial (M) cell from a transmural strip

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Figure 2. A. Sequential recordings of single Na channel current responses during depolarizing steps from -120 to -20 mV from 2 rabbit cardiac myocytes illustrating the behavior of single Na channels exposed to anthopleurin-A (AP-A). The left panel shows recordings under control conditions and the right panel shows recordings from a patch exposed to 1000 nmol/L of AP-A. At -20 mV, control Na channels opened briefly, on average only once, very soon after the potential step. In contrast, Na channels exposed to AP-A showed long-lasting bursts consisting of repetitive long openings interrupted by brief closures. Some of the bursts lasted for the entire duration of the potential step. The ensemble currents from both patches are shown on the bottom. The control ensemble current shows fast relaxation. Conversely, the ensemble current of the Na channel exposed to AP-A shows markedly slowed relaxation, with the current failing to relax completely by the end of the 95-ms step. Kinetic analysis suggested that AP-A results in modal gating behavior of the Na channel. B. Action potential recordings from a Purkinje fiber in an endocardial preparation and from a midmyocardial cell, from a transmural strip; both isolated from the left ventricle of a 10-week-old puppy and placed in the same chamber and perfused with 50 mg/L AP-A. The 2 preparations were stimulated at a cycle length (CL) of 3000 ms. The Purkinje fiber shows a series of early afterdepolarizations (EADs) that increased gradually in amplitude before final repolarization. On the other hand, the first action potential of the midmyocardial cell showed marked prolongation of action potential duration (APD) and low amplitude EADs at the end of phase 2. The subsequent action potential showed the occurrence of a potential at the end of phase 2 that is more representative of an electrotonic interaction rather than an EAD. This observation is emphasized in C, which shows simultaneous recordings from a subepicardial (EPI) cell, midmyocardial (M) cell, and a subendocardial (END) cell from a transmural strip isolated from the left ventricle of a 12-week-old puppy and transfused with 50 mg/L AP-A. The preparation was stimulated at a CL of 4000 ms. Control recordings show the characteristic prolongation of APD of the M cell compared to EPI and END cells. AP-A resulted in prolongation of all 3 cell types, but the effect was more marked in the M cell. In section C, spontaneous regular activity arose in the preparation at a CL of 1200 ms. There was a 1:1 response in the EPI cell but irregular responses in the M and END cells. In particular, the M cell, which had a markedly prolonged APD, showed an inflection on phase 3, suggestive of electrotonic interaction. There was also evidence of asynchronous activation in the preparation (possible substrate for reentrant excitation). In 4 other transmural preparations, M cells showed a steep relation between APD and CL. However, it was uncommon to see oscillatory responses characteristic of EAD in these cells compared to Purkinje fiber at similar CL and concentration of AP-A. Reproduced from reference 40, with permission.

that were placed in the same chamber and superfused with the same concentration of AP-A. The drug resulted in prolongation of the APD of the Purkinje fiber and the development of a series of EADs. On the

other hand, the drug resulted in marked prolongation of APD of the midmyocardial cell and low-amplitude EADs at the end of phase 2. The subsequent action potential showed the occurrence of a

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Figure 2. Continued.

potential at the end of phase 2 that is more representative of an electrotonic interaction rather than an EAD. This observation is emphasized in Figure 2C, which shows simultaneous recordings from a subepicardial (Epi) cell, M cell, and a subendocardial (End) cell from a transmural strip isolated from the left ventricular (LV) free wall of a 12-week-old puppy and transfused with AP-A. The recording illustrates the differential marked lengthening of the action potential of the M cell compared to both Epi and End cells; the development of conduction block between the Epi and M cells and the occurrence of asynchronous activation in the slice are suggestive of reentrant excitation. Figure 3 further investigates the effects of AP-A in the in vivo canine heart using high-resolution 3-dimensional isochronal mapping of both activation and repolarization. To map 3-dimensional repolarization in vivo, activation-recovery intervals (ARIs)17 were measured from unipolar extracellular electrograms recorded by multielectrode plunge needles. The ARI was shown to correspond to local repolarization.3,17 Microelectrode studies

in transmural preparations have shown that Epi, M, and End cells respond differently to changes in cycle length (CL): the M cells had the steepest APD-CL relationship, followed by End cells. The weakest relationship was observed in Epi cells.18,19 Figure 3A shows 8 transmural unipolar electrograms recorded across the basolateral wall of a canine LV during AP-A infusion at 4 different CLs. The figure shows that as the CL lengthened, the calculated ARI at M sites (#3 to #6) increased significantly more compared to End sites (#1 and #2) and Epi sites (#1 and #8). This resulted in a steep gradient of ARI, especially between Epi and M sites. This behavior is illustrated graphically in Figure 3B, which shows composite data of ARI distribution collected from 12 unipolar plunge needle recordings from the same heart. Figure 4 illustrates the final step in the synthesis of the in vivo electrophysiological mechanism of TdP. The figure shows the 3-dimensional activation pattern of a 12-beat run of nonsustained TdP. Figure 4A shows that the initiating beat of TdP arose from a focal subendocardial activity. The activation wavefront

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Figure 3. A. Recordings of 8 transmural unipolar electrograms, 1 mm apart, across the basolateral wall of the left ventricle at cycle lengths (CLs) of 400, 600, 1000, and 1400 ms, from a canine heart illustrating the behavior of single Na channels exposed to anthopleurin-A (AP-A) infusion. The calculated activation-recovery interval (ARI) is shown next to each electrogram (in ms). The figure illustrates the steep ARI-CL relation of midmyocardial sites compared with subepicardial (Epi) and subendocardial (Endo) sites, resulting in steep gradients of ARI at the transition zones at the longer CL. B. Composite data of ARI distribution collected from 12 unipolar plunge needle recordings in the basolateral wall of the left ventricle in a 4 x 10-mm section from the same experiment. After AP-A, ARIs increased 2 to 3 times compared with control at similar CLs. The steepest increase occurred at midmyocardial zones. At 600 ms, ARIs were slightly longer in midmyocardial zones, but the differences were not statistically significant. At 1000 and 1400 ms, a significant increase in ARIs was apparent in midmyocardial electrodes 3 to 6 compared with both subendocardial electrodes 1 and 2 and subepicardial electrodes 7 and 8. There was, however, marked variation in ARI dispersion at the 2 transitional zones between midmyocardial sites and both Epi and Endo sites. Differences in ARIs of up to 80 ms (at a CL of 1400 to 1500 ms) between contiguous sites, 1 mm apart, at the transition zones were not uncommon. C. Diagrammatic illustration of the plunge needle electrode used to collect ARI data. Modified from reference 3, with permission.

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Figure 4. Continues

encountered multiple zones of functional conduction block that developed at contiguous sites with disparate refractoriness as shown in Figure 3. The wavefront proceeded in a very slow counterclockwise

circular pathway around the LV cavity before reactivating sites in sections 3 and 4 at isochrone #20 to initiate the first reentrant cycle. Panels B through E of Figure 4 show that all subsequent beats

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Figure 4. Continues

of TdP resulted from reentrant excitation with varying 3-dimensional activation pattern. The TdP VT terminated when the reentrant wavefront blocked, thus ending the reentrant activity. The twist-

ing of the QRS axis during this run of TdP was more evident in the inferior lead, aVF. The initial transition in QRS axis (between V7 and V10) correlated with the bifurcation of a predominantly single

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Figure 4. (Continued) Three-dimensional ventricular activation patterns of a 12-beat nonsustained torsades de pointes (TdP) ventricular tachycardia (VT). The maps are presented as if the heart was cut transversely into 5 sections, oriented with the basal section on top and the apical section on bottom and labeled 1 to 5. In B to E, section 1 was deleted. The activation isochrones were drawn as closed contour at 20-ms intervals and labeled as 1, 2, 3, and so on to make it easier to follow the activation patterns of successive beats of the VT. Functional conduction block is represented in the maps by heavy solid lines. The thick bars under the surface ECG lead mark the time intervals covered by each of the 3-dimensional maps. The V1 beat arose as a focal subendocardial activity (marked by a star in section 1). A. Selected local electrograms recorded along the reentrant pathway during the V1 illustrating complete diastolic bridging during the first reentrant cycle of 400-ms duration. Bipolar electrograms recorded from the very slow conducting component of the circuit in section 4 had a wide multicomponent configuration. Electrograms recorded in close proximity to arcs of functional conduction block had double potentials representing an electrotonic potential (E) and an activation potential (A), respectively. Note that the electrotonic potentials were synchronous with activation at the opposite side of arcs of functional block (electrograms J, K, and Q). All subsequent beats of TdP were due to reentrant excitation with varying configuration of the reentrant circuit (B to E). The twisting QRS pattern was more evident in lead aVF during the second half of the VT episode. The transition in QRS axis (between V7 and V10) correlated with the bifurcation of a predominantly single rotating wavefront (scroll) into 2 separate simultaneous wavefronts rotating around the left and right ventricular (LV, RV, respectively) cavities. The final transition in QRS axis (between V10 and V11) correlated with the termination of the RV circuit and the reestablishment of a single LV circulating wavefront (both transition zones are marked by the 2 squares in D). P indicates P waves. Modified from reference 16, with permission.

rotating wavefront (scroll) with 2 separate simultaneous wavefronts rotating around the LV and right ventricular (RV) cavities. The final transition in QRS axis (between V10 and VI1) correlated with

the termination of the RV circuit and the reestablishment of a single LV circulating wavefront. In this and other examples of TdP, the initiating mechanism for the bifurcation of the single wavefront frequently

DISORDERS OF REPOLARIZATION AND ARRHYTHMOGENESIS IN LQTS was the development of functional conduction block between the anterior or posterior RV free wall and the interventricular septum. The termination of the RV wavefront was also frequently associated with the development of functional conduction block ahead of the circulating wavefront between the RV free wall and the anterior or posterior border of the septum. In other instances, the RV circulating wavefront was extinguished through collision with an opposing wavefront in the interventricular septum. The RV circulating wavefront usually did not exhibit a localized zone of slow conduction. This may suggest that the conduction block that develops at the border between the thin RV free wall and the much thicker interventricular septum may be, at least in part, secondary to an impedance mismatch mechanism.20 On the other hand, LV circuits frequently encompassed a varying zone of slow conduction, and conduction block usually developed in this slow zone probably secondary to decremental conduction. Although it was more difficult to correlate accurately, there was evidence that a period of transitional complexes covering more than one cycle was associated with gradual dominance of 1 of the 2 circulating wavefronts before termination of the other wavefront (see the transitional QRS complexes labeled V8 and V9 in Figure 4). Short-Long Cardiac Sequence and the Onset of TdP One or more short-long cardiac cycles, usually the result of a ventricular bigeminal rhythm, frequently precede the onset of malignant ventricular tachyarrhythmias. This is seen in patients with organic heart disease and apparently normal QT intervals21 as well as in patients with either the congenital22 or acquired23,24 LQTS. The electrophysiological mechanisms

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that underlie this relationship have not been fully explored. This was recently investigated in the canine AP-A model, a surrogate of LQTS.16 The bigeminal beats consistently arose from a subendocardial focal activity (SFA) from the same or different sites, while TdP was due to encroachment of the SFA on a substrate of dispersion of repolarization to induce reentrant arrhythmias. In the presence of a multifocal bigeminal rhythm, TdP followed the SFA that had both a critical site of origin and local coupling interval in relation to the underlying pattern of dispersion of repolarization that promoted reentry. In the presence of a unifocal bigeminal rhythm, the following mechanisms for the onset of TdP were observed: (1) a second SFA from a different site infringed on the dispersion of repolarization of the first SFA to initiate reentry; (2) a slight lengthening of the preceding CL(s) resulted in increased dispersion of repolarization at key sites due to differential increase of local repolarization at M zones compared to epicardial zones. This resulted in de novo arcs of functional conduction block and slowed conduction to initiate reentry (Figures 5 through 7). Thus, the transition of a bigeminal rhythm to TdP resulted from well-defined electrophysiological changes with predictable consequences that promoted reentrant excitation. QT/T Wave Alternans and TdP It has long been known that tachycardia-dependent T wave alternans occurs in patients with the congenital or idiopathic form of LQTS and may presage the onset of TdP.25,26 Interest in the repolarization alternans is attributed to the hypothesis that it may reflect underlying dispersion of repolarization in the ventricle, a well-recognized electrophysiological substrate for reentrant VT.27 Investigations of the arrhythmogenicity of QT/T

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Figure 5. ECG recordings from a canine anthopleurin-A (AP-A) surrogate model of LQT3 in which ventricular tachycardia was initiated by the ventricular premature beat (V2) that followed the first short-long cardiac sequence. The latter was due to the occurrence of a ventricular premature beat (V1—the short cycle) followed after a compensatory pause by a sinus beat (the long cycle). Note that V1 followed a sudden lengthening of the sinus cycle length. The numbers represent cardiac cycle length in milliseconds. Reproduced from reference 16, with permission.

wave alternans in experimental models of LQTS have provided significant insight into the role of dispersion of ventricular repolarization in the generation of reentrant VT. Chinushi et al.15 studied an in vivo canine surrogate model of LQTS using the neurotoxin AP-A, and analyzed 3dimensional repolarization and activation patterns during tachycardia-induced QT/T alternans (Figures 8 and 9). The arrhythmogenicity of QT/T alternans was primarily due to the greater degree of spatial dispersion of repolarization during alternans than during slower rates not associated with alternans. The dispersion of repolarization was most marked between M and Epi zones in the LV free wall. In the presence of a critical degree of dispersion of repolarization, propagation of the activation wavefront could be blocked between these zones to initiate reentrant excitation and polymorphic VT. Two factors contributed to the modulation of repolarization during QT/T alternans, resulting in greater magnitude of dispersion of repolarization between M and Epi zones at critical short CLs: (1) differences in restitution kinetics at M sites, characterized by larger differences of the AARI, an accurate in vivo marker of the duration of repolar-

ization, and a slower time constant (T) compared with epicardial sites; and (2) differences in the diastolic interval that would result in different input to the restitution curve at the same constant CL. The longer ARI of M sites resulted in shorter diastolic interval during the first short cycle and, thus, a greater degree of ARI shortening. An important observation was that marked repolarization alternans could be present in local electrograms without manifest alternation of the QT/T segment in the surface ECG. The latter was seen at critically short CLs associated with reversal of the gradient of repolarization between Epi and M sites, with a consequent reversal of polarity of the intramyocardial QT wave in alternate cycles. This observation provides the rationale for the digital processing techniques that attempt to detect subtle degrees of T wave alternans. The association of T wave alternans with a greater degree of dispersion of repolarization was later confirmed in 2 other experimental models. Shimizu et al.28 studied an in vitro surrogate model of LQTS using ATX-II and a perfused wedge preparation of canine LV wall. Simultaneous

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Figure 6. Three-dimensional activation maps of the V1 and V2 beats shown in Figure 5 (top) and selected electrograms along the reentrant pathway induced by the V2 beat (bottom). The 2 V beats arose from different sites in section 3 (marked by stars on the maps and electrograms). The V2 beat had a shorter "local" coupling interval than the V1 beat. The V1 beat resulted in multiple zones of functional conduction block, but there was no significant area of slow conduction, and the total ventricular activation time was 100 ms. By contrast, the V2 beat resulted in more extensive zones of functional conduction block and a slow circulating wavefront in section 2 to initiate the first reentrant cycle. Reproduced from reference 16, with permission.

transmembrane action potentials were recorded from Epi, M, and End cells together with a simulated unipolar ECG. When the preparation was paced at a critical fast rate, there was pronounced alter-

nation of APD of M cells, resulting in a reversal of repolarizing sequence across ventricular wall leading to alternation in the polarity of the T wave in the unipolar ECG (Figure 10). The authors concluded

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Figure 7. This image was obtained from the experiment illustrated in Figures 5 and 6, and shows unipolar electrograms recorded from 2 plunge needle electrodes (in sections 1 and 3, respectively). Recordings from electrode sites #1 and #4 in Needle A are not shown. The recordings illustrate the alterations in the repolarization pattern and dispersion of repolarization that followed the lengthening of preceding cycle length (CL) and that created the substrate for reentrant excitation. The numbers in the figure represent the local activation-recovery intervals (ARIs), and the numbers between parentheses are the cardiac CLs. Needle A shows that the increase of the sinus CL preceding V1 resulted in lengthening of ARI of all epicardial (Epi), midmyocardial (Mid), and endocardial (End) sites compared to preceding sinus beats with shorter and relatively constant CLs. The longer compensatory CL following V1 resulted in further lengthening of ARIs of the next sinus beat. Critical analysis revealed that the degree of lengthening of ARI at Epi sites was less compared to subEpi, Mid, and End sites, resulting in greater dispersion between these sites. For Needle A, the dispersion of ARIs between Epi site #8 and "adjacent" subEpi site #7, separated by 1 mm, was 10 ms during the stable sinus rhythm at a CL of 600 ms, and increased to 19 ms following the lengthening of the last sinus cycle before V1 to 700 ms. The ARI dispersion then increased to 37 ms following the longer CL of 833 ms of the S-L sequence. Needle B showed similar directional increases of local ARIs following the lengthening of the preceding CL but the degree of lengthening was more pronounced. Still, the lengthening of ARI at Epi sites was less marked compared to Mid and End sites. The lengthening of the sinus CL from 600 ms to 700 ms resulted in a 19-ms and a 38-ms increase of the ARI at the 2 most Epi sites #8 and #7, respectively, compared to Mid/End sites (ranging from 65 ms at site #6 to 195 ms at site #2). The most illustrative consequence of differential changes in ARI in response to lengthening of preceding CL is seen in the sinus beat following the short-long sequence in Needle B. Conduction block occurred between Mid sites #5 and #4. The ARIs could only be estimated at sites #6 to #8 and showed further lengthening compared to the sinus beat prior to V1. The ARI could not be accurately estimated at sites #1 to #5 because of superimposition of the local activation potential (site #5) or electrotonic potentials (sites #1 to #4) on the repolarization wave. It is clear, however, that the dispersion of local ARI between sites #5 and #4 was the substrate for the resulting functional conduction block. E = electrotonic potential. Reproduced from reference 16, with permission.

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Figure 8. Transmural recording from a plunge needle electrode in the left ventricular free wall from a dog during infusion of anthopleurin-A (AP-A). The recording illustrates unipolar electrograms from endocardial (End), midmyocardial (Mid), and epicardial (Epi) sites. QT alternans was induced by abrupt decrease of the cardiac cycle length (CL) from 1000 ms (S1) to 600 ms (P1, P2, P3, etc.). The numbers represent the activation-recovery interval (ARI) in milliseconds. Note that even though the overall QT interval is shorter at 600 ms compared to 1000 ms, the degree of ARI dispersion between Epi and Mid sites was greater at 600 ms. Also note the reversal of the gradient of ARI between Epi and Mid sites, with a consequent reversal of polarity of the intramyocardial QT wave in alternate cycles. B. Graphic illustration of mean ± SEM of ARI dispersion between Mid and Epi sites and between Mid and End sites during successive short CLs of 600 ms from 12 different sites from the left ventricular free wall from the same experiment. Modified from reference 15, with permission.

that T wave alternans observed at rapid rates under long QT conditions is largely the result of alternation of the M cell APD, leading to exaggeration of transmural dispersion of repolarization during alternate beats and, thus, the potential for development of TdP. The data also suggested that unlike transient forms of T wave alternans that damp out quickly and depend on electrical restitution factors, the steady-state electrical and mechanical alternans demonstrated in their study

appears to be largely the result of beatto-beat alternans of Ica. Pastore et al.29 investigated T wave alternans in a Langendorff-perfused guinea pig heart using optical mapping of epicardial action potentials, and showed that repolarization alternans at the level of the single cell accounts for T wave alternans on the surface ECG. They also showed that discordant alternans produces spatial gradients of repolarization of sufficient magnitude to cause unidirectional block and reentrant VT.

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Figure 9. Recordings obtained from a canine experiment in the presence of anthopleurin-A (AP-A) to create a surrogate model of LQT3. T wave alternans in ECG lead aVF was induced by abrupt shortening of ventricular paced cycle length (CL) from 700 ms (top panel) to 350 ms (bottom panel). Following the fifth paced beat at short CL (P5), polymorphic ventricular tachycardia developed, the first beat of which is labeled V1. The figure illustrates the 3-dimensional activation map during control paced rhythm at 700 ms (S1) (top). Activation began at the pacing site (indicated by star) in section 3. The total ventricular activation time was 80 ms, and there were no arcs of functional conduction block. Selected unipolar electrograms are shown on the right panel. There was no QT/T alternans at this CL at any site. Recordings from the same experiment during abrupt shortening of the cycle length to 350 ms (P) are shown at bottom. The activation map of the P5 beat that initiated reentrant excitation is shown on the left. Selected electrograms along the reentrant pathway that demonstrate complete diastolic bridging are shown on the right. Note the development of QT/T alternans, which was more marked at Mid sites E to H compared to Epi sites B, C, I, and J. The reentrant wavefront circulated around arcs of functional conduction block between Epi and Mid sites in sections 4 and 5 (represented by heavy solid lines) before reactivating a subepicardial site in section 4 at the 220-ms isochrone. Reproduced from reference 15, with permission.

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Figure 10. Cellular basis for alternans in T wave polarity from a canine perfused wedge preparation in the presence of ATX-II (20 nmol/L). The figure shows 7 intramural unipolar electrograms recorded from endocardial (Endo), midmyocardial (M; sites M1-M5), and epicardial (Epi) regions, transmembrane action potentials recorded from M (M2), and epicardial sites together with a transmural EGG. Numbers before and after depolarization of each unipolar electrogram indicate activation time (AT) and activation-recovery intervals. Numbers before and after upstroke of each action potential indicate AT and action potential duration at 90% of repolarization. Numbers associated with each ECG denote transmural dispersion of repolarization. Horizontal lines in each unipolar electrogram show time maximum of the first derivative of T wave. Note that the epicardium is the first to repolarize and the M region is the last when the T wave is positive (first and third beats). When in alternate beats repolarization gradients reverse (the M region repolarizes first and epicardium last), the T wave becomes negative (second beat). Traces were obtained under steadystate conditions (15 seconds after decreasing cycle length from 500 ms to 300 ms). Reproduced from reference 28, with permission.

The Autonomic Nervous System and LQTS Sympathetic imbalance has been involved to explain an arrhythmogenic sub-

strate of LQTS.30 The concept proposes that reduced right cardiac sympathetic innervation, presumably of a congenital basis, results in reflex elevation of left cardiac sympathetic activity. The hypothesis

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was originally based on earlier studies in dogs showing that left stellate ganglion stimulation and right stellate ganglion interruption prolong QT interval.31 The data were obtained from measurement of the QT interval in only one ECG lead. Later studies showed that neuronal or intravenous adrenergic stimulation can transiently prolong the QT interval, followed by shortening.32 Studies in the in vivo model of cesium-induced LQTS suggest that the left stellate ganglion exerts a "quantitatively" greater adrenergic influence on the ventricles than the right stellate ganglion.33 The larger EAD amplitude in monophasic action potential recordings from the LV observed with left or bilateral ansae subclaviae stimulation, compared to right ansae subclaviae stimulation, may simply reflect more epinephrine release or a greater mass of affected myocardium. The potential role of a1-adrenoreceptors in LQTS was highlighted by studies that showed that a1-adrenoreceptor stimulation increased and a1-adrenoreceptor blockade decreased EAD amplitude and incidence of VT in the canine cesium model of LQTS and TdP.34 In a rabbit model of LQTS and TdP, induced by Class III antiarrhythmic agents, the a1-adrenoreceptor agonist methoxamine significantly lengthened the QT interval and increased the incidence of TdP35; however, the effects of a1adrenoreceptor agonists can be complex. In another study,36 when using measurements of ARI in the rabbit, a1-agonist effect resulted in prolongation of ARIs but a decrease of the dispersion of ARIs on the epicardial surface. The latter effect was explained by the a1-agonist improving cellular coupling via enhanced gap-junctional conductance.37 It remains unknown, however, whether a1-agonists can affect dispersion of refractoriness in the 3-dimensional ventricle. Recent preliminary clinical observations suggest that the onset of TdP in LQTS

patients with a mutant Na channel may occur at rest or during sleep rather than during exercise, possibly in association with relative bradycardia.38 On the other hand, patients with mutant K channels, especially LQT1, usually have syncope or cardiac arrest under stressful conditions possibly because of an arrhythmogenic effect of catecholamine and/or differences in the rate and degree of accommodation of the QT interval to CL shortening.38 Schreick et al.39 investigated the differential effects of p-adrenergic stimulation on the frequency-dependent electrophysiological actions of 3 different Class III agents, dofetilide, a pure Ikr blocker, ambasilide, a nonselective Ik blocker, and chromanol 293B, a selective Iks blocker. The actionpotential-prolonging effect of dofetilide was significantly reduced by isoproterenol, while that of ambasilide was much less reduced. In contrast, the action-potentialprolonging effect of chromanol 293B was increased in the presence of isoproterenol. These observations are of interest, since the most significant correlation of autonomic stimulation and the onset of TdP is seen in LQTl patients in whom the Iks channel is mutated. Possible mechanisms for such a reversed effect of isoproterenol in the presence of chromanol remain speculative. From an electrophysiological mechanistic point of view, autonomic manipulations can be arrhythmogenic in LQTS by means of 2 interrelated mechanisms: (1) by enhancing or suppressing the generation of EADs and their conduction in the heart, and (2) by enhancing or suppressing the dispersion of repolarization. The latter mechanism is essential for the occurrence of reentrant excitation. It is possible that, in patients with LQTl, because of depressed Iks, autonomic stimulation results in a differential effect on APD in Epi versus M and End zones, with consequent increase of dispersion of repolarization and onset of reentrant excitation. Given this framework, it becomes obvious that a major limitation

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prolonged ventricular repolarization and increased 3-dimensional dispersion of repolarization (TDK) compared to nonhypertrophied heart.42 Further, the hyper trophied heart is more susceptible to the repolarization-prolonging effects of a Class III antiarrhythmic agent, dofetilide, a selective blocker of I^.43 Dofetilide resulted Acquired LQTS and TdP in significantly more prolongation of venThe clinical syndrome of acquired tricular repolarization of the hypertroLQTS occurs in association with certain phied heart. More importantly, the drug pharmacological agents, electrolyte ab- resulted in differentially greater prolonnormalities, and bradycardic states.40 gation of repolarization at endo/midmyoRecently the electrophysiological mecha- cardial regions, compared to epicardial nism of acquired LQTS was investigated in regions resulting in increased dispersion of a canine model of cardiac hypertrophy41 TDR. The increased TDK at contiguous in which dogs with chronic atrioventricu- myocardial sites represented the primary lar block develop ventricular hypertrophy electrophysiological substrate for the desecondary to chronic volume overload. The velopment of functional conduction block study demonstrated that volume overload and reentrant tachyarrhythmias such as hypertrophy in dogs is associated with TdP (Figures 11 through 14). The study in this area is the lack of quantitative data on the effects of autonomic manipulations on the 3-dimensional spatial dispersion of repolarization in vivo in a surrogate model ofLQTl.

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Figure 11. Electrocardiographic recordings obtained from a dog with chronic atrioventricular block and ventricular hypertrophy following infusion of 10 jj,g/kg of dofetilide. The ventricle was paced at a cycle length (CL) of 1000 ms (S1). A spontaneous ectopic beat (V^ initiated a 9-beat run of torsades de pointes at an average CL of 195 ms. This was followed by a slower run of multifocal ventricular rhythm at an average CL of 430 ms. Reproduced from reference 42, with permission.

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Figure 12. Recordings obtained from the experiment shown in Figure 11. Left: 3-dimensional activation maps of the ventricular paced beat (S-,) and the initiating beat of torsades de pointes (VJ following infusion 10 |ig/kg of dofetilide. Right: Selected local electrograms recorded along the reentrant pathway during V1? which illustrates complete diastolic bridging during the first reentrant cycle (V1 - V2 = 240 ms). Reproduced from reference 42, with permission.

demonstrated that a high dose of dofetilide resulted in prolongation of repolarization, increased TDK, and, uncommonly, TdP in normal heart. On the other hand, the hypertrophied heart is more susceptible to the proarrhythmic consequences of dofetilide at doses that are considered within the clinical range.43 The study provided the electrophysiological basis for the reported doserelated incidence of dofetilide-induced TdP in patients.44 It also justified the current

recommendations for dose-titration and close monitoring of the effects of the drug in the clinical setting.45 Dofetilide-induced prolongation of APD and increased dispersion of repolarization was bradycardia-dependent. However, there seem to be some differences in the extent of CL-dependent prolongation of repolarization and TDR when compared to the canine AP-A surrogate model of LQT3. The CL dependence in

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Figure 13. Repolarization (activation-recovery interval [ARI]) map of section 4 of the ventricular paced beat (SJ before and following dofetilide infusion from the experiment shown in Figures 11 and 12. Repolarization isochrones are drawn at 20-ms intervals. The bottom recordings illustrate selective unipolar electrograms from 2 plunge needle electrodes. The numbers on the electrograms represent the calculated ARI in milliseconds. The drug caused significant differential prolongation of the ARIs of epicardial sites A-B and E-F, compared to midmyocardial sites C-D and G-H, respectively. This resulted in 3-dimensional dispersion of repolarization between contiguous sites (represented by crowded repolarization isochrones). Reproduced from reference 42, with permission.

the LQTS model seems more exaggerated compared to the present model. In other words, the longer the CL, the greater the lengthening of repolarization and TDK in the LQTS model. In the present model, there was a gradual increase of repolarization as the CL prolonged, but the major increase in TDK occurred between CLs of 600 and 1000 ms. This may be related to differences in response of M cells to agents that delay Na+ inactivation (LQTS) versus those that depress IKr (LQT2). In the former situation, the enhanced inward slow Na+ current during the plateau of AP

shows less time dependence of inactivation10 compared to 1^.

Further Refinement of the Mechanism of TdP in LQTS (Role of EAD versus DAD)46 Figure 15 shows that the electrophysiological mechanism of VT in LQTS is somewhat more complex than that described above. The figure illustrates the process of deductive analysis when 2 or more experimental approaches are combined. Panel A

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Figure 14. Repolarization map of section #4 of the S-, beat that preceded the onset of torsades de pointes (TdP) and the activation map of the V-i beat that initiated TdP from the experiment shown in Figures 11 to 13. The bottom left panel shows selected electrograms of 2 S1 beats prior to TdP. The bottom right panel shows the same electrograms of the ST beat that immediately preceded the onset of TdP as well as the first 4 beats of TdP. The figure shows that the functional conduction block induced by the V1 beat between contiguous sites B-C and F-G occurred at those sites with marked spatial dispersion of repolarization as depicted by the crowded repolarization isochrones. Reproduced from reference 42, with permission.

is from one of the classic reviews of cellular mechanisms of cardiac arrhythmias.47 It shows a transmembrane action potential recording from a canine Purkinje fiber superfused with 20 mmol/L cesium chloride (a surrogate experimental model for LQT2). The recording illustrates the classic bradycardia-dependent prolongation of APD associated with membrane oscillation on late phase 2/early phase 3 of the repolarization phase characteristic of EADs. But it also shows that complete repolarization of the action potential is followed by a subthreshold delayed afterdepolariza-

tion (DAD). The latter is simply explained on the basis of increased intracellular Ca2+ associated with the prolonged APD triggering a transient outward current. This almost forgotten observation strongly suggests that some VT and ectopic beats in LQTS could be secondary to DADs. Panel B shows a corroboration of this observation from a different experimental model using different recording techniques. The ECG recordings were obtained from the in vivo canine AP-A surrogate model of LQTS. The top ECG tracing was obtained 10 minutes after infusion of AP-A and

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Figure 15. A. Transmembrane action potential recording from a Purkinje fiber superfused with 20 mmol/L cesium chloride showing both early and delayed afterdepolarizations. Reproduced from reference 47, with permission. B. ECG recording from an in vivo canine anthopleurin-A surrogate model of long QT syndrome showing both focal and reentrant ventricular tachycardia from the same experiment. See text for details. F = focal discharge; R = reentrant excitation. Reproduced from reference 46, with permission.

shows moderate prolongation of the QT interval and a run of nonsustained monomorphic VT at a rate of 150 beats per minute. The VT starts with a late coupled beat that is well beyond the end of the QT interval of the preceding sinus beat. Threedimensional mapping of activation showed that the VT arose as a focal discharge (F) from the same subendocardial site. For all practical purposes, the focal discharge could be attributed to DAD-triggered activity. The bottom ECG tracing was obtained from the same experiment 10 minutes later, and shows further prolongation of the QT interval. The ectopic beats labeled F now seem to be coupled to the end of the prolonged QT interval of

the preceding sinus beats. The middle of the tracing illustrates a 6-beat run of polymorphic VT, which, at least in lead V1, has a faint resemblance to TdP. Threedimensional mapping shows that the first beat arose from a subendocardial focal site and could be safely attributed to an EADtriggered activity, while subsequent beats resulted from reentrant excitation in the form of continuously varying scroll waves. A vivid graphic display of the subtle interplay between EAD-triggered activity, DAD-triggered activity, dispersion of repolarization, and reentrant excitation in LQTS is shown in Figures 16 through 18, which were obtained from a different canine AP-A experiment. Figure 16 shows

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Figure 16. Electrocardiographs recordings from an in vivo canine anthopleurin-A surrogate model of LQT3 illustrating the interaction between delayed afterdepolarization- and early afterdepolarizationtriggered beats in arrhythmia generation in the long QT syndrome. See text for details. Abbreviations as in Figure 15. Reproduced from reference 46, with permission.

ECG recordings obtained after a stable prolongation of the QT interval was achieved during sinus bradycardia. The recordings are arranged chronologically with few minutes between. Panel A shows a stable bigeminal and trigeminal rhythm due to subendocardial discharge attributed to an EAD-triggered activity from the same focus. This was followed several minutes later by runs of 4- or 5-beat polymorphic VT with remarkable repetition of the same QRS morphology. The first beat of each run arose from the same site of the bigeminal/ trigeminal beats in panel A. The second and third beats of each run arose from 2 different

subendocardial focal sites, while the fourth beat was reentrant in origin. The fifth beat in a 5-beat run was again focal in origin, arose well after the end of the reentrant excitation, and could be attributed to DADtriggered activity. After approximately 10 minutes of repetitive nonsustained VT, the same 3 initial focal beats were followed by reentrant excitation that degenerated into ventricular fibrillation (VF) (panel D). Figure 17 shows selected local electrograms of the 5-beat VT shown in Figure 16C (labeled VI to V5) and the activation map of V3, as well as the first 5 beats of the VT that degenerated into VF

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Figure 17. Selected electrograms of the nonsustained ventricular tachycardia (VT) shown in Figure 16C and of the run of VT that degenerated into ventricular fibrillation (VF) in Figure 16D. V1 to V5 refer to the first 5 beats of each run. Also shown are selected 3-dimensional activation maps of the V3 beat of the nonsustained VT and the V3 and V4 beats of the VT/VF run. See text for details. Sections 2 to 4 of the activation maps refer to sections selected out of a traditional representation of 5 transverse sections of the ventricles labeled 1 through 5 from base to apex as shown in Figure 4A. Reproduced from reference 46, with permission.

shown in Figure 16D (also labeled V1-V5) together with the activation maps of V3 and V4. The figure shows a self-terminating single reentrant cycle in the first case as contrasted with a more complex activation pattern induced by the same V3 beat

in the second case with 2 simultaneous reentrant wavefronts that rapidly degenerated into multiple reentrant wavefronts. Figure 18 illustrates the electrophysiological mechanism of the different consequences of the same V3 ectopic beat

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Figure 18. Selected electrograms of the 5-beat nonsustained ventricular tachycardia (VT) and the first 5 beats of the VT that degenerated into ventricular fibrillation (V1-V5) shown in Figures 15 through 17. Also shown is section 4 of the activation maps of both V3 beats. See text for details. The numbers without brackets represent cycle length in milliseconds and the numbers between brackets represent activation-recovery intervals. Reproduced from reference 46, with permission.

in the 2 episodes. It shows that the interectopic intervals VI-V2 and V2-V3 increased by approximately 30 to 40 ms in the second case (the equivalent of a slight slowing in the discharge of the focal activity). This resulted in lengthening of local repolarization following the V2 beat by 30 to 40 ms. However, the degree of lengthening of repolarization was slightly disparate at contiguous sites in section 4, resulting in functional conduction block and the initiation of a secondary reentrant wavefront. Figure 17 shows that the same disparate lengthening of repolarization can also explain the conduction block of the original reentrant wavefront between sites H and I in the VT that degenerated toVF. It is interesting to speculate on the electrophysiological mechanism of the 3 successive focal beats VI to V3. It is rea-

sonable to consider VI as an EAD-triggered beat. The mechanism of V2 and V3 is less certain. If these are also EAD-triggered beats we have to assume the presence of entrance block to the site of these 2 foci. Otherwise, if these foci are captured by the advancing wavefront of the preceding ectopic activity, their action potential will shorten significantly, thus mitigating against the generation of an EAD-triggered discharge. While it is customary for rapid succession of EADs to be generated from phase 2/early phase 3 of action potentials in isolated Purkinje strands subjected to manipulations that prolong action potential duration (see Figure ISA), the situation is different in the in vivo heart. Could the same focus generate fast EAD-triggered activity in vivo? Three-dimensional mapping of experimental LQTS shows that every beat of a fast VT is due to reentrant

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excitation, save for the first 1 or 2 initiating strategies including risk stratification and beats. A repetitive unifocal discharge, as the choice of therapeutic modalities. shown in Figure 15B, is relatively slow (usually